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1
Debattisti, Valentina, Diana Pendin, Elena Ziviani, Andrea Daga, and Luca Scorrano. "Reduction of endoplasmic reticulum stress attenuates the defects caused by Drosophila mitofusin depletion." Journal of Cell Biology 204, no. 3 (January 27, 2014): 303–12. http://dx.doi.org/10.1083/jcb.201306121.
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Ablation of the mitochondrial fusion and endoplasmic reticulum (ER)–tethering protein Mfn2 causes ER stress, but whether this is just an epiphenomenon of mitochondrial dysfunction or a contributor to the phenotypes in mitofusin (Mfn)-depleted Drosophila melanogaster is unclear. In this paper, we show that reduction of ER dysfunction ameliorates the functional and developmental defects of flies lacking the single Mfn mitochondrial assembly regulatory factor (Marf). Ubiquitous or neuron- and muscle-specific Marf ablation was lethal, altering mitochondrial and ER morphology and triggering ER stress that was conversely absent in flies lacking the fusion protein optic atrophy 1. Expression of Mfn2 and ER stress reduction in flies lacking Marf corrected ER shape, attenuating the developmental and motor defects. Thus, ER stress is a targetable pathogenetic component of the phenotypes caused by Drosophila Mfn ablation.
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Chen, Yutong, Zhixin Liu, Ning An, Jing Zhang, Weicheng Meng, Wenting Wang, Xiaoshuang Wu, Xingbin Hu, Yaozhen Chen, and Wen Yin. "Platelet-Derived Mitochondria Attenuate 5-FU-Induced Injury to Bone-Associated Mesenchymal Stem Cells." Stem Cells International 2023 (January 30, 2023): 1–20. http://dx.doi.org/10.1155/2023/7482546.
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Background. Myelosuppression is a common condition during chemotherapy. Bone-associated mesenchymal stem cells (BA-MSCs) play an essential role in the composition of the hematopoietic microenvironment and support hematopoietic activity. However, chemotherapy-induced damage to BA-MSCs is rarely studied. Recent studies have shown that platelets promote the wound-healing capability of MSCs by mitochondrial transfer. Therefore, this study is aimed at investigating the chemotherapy-induced damage to BA-MSCs and the therapeutic effect of platelet-derived mitochondria. Material/Methods. We established in vivo and in vitro BA-MSC chemotherapy injury models using the chemotherapy agent 5-fluorouracil (5-FU). Changes in the mitochondrial dynamics were detected by transmission electron microscopy, and the expression of mitochondrial fusion and fission genes was analyzed by qRT-PCR. In addition, mitochondrial functions were also explored by flow cytometry and luminometer. Platelet-derived mitochondria were incubated with 5-FU-damaged BA-MSCs to repair the injury, and BA-MSC functional changes were examined to assess the therapy efficacy. The mechanism of treatment was explored by studying the expression of mitochondrial fission and fusion genes and hematopoietic regulatory factor genes in BA-MSCs. Results. Stimulation with 5-FU increased the apoptosis and suppressed cell cycle progression of BA-MSCs both in vivo and in vitro. In addition, 5-FU chemotherapy inhibited the hematopoietic regulatory ability and disrupted the mitochondrial dynamics and functions of BA-MSCs. The mitochondrial membrane potential and ATP content of 5-FU-injured BA-MSCs were decreased. Interestingly, when platelet-derived mitochondria were transferred to BA-MSCs, the 5-FU-induced apoptosis was alleviated, and the hematopoietic regulatory ability of 5-FU-injured BA-MSCs was effectively improved by upregulating the expression of mitochondrial fusion genes and hematopoietic regulatory factor genes. Conclusion. BA-MSCs were severely damaged by 5-FU chemotherapy both in vivo and in vitro. Meanwhile, platelet-derived mitochondria could attenuate the 5-FU-induced injury to BA-MSCs, which provides future research directions for exploring the treatment strategies for chemotherapy-injured BA-MSCs and establishes a research basis for related fields.
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Lin, Ruizhu, and Risto Kerkelä. "Regulatory Mechanisms of Mitochondrial Function and Cardiac Aging." International Journal of Molecular Sciences 21, no. 4 (February 18, 2020): 1359. http://dx.doi.org/10.3390/ijms21041359.
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Aging is a major risk factor for cardiovascular diseases (CVDs), the major cause of death worldwide. Cardiac myocytes, which hold the most abundant mitochondrial population, are terminally differentiated cells with diminished regenerative capacity in the adult. Cardiomyocyte mitochondrial dysfunction is a characteristic feature of the aging heart and one out of the nine features of cellular aging. Aging and cardiac pathologies are also associated with increased senescence in the heart. However, the cause and consequences of cardiac senescence during aging or in cardiac pathologies are mostly unrecognized. Further, despite recent advancement in anti-senescence therapy, the targeted cell type and the effect on cardiac structure and function have been largely overlooked. The unique cellular composition of the heart, and especially the functional properties of cardiomyocytes, need to be considered when designing therapeutics to target cardiac aging. Here we review recent findings regarding key factors regulating cell senescence, mitochondrial health as well as cardiomyocyte rejuvenation.
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Morciano, Giampaolo, Carlotta Giorgi, Dario Balestra, Saverio Marchi, Daniela Perrone, Mirko Pinotti, and Paolo Pinton. "Mcl-1 involvement in mitochondrial dynamics is associated with apoptotic cell death." Molecular Biology of the Cell 27, no. 1 (January 2016): 20–34. http://dx.doi.org/10.1091/mbc.e15-01-0028.
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The B-cell lymphoma-2 (Bcl-2) family proteins are critical regulators of apoptosis and consist of both proapoptotic and antiapoptotic factors. Within this family, the myeloid cell leukemia factor 1 (Mcl-1) protein exists in two forms as the result of alternative splicing. The long variant (Mcl-1L) acts as an antiapoptotic factor, whereas the short isoform (Mcl-1S) displays proapoptotic activity. In this study, using splice-switching antisense oligonucleotides (ASOs), we increased the synthesis of Mcl-1S, which induced a concurrent reduction of Mcl-1L, resulting in increased sensitivity of cancer cells to apoptotic stimuli. The Mcl-1 ASOs also induced mitochondrial hyperpolarization and a consequent increase in mitochondrial calcium (Ca2+) accumulation. The high Mcl-1S/L ratio correlated with significant hyperfusion of the entire mitochondrial network, which occurred in a dynamin-related protein (Drp1)–dependent manner. Our data indicate that the balance between the long and short variants of the Mcl-1 gene represents a key aspect of the regulation of mitochondrial physiology. We propose that the Mcl-1L/S balance is a novel regulatory factor controlling the mitochondrial fusion and fission machinery.
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Hwang, Keun Young, and Young Bong Choi. "Modulation of Mitochondrial Antiviral Signaling by Human Herpesvirus 8 Interferon Regulatory Factor 1." Journal of Virology 90, no. 1 (October 28, 2015): 506–20. http://dx.doi.org/10.1128/jvi.01903-15.
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ABSTRACTMitochondrial lipid raft-like microdomains, experimentally also termed mitochondrial detergent-resistant membrane fractions (mDRM), play a role as platforms for recruiting signaling molecules involved in antiviral responses such as apoptosis and innate immunity. Viruses can modulate mitochondrial functions for their own survival and replication. However, viral regulation of the antiviral responses via mDRM remains incompletely understood. Here, we report that human herpesvirus 8 (HHV-8) gene product viral interferon regulatory factor 1 (vIRF-1) is targeted to mDRM during virus replication and negatively regulates the mitochondrial antiviral signaling protein (MAVS)-mediated antiviral responses. The N-terminal region of vIRF-1 interacts directly with membrane lipids, including cardiolipin. In addition, a GxRP motif within the N terminus of vIRF-1, conserved in the mDRM-targeting region of mitochondrial proteins, including PTEN-induced putative kinase 1 (PINK1) and MAVS, was found to be important for vIRF-1 association with mitochondria. Furthermore, MAVS, which has the potential to promote vIRF-1 targeting to mDRM possibly by inducing cardiolipin exposure on the outer membrane of mitochondria, interacts with vIRF-1, which, in turn, inhibits MAVS-mediated antiviral signaling. Consistent with these results, vIRF-1 targeting to mDRM contributes to promotion of HHV-8 productive replication and inhibition of associated apoptosis. Combined, our results suggest novel molecular mechanisms for negative-feedback regulation of MAVS by vIRF-1 during virus replication.IMPORTANCESuccessful virus replication is in large part achieved by the ability of viruses to counteract apoptosis and innate immune responses elicited by infection of host cells. Recently, mitochondria have emerged to play a central role in antiviral signaling. In particular, mitochondrial lipid raft-like microdomains appear to function as platforms in cell apoptosis signaling. However, viral regulation of antiviral signaling through the mitochondrial microdomains remains incompletely understood. The present study demonstrates that HHV-8-encoded vIRF-1 targets to the mitochondrial detergent-resistant microdomains via direct interaction with cardiolipin and inhibits MAVS protein-mediated apoptosis and type I interferon gene expression in a negative-feedback manner, thus promoting HHV-8 productive replication. These results suggest that vIRF-1 is the first example of a viral protein to inhibit mitochondrial antiviral signaling through lipid raft-like microdomains.
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Laban, Hebatullah, Sophia Siegmund, Maren Zappe, Felix A. Trogisch, Jörg Heineke, Carolina De La Torre, Beate Fisslthaler, et al. "NFAT5/TonEBP Limits Pulmonary Vascular Resistance in the Hypoxic Lung by Controlling Mitochondrial Reactive Oxygen Species Generation in Arterial Smooth Muscle Cells." Cells 10, no. 12 (November 24, 2021): 3293. http://dx.doi.org/10.3390/cells10123293.
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Chronic hypoxia increases the resistance of pulmonary arteries by stimulating their contraction and augmenting their coverage by smooth muscle cells (SMCs). While these responses require adjustment of the vascular SMC transcriptome, regulatory elements are not well defined in this context. Here, we explored the functional role of the transcription factor nuclear factor of activated T-cells 5 (NFAT5/TonEBP) in the hypoxic lung. Regulatory functions of NFAT5 were investigated in cultured artery SMCs and lungs from control (Nfat5fl/fl) and SMC-specific Nfat5-deficient (Nfat5(SMC)−/−) mice. Exposure to hypoxia promoted the expression of genes associated with metabolism and mitochondrial oxidative phosphorylation (OXPHOS) in Nfat5(SMC)−/− versus Nfat5fl/fl lungs. In vitro, hypoxia-exposed Nfat5-deficient pulmonary artery SMCs elevated the level of OXPHOS-related transcripts, mitochondrial respiration, and production of reactive oxygen species (ROS). Right ventricular functions were impaired while pulmonary right ventricular systolic pressure (RVSP) was amplified in hypoxia-exposed Nfat5(SMC)−/− versus Nfat5fl/fl mice. Scavenging of mitochondrial ROS normalized the raise in RVSP. Our findings suggest a critical role for NFAT5 as a suppressor of OXPHOS-associated gene expression, mitochondrial respiration, and ROS production in pulmonary artery SMCs that is vital to limit ROS-dependent arterial resistance in a hypoxic environment.
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D'souza, Donna, Ruanne Y. J. Lai, Michael Shuen, and David A. Hood. "mRNA stability as a function of striated muscle oxidative capacity." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 303, no. 4 (August 15, 2012): R408—R417. http://dx.doi.org/10.1152/ajpregu.00085.2012.
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A change in mRNA stability alters the abundance of mRNA available for translation and is emerging as a critical pathway influencing gene expression. Variations in the stability of functional and regulatory mitochondrial proteins may contribute to the divergent mitochondrial densities observed in striated muscle. Thus we hypothesized that the stability of mRNAs encoding for regulatory nuclear and mitochondrial transcription factors would be inversely proportional to muscle oxidative capacity and would be facilitated by the activity of RNA binding proteins (RBPs). The stability of mitochondrial transcription factor A (Tfam), peroxisome proliferator-activated receptor gamma coactivator 1α (PGC-1α), and nuclear respiratory factor 2α (NRF-2α) mRNA was assessed in striated muscles with distinct oxidative capacities using in vitro decay assays. All three mitochondrial regulators were rapidly degraded in cardiac and slow-twitch red (STR) muscle, resulting in a ∼60–65% lower ( P < 0.05) mRNA half-life ( t1/2) compared with fast-twitch white (FTW) fibers. This accelerated rate of Tfam mRNA decay was matched by a 2.5-fold increase in Tfam transcription in slow- compared with fast-twitch muscle ( P = 0.05). Protein expression of four unique RBPs [AU-rich binding factor 1 (AUF1), human antigen R (HuR), KH-homology splicing regulatory protein (KSRP), and CUG binding protein 1 (CUGBP1)] believed to modulate mRNA stability was elevated in cardiac and STR muscles ( P < 0.05) and was moderately associated with the decay of Tfam, PGC-1α, and NRF-2α mRNA. Variable rates of transcript degradation were apparent when comparing all transcripts within the same muscle type. Thus the distribution of RBPs appears to follow a fiber-type specific pattern and subsequently functions to alter the stability of specific mitochondrial regulators in a transcript- and tissue-specific fashion.
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Wolin, Michael S. "Evidence for novel aspects of Nox4 oxidase regulation of mitochondrial function and peroxide generation in an endothelial cell model of senescence." Biochemical Journal 452, no. 2 (May 10, 2013): e1-e2. http://dx.doi.org/10.1042/bj20130484.
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Observations by Kozieł et al. reported in this issue of the Biochemical Journal suggest the existence of novel regulatory processes associated with new evidence for increased Nox4 (NAPDH oxidase 4) regulation of mitochondrial function in a cultured endothelial cell aging-induced senescence model. Cellular aging appears to promote a Nox4 interaction with mitochondria that disrupts complex I in the electron transport chain and increases the detection of mitochondrial H2O2. Nox4 appears to maintain a highly interconnected mitochondrial network, which may influence mitochondrial fission and/or fusion mechanisms in a manner that could be a contributing factor in the loss of replicative lifespan seen in senescence.
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Farge, Géraldine, and Maria Falkenberg. "Organization of DNA in Mammalian Mitochondria." International Journal of Molecular Sciences 20, no. 11 (June 5, 2019): 2770. http://dx.doi.org/10.3390/ijms20112770.
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As with all organisms that must organize and condense their DNA to fit within the limited volume of a cell or a nucleus, mammalian mitochondrial DNA (mtDNA) is packaged into nucleoprotein structures called nucleoids. In this study, we first introduce the general modes of DNA compaction, especially the role of the nucleoid-associated proteins (NAPs) that structure the bacterial chromosome. We then present the mitochondrial nucleoid and the main factors responsible for packaging of mtDNA: ARS- (autonomously replicating sequence-) binding factor 2 protein (Abf2p) in yeast and mitochondrial transcription factor A (TFAM) in mammals. We summarize the single-molecule manipulation experiments on mtDNA compaction and visualization of mitochondrial nucleoids that have led to our current knowledge on mtDNA compaction. Lastly, we discuss the possible regulatory role of DNA packaging by TFAM in DNA transactions such as mtDNA replication and transcription.
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Siekacz, Kamil, Anna Kumor-Kisielewska, Joanna Miłkowska-Dymanowska, Małgorzata Pietrusińska, Krystian Bartczak, Sebastian Majewski, Adam Stańczyk, Wojciech J. Piotrowski, and Adam J. Białas. "Oxidative Biomarkers Associated with the Pulmonary Manifestation of Post-COVID-19 Complications." Journal of Clinical Medicine 12, no. 13 (June 25, 2023): 4253. http://dx.doi.org/10.3390/jcm12134253.
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Introduction: The role of mitochondria in post coronavirus disease 2019 (post-COVID-19) complications is unclear, especially in the long-term pulmonary complications. This study aims to investigate the association between post-COVID-19 pulmonary complications and mitochondrial regulatory proteins in the context of oxidative stress. Methodology: Patients who had recovered from COVID-19 were enrolled. According to the evidence of persistent interstitial lung lesions on computed tomography (CT), patients were divided into a long-term pulmonary complications group (P(+)) and a control group without long-term pulmonary complications (P(−)). We randomly selected 80 patients for investigation (40 subjects for each group). Biomarkers levels were determined by enzyme-linked immunosorbent assay (ELISA). Results: The serum concentrations of mitochondrial regulatory proteins were significantly higher in the P(+) group, including PTEN-induced kinase 1 (PINK1): 1.62 [1.02–2.29] ng/mL vs. 1.34 [0.94–1.74] ng/mL (p = 0.046); Dynamin-1-like protein (DNM1L): 1.6 [0.9–2.4] ng/mL IQR vs. 0.9 [0.5–1.6] ng/mL (p = 0.004); and Mitofusin-2 (MFN2): 0.3 [0.2–0.5] ng/mL vs. 0.2 [0.1–0.3] ng/mL IQR (p = 0.001). Patients from the P(+) group also had higher serum levels of chemokine ligand 18 (PARC, CCL18), IL-6, and tumour necrosis factor-alpha (TNF-α) cytokines than the P(−) group. The concentration of interferon alpha (IFN-α) was decreased in the P(+) group. Furthermore, we observed statistically significant correlations between the advanced glycation end product (sRAGE) and TNF-α (Pearson’s factor R = 0.637; p < 0.001) and between serum levels of DNM1L and IFN-α (Pearson’s factor R = 0.501; p = 0.002) in P(+) patients. Conclusions: Elevated concentrations of mitochondrial biomarkers in post-COVID-19 patients with long-term pulmonary complications indicate their possible role in the pathobiology of COVID-19 pulmonary sequelae. Oxidative stress is associated with the immune response and inflammation after COVID-19. TNF-α could be a promising biomarker for predicting pulmonary complications and may be a potential target for therapeutic intervention in patients with post-COVID-19 complications.
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Gordon, Joe W., Arne A. Rungi, Hidetoshi Inagaki, and David A. Hood. "Selected Contribution: Effects of contractile activity on mitochondrial transcription factor A expression in skeletal muscle." Journal of Applied Physiology 90, no. 1 (January 1, 2001): 389–96. http://dx.doi.org/10.1152/jappl.2001.90.1.389.
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Mitochondrial transcription factor A (Tfam) is a nuclear-encoded gene product that is imported into mitochondria and is required for the transcription of mitochondrial DNA (mtDNA). We hypothesized that conditions known to produce mitochondrial biogenesis in skeletal muscle would be preceded by an increase in Tfam expression. Therefore, rat muscle was stimulated (10 Hz, 3 h/day). Tfam mRNA levels were significantly elevated (by 55%) at 4 days and returned to control levels at 14 days. Tfam import into intermyofibrillar (IMF) mitochondria was increased by 52 and 61% ( P < 0.05) at 5 and 7 days, respectively. This corresponded to an increase in the level of import machinery components. Immunoblotting data indicated that IMF Tfam protein content was increased by 63% ( P < 0.05) at 7 days of stimulation. This was associated with a 49% ( P < 0.05) increase in complex formation at the mtDNA promoter and a 65% ( P< 0.05) increase in the levels of a mitochondrial transcript, cytochrome- c oxidase (COX) subunit III. Similarly, COX enzyme activity was elevated by 71% ( P < 0.05) after 7 days of contractile activity. These results indicate that early events in mitochondrial biogenesis include increases in Tfam mRNA, followed by accelerations in mitochondrial import and increased Tfam content, which correspond with increased binding to the mtDNA promoter region. This was accompanied by increased mitochondrial transcript levels and elevated COX activity. These data support the role of Tfam as a regulatory protein involved in contractile activity-induced mitochondrial biogenesis.
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Kobayashi, Masaki, Seira Uta, Minami Otsubo, Yusuke Deguchi, Ryoma Tagawa, Yuhei Mizunoe, Yoshimi Nakagawa, Hitoshi Shimano, and Yoshikazu Higami. "Srebp-1c/Fgf21/Pgc-1α Axis Regulated by Leptin Signaling in Adipocytes—Possible Mechanism of Caloric Restriction-Associated Metabolic Remodeling of White Adipose Tissue." Nutrients 12, no. 7 (July 10, 2020): 2054. http://dx.doi.org/10.3390/nu12072054.
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Caloric restriction (CR) improves whole body metabolism, suppresses age-related pathophysiology, and extends lifespan in rodents. Metabolic remodeling, including fatty acid (FA) biosynthesis and mitochondrial biogenesis, in white adipose tissue (WAT) plays an important role in the beneficial effects of CR. We have proposed that CR-induced mitochondrial biogenesis in WAT is mediated by peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), which is transcriptionally regulated by sterol regulatory element-binding protein 1c (SREBP-1c), a master regulator of FA biosynthesis. We have also proposed that the CR-associated upregulation of SREBP-1 and PGC-1α might result from the attenuation of leptin signaling and the upregulation of fibroblast growth factor 21 (FGF21) in WAT. However, the detailed molecular mechanisms remain unclear. Here, we interrogate the regulatory mechanisms involving leptin signaling, SREBP-1c, FGF21, and PGC-1α using Srebp-1c knockout (KO) mice, mouse embryonic fibroblasts, and 3T3-L1 adipocytes, by altering the expression of SREBP-1c or FGF21. We show that a reduction in leptin signaling induces the expression of proteins involved in FA biosynthesis and mitochondrial biogenesis via SREBP-1c in adipocytes. The upregulation of SREBP-1c activates PGC-1α transcription via FGF21, but it is unlikely that the FGF21-associated upregulation of PGC-1α expression is a predominant contributor to mitochondrial biogenesis in adipocytes.
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He, Feng, Xiaoli Ru, and Tao Wen. "NRF2, a Transcription Factor for Stress Response and Beyond." International Journal of Molecular Sciences 21, no. 13 (July 6, 2020): 4777. http://dx.doi.org/10.3390/ijms21134777.
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Nuclear factor erythroid 2-related factor 2 (NRF2) is a transcription factor that regulates the cellular defense against toxic and oxidative insults through the expression of genes involved in oxidative stress response and drug detoxification. NRF2 activation renders cells resistant to chemical carcinogens and inflammatory challenges. In addition to antioxidant responses, NRF2 is involved in many other cellular processes, including metabolism and inflammation, and its functions are beyond the originally envisioned. NRF2 activity is tightly regulated through a complex transcriptional and post-translational network that enables it to orchestrate the cell’s response and adaptation to various pathological stressors for the homeostasis maintenance. Elevated or decreased NRF2 activity by pharmacological and genetic manipulations of NRF2 activation is associated with many metabolism- or inflammation-related diseases. Emerging evidence shows that NRF2 lies at the center of a complex regulatory network and establishes NRF2 as a truly pleiotropic transcription factor. Here we summarize the complex regulatory network of NRF2 activity and its roles in metabolic reprogramming, unfolded protein response, proteostasis, autophagy, mitochondrial biogenesis, inflammation, and immunity.
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Li, Min, Li Chen, Aziz Khan, Xiangjun Kong, Muhammad Rabnawaz Khan, Muhammad Junaid Rao, Jibin Wang, Lingqiang Wang, and Ruiyang Zhou. "Transcriptome and MiRNAomics Analyses Identify Genes Associated with Cytoplasmic Male Sterility in Cotton (Gossypium hirsutum L.)." International Journal of Molecular Sciences 22, no. 9 (April 28, 2021): 4684. http://dx.doi.org/10.3390/ijms22094684.
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Cytoplasmic male sterility (CMS) is important for large-scale hybrid seed production. Rearrangements in the mitochondrial DNA (mtDNA) for the cotton (Gossypium hirsutum L.) CMS line J4A were responsible for pollen abortion. However, the expression patterns of nuclear genes associated with pollen abortion and the molecular basis of CMS for J4A are unknown, and were the objectives of this study by comparing J4A with the J4B maintainer line. Cytological evaluation of J4A anthers showed that microspore abortion occurs during meiosis preventing pollen development. Changes in enzyme activity of mitochondrial respiratory chain complex IV and mitochondrial respiratory chain complex V and the content of ribosomal protein and ATP during anther abortion were observed for J4A suggesting insufficient synthesis of ATP hindered pollen production. Additionally, levels of sucrose, starch, soluble sugar, and fructose were significantly altered in J4A during the meiosis stage, suggesting reduced sugar metabolism contributed to sterility. Transcriptome and miRNAomics analyses identified 4461 differentially expressed mRNAs (DEGs) and 26 differentially expressed microRNAs (DEMIs). Pathway enrichment analysis indicated that the DEMIs were associated with starch and sugar metabolism. Six deduced target gene regulatory pairs that may participate in CMS were identified, ghi-MIR7484-10/mitogen-activated protein kinase kinase 6 (MAPKK6), ghi-undef-156/agamous-like MADS-box protein AGL19 (AGL19), ghi-MIR171-1-22/SNF1-related protein kinase regulatory subunit gamma-1 and protein trichome birefringence-like 38, and ghi-MIR156-(8/36)/WRKY transcription factor 28 (WRKY28). Overall, a putative CMS mechanism involving mitochondrial dysfunction, the ghi-MIR7484-10/MAPKK6 network, and reduced glucose metabolism was suggested, and ghi-MIR7484-10/MAPKK6 may be related to abnormal microspore meiosis and induction of excessive sucrose accumulation in anthers.
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Inguscio, Chiara Rita, Elisa Dalla Pozza, Ilaria Dando, Federico Boschi, Gabriele Tabaracci, Osvaldo Angelini, Pietro Maria Picotti, Manuela Malatesta, and Barbara Cisterna. "Mitochondrial Features of Mouse Myoblasts Are Finely Tuned by Low Doses of Ozone: The Evidence In Vitro." International Journal of Molecular Sciences 24, no. 10 (May 17, 2023): 8900. http://dx.doi.org/10.3390/ijms24108900.
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The mild oxidative stress induced by low doses of gaseous ozone (O3) activates the antioxidant cell response through the nuclear factor erythroid 2-related factor 2 (Nrf2), thus inducing beneficial effects without cell damage. Mitochondria are sensitive to mild oxidative stress and represent a susceptible O3 target. In this in vitro study, we investigated the mitochondrial response to low O3 doses in the immortalized, non-tumoral muscle C2C12 cells; a multimodal approach including fluorescence microscopy, transmission electron microscopy and biochemistry was used. Results demonstrated that mitochondrial features are finely tuned by low O3 doses. The O3 concentration of 10 μg maintained normal levels of mitochondria-associated Nrf2, promoted the mitochondrial increase of size and cristae extension, reduced cellular reactive oxygen species (ROS) and prevented cell death. Conversely, in 20 μg O3-treated cells, where the association of Nrf2 with the mitochondria drastically dropped, mitochondria underwent more significant swelling, and ROS and cell death increased. This study, therefore, adds original evidence for the involvement of Nrf2 in the dose-dependent response to low O3 concentrations not only as an Antioxidant Response Elements (ARE) gene activator but also as a regulatory/protective factor of mitochondrial function.
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Koval, Olha M., Emily K. Nguyen, Velarchana Santhana, Trevor P. Fidler, Sara C. Sebag, Tyler P. Rasmussen, Dylan J. Mittauer, et al. "Loss of MCU prevents mitochondrial fusion in G1-S phase and blocks cell cycle progression and proliferation." Science Signaling 12, no. 579 (April 30, 2019): eaav1439. http://dx.doi.org/10.1126/scisignal.aav1439.
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The role of the mitochondrial Ca2+uniporter (MCU) in physiologic cell proliferation remains to be defined. Here, we demonstrated that the MCU was required to match mitochondrial function to metabolic demands during the cell cycle. During the G1-S transition (the cycle phase with the highest mitochondrial ATP output), mitochondrial fusion, oxygen consumption, and Ca2+uptake increased in wild-type cells but not in cells lacking MCU. In proliferating wild-type control cells, the addition of the growth factors promoted the activation of the Ca2+/calmodulin-dependent kinase II (CaMKII) and the phosphorylation of the mitochondrial fission factor Drp1 at Ser616. The lack of the MCU was associated with baseline activation of CaMKII, mitochondrial fragmentation due to increased Drp1 phosphorylation, and impaired mitochondrial respiration and glycolysis. The mitochondrial fission/fusion ratio and proliferation in MCU-deficient cells recovered after MCU restoration or inhibition of mitochondrial fragmentation or of CaMKII in the cytosol. Our data highlight a key function for the MCU in mitochondrial adaptation to the metabolic demands during cell cycle progression. Cytosolic CaMKII and the MCU participate in a regulatory circuit, whereby mitochondrial Ca2+uptake affects cell proliferation through Drp1.
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Aerbajinai, Wulin, Manik C. Ghosh, Jie Liu, Chutima Kumkhaek, Jianqing Zhu, Kyung Chin, Tracey A. Rouault, and Griffin P. Rodgers. "Glia maturation factor-γ regulates murine macrophage iron metabolism and M2 polarization through mitochondrial ROS." Blood Advances 3, no. 8 (April 10, 2019): 1211–25. http://dx.doi.org/10.1182/bloodadvances.2018026070.
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Abstract In macrophages, cellular iron metabolism status is tightly integrated with macrophage phenotype and associated with mitochondrial function. However, how molecular events regulate mitochondrial activity to integrate regulation of iron metabolism and macrophage phenotype remains unclear. Here, we explored the important role of the actin-regulatory protein glia maturation factor-γ (GMFG) in the regulation of cellular iron metabolism and macrophage phenotype. We found that GMFG was downregulated in murine macrophages by exposure to iron and hydrogen peroxide. GMFG knockdown altered the expression of iron metabolism proteins and increased iron levels in murine macrophages and concomitantly promoted their polarization toward an anti-inflammatory M2 phenotype. GMFG-knockdown macrophages exhibited moderately increased levels of mitochondrial reactive oxygen species (mtROS), which were accompanied by decreased expression of some mitochondrial respiration chain components, including the iron-sulfur cluster assembly scaffold protein ISCU as well as the antioxidant enzymes SOD1 and SOD2. Importantly, treatment of GMFG-knockdown macrophages with the antioxidant N-acetylcysteine reversed the altered expression of iron metabolism proteins and significantly inhibited the enhanced gene expression of M2 macrophage markers, suggesting that mtROS is mechanistically linked to cellular iron metabolism and macrophage phenotype. Finally, GMFG interacted with the mitochondrial membrane ATPase ATAD3A, suggesting that GMFG knockdown–induced mtROS production might be attributed to alteration of mitochondrial function in macrophages. Our findings suggest that GMFG is an important regulator in cellular iron metabolism and macrophage phenotype and could be a novel therapeutic target for modulating macrophage function in immune and metabolic disorders.
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Pokkunuri, Indira D., Mustafa F. Lokhandwala, and Anees Ahmad Banday. "Protein disulfide isomerase inhibition impairs Keap1/Nrf2 signaling and mitochondrial function and induces apoptosis in renal proximal tubular cells." American Journal of Physiology-Renal Physiology 319, no. 4 (October 1, 2020): F686—F696. http://dx.doi.org/10.1152/ajprenal.00049.2020.
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Renal proximal tubular apoptosis plays a critical role in kidney health and disease. However, cellular molecules that trigger renal apoptosis remain elusive. Here, we evaluated the effect of inhibiting protein disulfide isomerase (PDI), a critical thioredoxin chaperone protein, on apoptosis as well as the underlying mechanisms in human renal proximal tubular (HK2) cells. HK2 cells were transfected with PDI-specific siRNA in the absence and presence of an antioxidant, tempol. PDI siRNA transfection resulted in a decrease of ~70% in PDI protein expression and enzyme activity. PDI inhibition increased caspase-3 activity and induced profound cell apoptosis. Mitochondrial function, as assessed by mitochondrial cytochrome c levels, mitochondrial membrane potential, oxygen consumption, and ATP levels, was significantly reduced in PDI-inhibited cells. Also, PDI inhibition caused nuclear factor erythroid 2-related factor 2 (Nrf2; a redox-sensitive transcription factor) cytoplasmic sequestration, decreased superoxide dismutase and glutathione- S-transferase activities, and increased oxidative stress. In PDI-inhibited cells, tempol reduced apoptosis, caspase-3 activity, and oxidative stress and also restored Nrf2 nuclear translocation and mitochondrial function. Silencing Nrf2 in the cells abrogated the beneficial effect of tempol, whereas Kelch-like ECH-associated protein 1 (an Nrf2 regulatory protein) silencing protected cells from PDI inhibitory effects. Collectively, our data indicate that PDI inhibition diminishes Nrf2 nuclear translocation, causing oxidative stress that further triggers mitochondrial dysfunction and renal cell apoptosis. This study suggests an important role for PDI in renal cell apoptosis involving Nrf2 and mitochondrial dysfunction.
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Ma, Sai, Jing Feng, Ran Zhang, Jiangwei Chen, Dong Han, Xiang Li, Bo Yang, et al. "SIRT1 Activation by Resveratrol Alleviates Cardiac Dysfunction via Mitochondrial Regulation in Diabetic Cardiomyopathy Mice." Oxidative Medicine and Cellular Longevity 2017 (2017): 1–15. http://dx.doi.org/10.1155/2017/4602715.
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Background. Diabetic cardiomyopathy (DCM) is a major threat for diabetic patients. Silent information regulator 1 (SIRT1) has a regulatory effect on mitochondrial dynamics, which is associated with DCM pathological changes. Our study aims to investigate whether resveratrol, a SRIT1 activator, could exert a protective effect against DCM. Methods and Results. Cardiac-specific SIRT1 knockout (SIRT1KO) mice were generated using Cre-loxP system. SIRT1KO mice displayed symptoms of DCM, including cardiac hypertrophy and dysfunction, insulin resistance, and abnormal glucose metabolism. DCM and SIRT1KO hearts showed impaired mitochondrial biogenesis and function, while SIRT1 activation by resveratrol reversed this in DCM mice. High glucose caused increased apoptosis, impaired mitochondrial biogenesis, and function in cardiomyocytes, which was alleviated by resveratrol. SIRT1 deletion by both SIRT1KO and shRNA abolished the beneficial effects of resveratrol. Furthermore, the function of SIRT1 is mediated via the deacetylation effect on peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), thus inducing increased expression of nuclear respiratory factor 1 (NRF-1), NRF-2, estrogen-related receptor-α (ERR-α), and mitochondrial transcription factor A (TFAM). Conclusions. Cardiac deletion of SIRT1 caused phenotypes resembling DCM. Activation of SIRT1 by resveratrol ameliorated cardiac injuries in DCM through PGC-1α-mediated mitochondrial regulation. Collectively, SIRT1 may serve as a potential therapeutic target for DCM.
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Nakayama, Hiroyuki, and Kinya Otsu. "Mitochondrial DNA as an inflammatory mediator in cardiovascular diseases." Biochemical Journal 475, no. 5 (March 6, 2018): 839–52. http://dx.doi.org/10.1042/bcj20170714.
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Mitochondria play a central role in multiple cellular functions, including energy production, calcium homeostasis, and cell death. Currently, growing evidence indicates the vital roles of mitochondria in triggering and maintaining inflammation. Chronic inflammation without microbial infection — termed sterile inflammation — is strongly involved in the development of heart failure. Sterile inflammation is triggered by the activation of pattern recognition receptors (PRRs) that sense endogenous ligands called damage-associated molecular patterns (DAMPs). Mitochondria release multiple DAMPs including mitochondrial DNA, peptides, and lipids, which induce inflammation via the stimulation of multiple PRRs. Among the mitochondrial DAMPs, mitochondrial DNA (mtDNA) is currently highlighted as the DAMP that mediates the activation of multiple PRRs, including Toll-like receptor 9, Nod-like receptors, and cyclic GMP–AMP synthetase/stimulator of interferon gene pathways. These PRR signalling pathways, in turn, lead to the activation of nuclear factor-κB and interferon regulatory factor, which enhances the transcriptional activity of inflammatory cytokines and interferons, and induces the recruitment of inflammatory cells. As the heart is an organ comprising abundant mitochondria for its ATP consumption (needed to maintain constant cyclic contraction and relaxation), the generation of massive amounts of mitochondrial radical oxygen species and mitochondrial DAMPs are predicted to occur and promote cardiac inflammation. Here, we will focus on the role of mtDNA in cardiac inflammation and review the mechanism and pathological significance of mtDNA-induced inflammatory responses in cardiac diseases.
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Gil-Varea, Elia, Maria Fedetz, Herena Eixarch, Nino Spataro, Luisa María Villar, Elena Urcelay, Albert Saiz, et al. "A New Risk Variant for Multiple Sclerosis at 11q23.3 Locus Is Associated with Expansion of CXCR5+ Circulating Regulatory T Cells." Journal of Clinical Medicine 9, no. 3 (February 26, 2020): 625. http://dx.doi.org/10.3390/jcm9030625.
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Genome-wide association studies and meta-analysis have contributed to the identification of more than 200 loci associated with multiple sclerosis (MS). However, a proportion of MS heritability remains unknown. We aimed to uncover new genetic variants associated with MS and determine their functional effects. For this, we resequenced the exons and regulatory sequences of 14 MS risk genes in a cohort of MS patients and healthy individuals (n = 1070) and attempted to validate a selection of signals through genotyping in an independent cohort (n = 5138). We identified three new MS-associated variants at C-X-C motif chemokine receptor 5 (CXCR5), Ts translation elongation factor, mitochondrial (TSFM) and cytochrome P450 family 24 subfamily A member 1 (CYP24A1). Rs10892307 resulted in a new signal at the CXCR5 region that explains one of the associations with MS within the locus. This polymorphism and three others in high linkage disequilibrium mapped within regulatory regions. Of them, rs11602393 showed allele-dependent enhancer activity in the forward orientation as determined by luciferase reporter assays. Immunophenotyping using peripheral blood mononuclear cells from MS patients associated the minor allele of rs10892307 with increased percentage of regulatory T cells expressing CXCR5. This work reports a new signal for the CXCR5 MS risk locus and points to rs11602393 as the causal variant. The expansion of CXCR5+ circulating regulatory T cells induced by this variant could cause its MS association.
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Watson, Peter A., Nicholas Birdsey, Gordon S. Huggins, Eric Svensson, Daniel Heppe, and Leslie Knaub. "Cardiac-specific overexpression of dominant-negative CREB leads to increased mortality and mitochondrial dysfunction in female mice." American Journal of Physiology-Heart and Circulatory Physiology 299, no. 6 (December 2010): H2056—H2068. http://dx.doi.org/10.1152/ajpheart.00394.2010.
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Cardiac failure is associated with diminished activation of the transcription factor cyclic nucleotide regulatory element binding-protein (CREB), and heart-specific expression of a phosphorylation-deficient CREB mutant in transgenic mice [dominant negative CREB (dnCREB) mice] recapitulates the contractile phenotypes of cardiac failure (Fentzke RC, Korcarz CE, Lang RM, Lin H, Leiden JM. Dilated cardiomyopathy in transgenic mice expressing a dominant-negative CREB transcription factor in the heart. J Clin Invest 101: 2415–2426, 1998). In the present study, we demonstrated significantly elevated mortality and contractile dysfunction in female compared with male dnCREB mice. Female dnCREB mice demonstrated a 21-wk survival of only 17% compared with 67% in males ( P < 0.05) and exclusively manifest decreased cardiac peroxisome proliferator-activated receptor-γ coactivator-1α and estrogen-related receptor-α content, suggesting sex-related effects on cardiac mitochondrial function. Hearts from 4-wk-old dnCREB mice of both sexes demonstrated diminished mitochondrial respiratory capacity compared with nontransgenic controls. However, by 12 wk of age, there was a significant decrease in mitochondrial density (citrate synthase activity) and deterioration of mitochondrial structure, as demonstrated by transmission electron microscopy, in female dnCREB mice, which were not found in male transgenic littermates. Subsarcolemmal mitochondria isolated from hearts of female, but not male, dnCREB mice demonstrated increased ROS accompanied by decreases in the expression/activity of the mitochondrial antioxidants MnSOD and glutathione peroxidase. These results demonstrate that heart-specific dnCREB expression results in mitochondrial respiratory dysfunction in both sexes; however, increased oxidant burden, reduced antioxidant expression, and disrupted mitochondrial structure are exacerbated by the female sex, preceding and contributing to the greater contractile morbidity and mortality. These results provide further support for the role of the CREB transcription factor in regulating mitochondrial integrity and identify a critical pathway that may contribute to sex differences in heart failure.
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Yang, Ziqiang, Wei Cheng, Lixin Hong, Wanze Chen, Yanhai Wang, Shengcai Lin, Jiahuai Han, Huamin Zhou, and Jun Gu. "Adenine Nucleotide (ADP/ATP) Translocase 3 Participates in the Tumor Necrosis Factor–induced Apoptosis of MCF-7 Cells." Molecular Biology of the Cell 18, no. 11 (November 2007): 4681–89. http://dx.doi.org/10.1091/mbc.e06-12-1161.
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Mitochondrial adenine nucleotide translocase (ANT) is believed to be a component or a regulatory component of the mitochondrial permeability transition pore (mtPTP), which controls mitochondrial permeability transition during apoptosis. However, the role of ANT in apoptosis is still uncertain, because hepatocytes isolated from ANT knockout and wild-type mice are equally sensitive to TNF- and Fas-induced apoptosis. In a screen for genes required for tumor necrosis factor α (TNF-α)-induced apoptosis in MCF-7 human breast cancer cells using retrovirus insertion–mediated random mutagenesis, we discovered that the ANT3 gene is involved in TNF-α–induced cell death in MCF-7 cells. We further found that ANT3 is selectively required for TNF- and oxidative stress–induced cell death in MCF-7 cells, but it is dispensable for cell death induced by several other inducers. This data supplements previous data obtained from ANT knockout studies, indicating that ANT is involved in some apoptotic processes. We found that the resistance to TNF-α–induced apoptosis observed in ANT3 mutant (ANT3mut) cells is associated with a deficiency in the regulation of the mitochondrial membrane potential and cytochrome c release. It is not related to intracellular ATP levels or survival pathways, supporting a previous model in which ANT regulates mtPTP. Our study provides genetic evidence supporting a role of ANT in apoptosis and suggests that the involvement of ANT in cell death is cell type– and stimulus-dependent.
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Li, Chaoran, Pulavendran Sivasami, Cody Elkins, Kyndal Goss, Pamela P. Diaz-Saldana, Amy Peng, Michael Hamersky, et al. "Obesity-induced dysregulation of a unique subset of Tregs promotes skin inflammation." Journal of Immunology 210, no. 1_Supplement (May 1, 2023): 248.02. http://dx.doi.org/10.4049/jimmunol.210.supp.248.02.
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Abstract Obesity is associated with increased skin inflammation and is a major risk factor for psoriasis, raising the question of how obesity disrupts the regulatory mechanisms that keep skin inflammation in check at steady state. We found that skin was enriched with a unique subset of CD4 +Foxp3 +regulatory T cells (Tregs), which is critical to limit IL-17A-mediated psoriatic inflammation. Diet-induced obesity, however, resulted in a significant reduction of this subset of skin Tregs and a corresponding loss of control over IL-17A-mediated inflammation. Mechanistically, this specific skin Treg population preferentially took up elevated levels of long-chain saturated fatty acids during obesity, which led to cellular lipotoxicity and mitochondrial dysfunction. Harnessing the anti-inflammatory property of this unique subset of skin Tregs could have therapeutic potential for obesity-associated inflammatory skin diseases. Supported from grants from NIH/NIDDK (1R01DK128061), National Psoriasis Foundation, and Emory University Research Committee (URC).
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Gleyzer, Natalie, Kristel Vercauteren, and Richard C. Scarpulla. "Control of Mitochondrial Transcription Specificity Factors (TFB1M and TFB2M) by Nuclear Respiratory Factors (NRF-1 and NRF-2) and PGC-1 Family Coactivators." Molecular and Cellular Biology 25, no. 4 (February 15, 2005): 1354–66. http://dx.doi.org/10.1128/mcb.25.4.1354-1366.2005.
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ABSTRACT In vertebrates, mitochondrial DNA (mtDNA) transcription is initiated bidirectionally from closely spaced promoters, HSP and LSP, within the D-loop regulatory region. Early studies demonstrated that mtDNA transcription requires mitochondrial RNA polymerase and Tfam, a DNA binding stimulatory factor that is required for mtDNA maintenance. Recently, mitochondrial transcription specificity factors (TFB1M and TFB2M), which markedly enhance mtDNA transcription in the presence of Tfam and mitochondrial RNA polymerase, have been identified in mammalian cells. Here, we establish that the expression of human TFB1M and TFB2M promoters is governed by nuclear respiratory factors (NRF-1 and NRF-2), key transcription factors implicated in mitochondrial biogenesis. In addition, we show that NRF recognition sites within both TFB promoters are required for maximal trans activation by the PGC-1 family coactivators, PGC-1α and PRC. The physiological induction of these coactivators has been associated with the integration of NRFs and other transcription factors in a program of mitochondrial biogenesis. Finally, we demonstrate that the TFB genes are up-regulated along with Tfam and either PGC-1α or PRC in cellular systems where mitochondrial biogenesis is induced. Moreover, ectopic expression of PGC-1α is sufficient to induce the coordinate expression of all three nucleus-encoded mitochondrial transcription factors along with nuclear and mitochondrial respiratory subunits. These results support the conclusion that the coordinate regulation of nucleus-encoded mitochondrial transcription factors by NRFs and PGC-1 family coactivators is essential to the control of mitochondrial biogenesis.
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Chen, Guan-Yu, Yu-Chieh Shu, Duen-Yau Chuang, and Yuan-Chuen Wang. "Inflammatory and Apoptotic Regulatory Activity of Tanshinone IIA in Helicobacter pylori-Infected Cells." American Journal of Chinese Medicine 44, no. 06 (January 2016): 1187–206. http://dx.doi.org/10.1142/s0192415x1650066x.
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Helicobacter pylori infections induce host cell inflammation and apoptosis, however, they are conflicting. Tanshinone IIA is an active compound of Salvia miltiorrhiza Bge. In this study, we investigated the regulatory effects of tanshinone IIA on H. pylori-induced inflammation and apoptosis in vitro. Tanshinone IIA treatments (13.6–54.4[Formula: see text][Formula: see text]M) significantly decreased nuclear factor kappa B (NF-kB) and mitogen-activated protein kinase (MAPK) [p-38 and C-terminal Jun-kinase 1/2 (JNK1/2)] protein expressions and inflammatory substance [cyclooxygenase-2 (COX-2), 5-lipooxygenase (5-LOX), intercellular adhesion molecule-1 (ICAM-1), reactive oxygen species (ROS), nitric oxide (NO), inducible nitric oxide synthase (iNOS), interleukin-1[Formula: see text] (IL-1[Formula: see text], IL-6, and IL-8] production in the H. pylori-infected cells. In contrast, tanshinone IIA treatments significantly increased apoptotic relevant protein [Bcl-2-associated X protein (Bax) and caspase 9] expressions and increased mitochondrial transmembrane potential ([Formula: see text] disruption, mitochondrial cytochrome [Formula: see text] (cyt [Formula: see text] release, and caspase cascades. Tanshinone IIA treatments effectively decreased H. pylori-induced inflammation and significantly promoted H. pylori-induced intrinsic apoptosis through NF-kB and MAPK (p-38 and JNK) pathways. Tanshinone IIA has great potential as a candidate to protect host cells from H. pylori-induced severe inflammation and gastric cancer.
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Chou, Chih-Wei, Xi Tan, Chia-Nung Hung, Brandon Lieberman, Meizhen Chen, Meena Kusi, Kohzoh Mitsuya, et al. "Menin and Menin-Associated Proteins Coregulate Cancer Energy Metabolism." Cancers 12, no. 9 (September 22, 2020): 2715. http://dx.doi.org/10.3390/cancers12092715.
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The interplay between glycolysis and mitochondrial oxidative phosphorylation (OXPHOS) is central to maintain energy homeostasis. It remains to be determined whether there is a mechanism governing metabolic fluxes based on substrate availability in microenvironments. Here we show that menin is a key transcription factor regulating the expression of OXPHOS and glycolytic genes in cancer cells and primary tumors with poor prognosis. A group of menin-associated proteins (MAPs), including KMT2A, MED12, WAPL, and GATA3, is found to restrain menin’s full function in this transcription regulation. shRNA knockdowns of menin and MAPs result in reduced ATP production with proportional alterations of cellular energy generated through glycolysis and OXPHOS. When shRNA knockdown cells are exposed to metabolic stress, the dual functionality can clearly be distinguished among these metabolic regulators. A MAP can negatively counteract the regulatory mode of menin for OXPHOS while the same protein positively influences glycolysis. A close-proximity interaction between menin and MAPs allows transcriptional regulation for metabolic adjustment. This coordinate regulation by menin and MAPs is necessary for cells to rapidly adapt to fluctuating microenvironments and to maintain essential metabolic functions.
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Ziegelhöffer, Attila, Iveta Waczulíková, Miroslav Ferko, Dana Kincelová, Barbara Ziegelhöffer, Táňa Ravingerová, Michal Cagalinec, et al. "Calcium signaling-mediated endogenous protection of cell energetics in the acutely diabetic myocardiumThis article is one of a selection of papers published in a special issue on Advances in Cardiovascular Research." Canadian Journal of Physiology and Pharmacology 87, no. 12 (December 2009): 1083–94. http://dx.doi.org/10.1139/y09-108.
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In acute diabetic myocardium, calcium signals propagated by intracellular calcium transients participate in the protection of cell energetics via upregulating the formation of mitochondrial energy transition pores (ETP). Mechanisms coupling ETP formation with an increase in membrane fluidity and a decrease in transmembrane potential of the mitochondria are discussed. Our results indicate that the amplification of calcium transients in the diabetic heart is associated with an increase in their amplitude. Moreover, the signals transferred by calcium transients also regulated ETP formation in nondiabetic myocardium. Evidence for the indispensable role of calcium in the regulation of transition pore formation is provided whereby an exchange of cadmium for calcium ions led to a rapid and dramatic decrease in the amount of ETP. Another possible regulatory factor of the mitochondrial function may be radical-induced damage to the diabetic heart. Nevertheless, our data indicate that radical-induced changes in mitochondria predominantly concern the respiratory chain and have no appreciable effect on the fluidity of the mitochondrial membranes. The residual mitochondrial production of ATP owing to its augmented transfer to the cytosol proved to be adequate to preserve sufficient levels of adenine nucleotides in the acute diabetic myocardium.
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Paulmann, Dajana, Thomas Magulski, Rebecca Schwarz, Lisa Heitmann, Bertram Flehmig, Angelika Vallbracht, and Andreas Dotzauer. "Hepatitis A virus protein 2B suppresses beta interferon (IFN) gene transcription by interfering with IFN regulatory factor 3 activation." Journal of General Virology 89, no. 7 (July 1, 2008): 1593–604. http://dx.doi.org/10.1099/vir.0.83521-0.
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Hepatitis A virus (HAV) antagonizes the innate immune response by inhibition of retinoic acid-inducible gene I-mediated and melanoma differentiation-associated gene 5-mediated beta interferon (IFN-β) gene expression. This study showed that this is due to an interaction of HAV with mitochondrial antiviral signalling protein (MAVS)-dependent signalling, in which the viral non-structural protein 2B and the protein intermediate 3ABC recently suggested in this context seem to be involved, cooperatively affecting the activities of MAVS and the kinases TANK-binding kinase 1 (TBK1) and the inhibitor of NF-κB kinase ϵ (IKKϵ). In consequence, interferon regulatory factor 3 (IRF-3) is not activated. As IRF-3 is necessary for IFN-β transcription, inhibition of this factor results in efficient suppression of IFN-β synthesis. This ability might be of vital importance for HAV, which is an exceptionally slow growing virus sensitive to IFN-β, as it allows the virus to establish infection and maintain virus replication for a longer period of time.
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Peng, Xiandong, Min Yu, and Jiazhou Chen. "Transcriptome sequencing identifies genes associated with invasion of ovarian cancer." Journal of International Medical Research 48, no. 9 (September 2020): 030006052095091. http://dx.doi.org/10.1177/0300060520950912.
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Objective To identify key genes in ovarian cancer using transcriptome sequencing in two cell lines: MCV152 (benign ovarian epithelial tumour) and SKOV-3 (ovarian serous carcinoma). Methods Differentially expressed genes (DEGs) between SKOV-3 and MCV152 were identified. Candidate genes were assessed for enrichment in gene ontology function and Kyoto Encyclopaedia of Genes and Genomes pathway. Candidate gene expression in SKOV-3 and MCV152 cells was validated using Western blots. Results A total of 2020 upregulated and 1673 downregulated DEGs between SKOV3 and MCV152 cells were identified that were significantly enriched in the cell adhesion function. Upregulated DEGs, such as angiopoietin 2 ( ANGPT2), CD19 molecule ( CD19), collagen type IV alpha 3 chain ( COL4A3), fibroblast growth factor 18 ( FGF18), integrin subunit beta 4 ( ITGB4), integrin subunit beta 8 ( ITGB8), laminin subunit alpha 3 ( LAMA3), laminin subunit gamma 2 ( LAMC2), protein phosphatase 2 regulatory subunit Bgamma ( PPP2R2C) and spleen associated tyrosine kinase ( SYK) were significantly involved in the extracellular matrix-receptor interaction pathway. Downregulated DEGs, such as AKT serine/threonine kinase 3 ( AKT3), collagen type VI alpha 1 chain ( COL6A1), colony stimulating factor 3 ( CSF3), fibroblast growth factor 1 ( FGF1), integrin subunit alpha 2 ( ITGA2), integrin subunit alpha 11 ( ITGA11), MYB proto-oncogene, transcription factor ( MYB), phosphoenolpyruvate carboxykinase 2, mitochondrial ( PCK2), placental growth factor ( PGF), phosphoinositide-3-kinase adaptor protein 1 ( PIK3AP1), serum/glucocorticoid regulated kinase 1 ( SGK1), toll like receptor 4 ( TLR4) and tumour protein p53 ( TP53) were involved in PI3K-Akt signalling. Expression of these DEGs was confirmed by Western blot analyses. Conclusion Candidate genes enriched in cell adhesion, extracellular matrix–receptor interaction and PI3K-Akt signalling pathways were identified that may be closely associated with ovarian cancer invasion and potential targets for ovarian cancer treatment.
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Paul, Sanjoy, Jennifer A. Schmidt, and W. Scott Moye-Rowley. "Regulation of the CgPdr1 Transcription Factor from the Pathogen Candida glabrata." Eukaryotic Cell 10, no. 2 (December 3, 2010): 187–97. http://dx.doi.org/10.1128/ec.00277-10.
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ABSTRACTCandida glabratais an opportunistic human pathogen that is increasingly associated with candidemia, owing in part to the intrinsic and acquired high tolerance the organism exhibits for the important clinical antifungal drug fluconazole. This elevated fluconazole resistance often develops through gain-of-function mutations in the zinc cluster-containing transcriptional regulatorC. glabrataPdr1 (CgPdr1). CgPdr1 induces the expression of an ATP-binding cassette (ABC) transporter-encoding gene, CgCDR1.Saccharomyces cerevisiaehas two CgPdr1 homologues called ScPdr1 and ScPdr3. These factors control the expression of an ABC transporter-encoding gene called ScPDR5, which encodes a homologue of CgCDR1. Loss of the mitochondrial genome (ρ0cell) or overexpression of the mitochondrial enzyme ScPsd1 induces ScPDR5expression in a strictly ScPdr3-dependent fashion. ScPdr3 requires the presence of a transcriptional Mediator subunit called Gal11 (Med15) to fully induce ScPDR5transcription in response to ρ0signaling. ScPdr1 does not respond to either ρ0signals or ScPsd1 overproduction. In this study, we employed transcriptional fusions between CgPdr1 target promoters, like CgCDR1, to demonstrate that CgPdr1 stimulates gene expression via binding to elements called pleiotropic drug response elements (PDREs). Deletion mapping and electrophoretic mobility shift assays demonstrated that a single PDRE in the CgCDR1promoter was capable of supporting ρ0-induced gene expression. Removal of one of the two ScGal11 homologues fromC. glabratacaused a major defect in drug-induced expression of CgCDR1but had a quantitatively minor effect on ρ0-stimulated transcription. These data demonstrate that CgPdr1 appears to combine features of ScPdr1 and ScPdr3 to produce a transcription factor with chimeric regulatory properties.
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Wang, Yani, Xiang Peng, Maomao Zhang, Ying Jia, Bo Yu, and Jinwei Tian. "Revisiting Tumors and the Cardiovascular System: Mechanistic Intersections and Divergences in Ferroptosis." Oxidative Medicine and Cellular Longevity 2020 (August 18, 2020): 1–13. http://dx.doi.org/10.1155/2020/9738143.
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Ferroptosis was recently identified as an iron-dependent regulatory necrosis process mediated by polyunsaturated fatty acid (PUFA) peroxidation. The pivotal events related to oxidative stress in ferroptosis include direct or indirect glutathione peroxidase 4 (GPX4) inhibition, ferrous iron overload, and lipid peroxidation. The links between ferroptosis and multiple pathological processes including tumor and cardiovascular system disease have become increasingly apparent, and the mechanisms and compounds involved in ferroptosis, such as reduction of coenzyme Q10 (ubiquinone/CoQ10), are gradually emerging. Current reports have revealed crossroads between ferroptosis and other multiple responses. This overview of the current research illuminates the mechanisms involving ferroptosis-related compounds and emphasizes the crosstalk between ferroptosis and other responses, including mitochondrial damage, endoplasmic reticulum stress (ER stress), autophagy, and the release of damage-associated molecular patterns (DAMPs), to reveal the intersections of regulatory mechanisms. This review also outlines the discovery, characterization, and pathological relevance of ferroptosis and notes controversial elements in ferroptosis-related mechanisms, such as nuclear factor E2-related factor 2 (Nrf2), sequestosome 1 (p62/SQSTM1), and heat shock protein family A member 5 (HSPA5). We hope our inferences will supply a partial reference for disorder prevention and treatment.
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Yang, Minghui, Shengyu Guan, Jingli Tao, Kuanfeng Zhu, Dongying Lv, Jing Wang, Guangdong Li, et al. "Melatonin promotes male reproductive performance and increases testosterone synthesis in mammalian Leydig cells." Biology of Reproduction 104, no. 6 (March 11, 2021): 1322–36. http://dx.doi.org/10.1093/biolre/ioab046.
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Abstract Leydig cells play a critical role in male reproductive physiology, and their dysfunction is usually associated with male infertility. Melatonin has an important protective and regulatory role in these cells. However, the lack of suitable animal models impedes us from addressing the impact of endogenous melatonin on these cells. In the current study, by using arylalkylamine N-acetyltransferase (AANAT) overexpression transgenic sheep and AANAT knockout mice, we confirmed the regulatory effects of endogenously occurring melatonin on Leydig cells as well as its beneficial effects on male reproductive performance. The results showed that the endogenously elevated melatonin level was correlated with decreased Leydig cell apoptosis, increased testosterone production, and improved quality of sperm in melatonin-enriched transgenic mammals. Signal transduction analysis indicated that melatonin targeted the mitochondrial apoptotic Bax/Bcl2 pathway and thus suppressed Leydig cell apoptosis. In addition, melatonin upregulated the expression of testosterone synthesis-related genes of Steroidogenic Acute Regulatory Protein (StAR), Steroidogenic factor 1 (SF1), and Transcription factor GATA-4 (Gata4) in Leydig cells. This action was primarily mediated by the melatonin nuclear receptor RAR-related orphan receptor alpha (RORα) since blockade of this receptor suppressed the effect of melatonin on testosterone synthesis. All of these actions of melatonin cause Leydig cells to generate more testosterone, which is necessary for spermatogenesis in mammals. In contrast, AANAT knockout animals have dysfunctional Leydig cells and reduced reproductive performance.
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Niazi, Adnan Khan, Etienne Delannoy, Rana Khalid Iqbal, Daria Mileshina, Romain Val, Marta Gabryelska, Eliza Wyszko, et al. "Mitochondrial Transcriptome Control and Intercompartment Cross-Talk During Plant Development." Cells 8, no. 6 (June 13, 2019): 583. http://dx.doi.org/10.3390/cells8060583.
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We address here organellar genetic regulation and intercompartment genome coordination. We developed earlier a strategy relying on a tRNA-like shuttle to mediate import of nuclear transgene-encoded custom RNAs into mitochondria in plants. In the present work, we used this strategy to drive trans-cleaving hammerhead ribozymes into the organelles, to knock down specific mitochondrial RNAs and analyze the regulatory impact. In a similar approach, the tRNA mimic was used to import into mitochondria in Arabidopsis thaliana the orf77, an RNA associated with cytoplasmic male sterility in maize and possessing sequence identities with the atp9 mitochondrial RNA. In both cases, inducible expression of the transgenes allowed to characterise early regulation and signaling responses triggered by these respective manipulations of the organellar transcriptome. The results imply that the mitochondrial transcriptome is tightly controlled by a “buffering” mechanism at the early and intermediate stages of plant development, a control that is released at later stages. On the other hand, high throughput analyses showed that knocking down a specific mitochondrial mRNA triggered a retrograde signaling and an anterograde nuclear transcriptome response involving a series of transcription factor genes and small RNAs. Our results strongly support transcriptome coordination mechanisms within the organelles and between the organelles and the nucleus.
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Tulen, Christy B. M., Antoon Opperhuizen, Frederik-Jan van Schooten, and Alexander H. V. Remels. "Disruption of the Molecular Regulation of Mitochondrial Metabolism in Airway and Lung Epithelial Cells by Cigarette Smoke: Are Aldehydes the Culprit?" Cells 12, no. 2 (January 12, 2023): 299. http://dx.doi.org/10.3390/cells12020299.
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Chronic obstructive pulmonary disease (COPD) is a devastating lung disease for which cigarette smoking is the main risk factor. Acetaldehyde, acrolein, and formaldehyde are short-chain aldehydes known to be formed during pyrolysis and combustion of tobacco and have been linked to respiratory toxicity. Mitochondrial dysfunction is suggested to be mechanistically and causally involved in the pathogenesis of smoking-associated lung diseases such as COPD. Cigarette smoke (CS) has been shown to impair the molecular regulation of mitochondrial metabolism and content in epithelial cells of the airways and lungs. Although it is unknown which specific chemicals present in CS are responsible for this, it has been suggested that aldehydes may be involved. Therefore, it has been proposed by the World Health Organization to regulate aldehydes in commercially-available cigarettes. In this review, we comprehensively describe and discuss the impact of acetaldehyde, acrolein, and formaldehyde on mitochondrial function and content and the molecular pathways controlling this (biogenesis versus mitophagy) in epithelial cells of the airways and lungs. In addition, potential therapeutic applications targeting (aldehyde-induced) mitochondrial dysfunction, as well as regulatory implications, and the necessary required future studies to provide scientific support for this regulation, have been covered in this review.
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Chong, Zhao Zhong, Shi-Hua Lin, and Kenneth Maiese. "The NAD+ Precursor Nicotinamide Governs Neuronal Survival During Oxidative Stress Through Protein Kinase B Coupled to FOXO3a and Mitochondrial Membrane Potential." Journal of Cerebral Blood Flow & Metabolism 24, no. 7 (July 2004): 728–43. http://dx.doi.org/10.1097/01.wcb.0000122746.72175.0e.
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Nicotinamide, a ß-nicotinamide adenine dinucleotide (NAD+) precursor and an essential nutrient for cell growth and function, may offer critical insights into the specific cellular mechanisms that determine neuronal survival, since this agent significantly impacts upon both neuronal and vascular integrity in the central nervous system. The authors show that nicotinamide provides broad, but concentration-specific, protection against apoptotic genomic DNA fragmentation and membrane phosphatidylserine exposure during oxidative stress to secure cellular integrity and prevent phagocytic cellular demise. Activation of the protein kinase B (Akt1) pathway is a necessary requirement for nicotinamide protection, because transfection of primary hippocampal neurons with a plasmid encoding a kinase-deficient dominant-negative Akt1 as well as pharmacologic inhibition of phosphatidylinositol-3-kinase phosphorylation of Akt1 eliminates cytoprotection by nicotinamide. Nicotinamide fosters neuronal survival through a series of intimately associated pathways. At one level, nicotinamide directly modulates mitochondrial membrane potential and pore formation to prevent cytochrome c release and caspase-3–and 9–like activities through mechanisms that are independent of the apoptotic protease activating factor-1. At a second level, nicotinamide maintains an inhibitory phosphorylation of the forkhead transcription factor FOXO3a at the regulatory sites of Thr32 and Ser253 and governs a unique regulatory loop that prevents the degradation of phosphorylated FOXO3a by caspase-3. Their work elucidates some of the unique neuroprotective pathways used by the essential cellular nutrient nicotinamide that may direct future therapeutic approaches for neurodegenerative disorders.
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Christian, Patricia, and Qiaozhu Su. "MicroRNA regulation of mitochondrial and ER stress signaling pathways: implications for lipoprotein metabolism in metabolic syndrome." American Journal of Physiology-Endocrinology and Metabolism 307, no. 9 (November 1, 2014): E729—E737. http://dx.doi.org/10.1152/ajpendo.00194.2014.
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The development of metabolic syndrome is closely associated with the deregulation of lipid metabolism. Emerging evidence has demonstrated that microRNAs (miRNAs) are intensively engaged in lipid and lipoprotein metabolism by regulating genes involved in control of intracellular lipid synthesis, mitochondrial fatty acid oxidation, and lipoprotein assembly. Mitochondrial dysfunction induced by altered miRNA expression has been proposed to be a contributing factor in the onset of metabolic diseases, while at the same time, aberrant expression of certain miRNAs is associated with the induction of endoplasmic reticulum (ER) stress induced by nutrient-surplus. These studies position miRNAs as a link between oxidative stress and ER stress, two cellular stress pathways that are deregulated in metabolic disease and are associated with very-low-density lipoprotein (VLDL) overproduction. Dyslipoproteinemia frequently accompanied with metabolic syndrome is initiated largely by the overproduction of VLDL and altered biogenesis of high-density lipoprotein (HDL). In this review, we highlight recent findings on the regulatory impact of miRNAs on the metabolic homeostasis of mitochondria and ER as well as their contribution to the aberrant biogenesis of both VLDL and HDL in the context of metabolic disorders, in an attempt to gain further insights into the molecular mechanisms of dyslipidemia in the metabolic syndrome.
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Sessions-Bresnahan, Dawn R., and Elaine M. Carnevale. "Age-associated changes in granulosa cell transcript abundance in equine preovulatory follicles." Reproduction, Fertility and Development 27, no. 6 (2015): 906. http://dx.doi.org/10.1071/rd14467.
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Age-related changes in follicle paracrine signalling are not defined, and follicular gene transcript abundance could predict oocyte viability. Granulosa cells from preovulatory follicles of mares considered Young (n = 12; 4–14 years), Mid-aged (n = 9; 15–19 years) and Old (n = 14; 20–27 years) were evaluated for transcript abundance related to systemic and follicle-specific pathways. Gene transcript abundance for receptors of insulin, adiponectin and peroxisome proliferating factor-γ were higher or tended to be higher in Mid-aged or Old than Young mares. Transcript abundance for interleukin (IL)-6 was elevated in Old versus Young mares, and IL-6 signal transducer was elevated in Old versus younger groups. Expression of tumour necrosis factor (TNF) receptor superfamily member 1A was higher in Mid-aged than Young mares, whereas TNF-inducible gene 6 protein mRNA tended to decrease in Mid-aged versus Young and Old mares. Genes for LH receptor and steroidogenic acute regulatory protein tended to be increased in Old versus Mid-aged and Young mares, respectively. Young and Old mares had higher mRNA for tissue-type plasminogen activator than Mid-aged mares. Thioredoxin-2 mRNA was higher in Old than younger groups. We observed age-related changes in mRNA of receptors for metabolic hormones, inflammatory processes, steroidogenic hormones, tissue remodelling and mitochondrial function, which could contribute to and/or mark alterations in follicular function and fertility.
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VILLENA, Josep A., Octavi VIÑAS, Teresa MAMPEL, Roser IGLESIAS, Marta GIRALT, and Francesc VILLARROYA. "Regulation of mitochondrial biogenesis in brown adipose tissue: nuclear respiratory factor-2/GA-binding protein is responsible for the transcriptional regulation of the gene for the mitochondrial ATP synthase β subunit." Biochemical Journal 331, no. 1 (April 1, 1998): 121–27. http://dx.doi.org/10.1042/bj3310121.
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The regulation of transcription of the gene for the β subunit of the FoF1 ATP synthase (ATPsynβ) in brown adipose tissue has been studied as a model to determine the molecular mechanisms for mitochondrial biogenesis associated with brown adipocyte differentiation. The expression of the ATPsynβ mRNA is induced during the brown adipocyte differentiation that occurs during murine prenatal development or when brown adipocytes differentiate in culture. This induction occurs in parallel with enhanced gene expression for other nuclear and mitochondrially-encoded components of the respiratory chain/oxidative phosphorylation system (OXPHOS). Transient transfection assays indicated that the expression of the ATPsynβ gene promoter is higher in differentiated HIB-1B brown adipocytes than in non-differentiated HIB-1B cells. A major transcriptional regulatory site was identified between nt -306 and -266 in the ATPsynβ promoter. This element has a higher enhancer capacity in differentiated brown adipocyte HIB-1B cells than in non-differentiated cells. Electrophoretic shift analysis indicated that Sp1and nuclear respiratory factor-2/GA-binding protein (NRF2/GABP) were the main nuclear proteins present in brown adipose tissue that bind this site. Double-point mutant analysis indicated a major role for the NRF2/GABP site in the enhancer capacity of this element in brown fat cells. It is proposed that NRF2/GABP plays a pivotal role in the co-ordinated enhancement of OXPHOS gene expression associated with mitochondrial biogenesis in brown adipocyte differentiation.
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Tang, Eric D., and Cun-Yu Wang. "MAVS Self-Association Mediates Antiviral Innate Immune Signaling." Journal of Virology 83, no. 8 (February 4, 2009): 3420–28. http://dx.doi.org/10.1128/jvi.02623-08.
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ABSTRACT The innate immune system recognizes nucleic acids during viral infection and stimulates cellular antiviral responses. Intracellular detection of RNA virus infection is mediated by the RNA helicases RIG-I (retinoic acid inducible gene I) and MDA-5, which recognize viral RNA and signal through the adaptor molecule MAVS (mitochondrial antiviral signaling) to stimulate the phosphorylation and activation of the transcription factors IRF3 (interferon regulatory factor 3) and IRF7. Once activated, IRF3 and IRF7 turn on the expression of type I interferons, such as beta interferon. Interestingly, unlike other signaling molecules identified in this pathway, MAVS contains a C-terminal transmembrane (TM) domain that is essential for both type I interferon induction and localization of MAVS to the mitochondrial outer membrane. However, the role the MAVS TM domain plays in signaling remains unclear. Here we report the identification of a function for the TM domain in mediating MAVS self-association. The activation of RIG-I/MDA-5 leads to the TM-dependent dimerization of the MAVS N-terminal caspase recruitment domain, thereby providing an interface for direct binding to and activation of the downstream effector TRAF3 (tumor necrosis factor receptor-associated factor 3). Our results reveal a role for MAVS self-association in antiviral innate immunity signaling and provide a molecular mechanism for downstream signal transduction.
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Porter, Kim Maria Frances, Iain Parry Hargreaves, Stephen De Souza, and Rebecca Goddard. "Treatment with the direct oral anticoagulants (DOACs) apixaban and rivaroxaban associated with significant worsening of behavioural and psychological symptoms of dementia (BPSD)." BMJ Case Reports 14, no. 3 (March 2021): e240059. http://dx.doi.org/10.1136/bcr-2020-240059.
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We report the cases of two patients who developed worsening behavioural and psychological symptoms of dementia (BPSD), coinciding with starting the factor Xa inhibitor direct oral anticoagulant medications apixaban and rivaroxaban, respectively. Both patients required detaining under the Mental Health Act. Their symptoms improved significantly, within 2 weeks, on switching to alternative anticoagulant therapies and they were both discharged from the acute psychiatric ward. Front-line staff should partake in postmarketing surveillance of medications, completing the Medicines and Healthcare products Regulatory Agency yellow cards for example (UK). There is increasing evidence for an aetiological role of cerebral mitochondrial dysfunction in neuropsychiatric disorders. Development of a rating scale of drugs that are potentially less toxic to cerebral mitochondria could inform national prescribing guidelines and enable safer treatments to be offered to older people, reducing the likely hood of them experiencing apparent BPSD.
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Kim, Min Ji, Pascale Leclercq, Emilie Lanoy, Pascale Cervera, Barbara Antuna-Puente, Mustapha Maachi, Elena Dorofeev, et al. "A 6-Month Interruption of Antiretroviral Therapy Improves Adipose Tissue Function in HIV-Infected Patients: The ANRS EP29 Lipostop Study." Antiviral Therapy 12, no. 8 (November 2007): 1273–84. http://dx.doi.org/10.1177/135965350701200809.
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Objective To examine the reversibility of adipose tissue alterations in HIV-infected patients after a 6-month interruption of antiretroviral therapy (ART). Methods Forty HIV-infected patients on stable effective ART were enrolled, 33 of them completed the study. Patients underwent a physical examination, laboratory tests and needle biopsy of subcutaneous abdominal adipose tissue both at inclusion and at month 6. Changes in fat morphology, mitochondrial DNA (mtDNA) content and gene expression were examined in 29, 23 and 20 patients, respectively. Results Body fat distribution was not clearly modified at month 6. Adipose tissue inflammation improved markedly, with fewer infiltrating macrophages and fewer tumour necrosis factor a (TNFα)- and interleukin 6 (IL6)-expressing cells. Expression of peroxisome proliferator-activated receptor γ (PPAR-γ) and of markers of mitochondrial function and biogenesis (cytochrome oxidase 2 and PPAR-γ coreceptor 1α) improved after protease inhibitor (PI) withdrawal. In patients who stopped taking stavudine or zidovudine, the number of TNFα- and IL6-expressing cells was lower at month 6 than at month 0, and so was CD68 expression, a macrophage marker. Adipocyte mitochondrial status also improved, with lower mitochondrial density and cytochrome oxidase 4 mRNA levels, and higher mtDNA content. Sterol regulatory element binding protein 1 mRNA levels increased, reflecting better adipocyte differentiation. Conclusions A 6-month ART interruption markedly improved adipose tissue functions, although fat distribution did not visibly change. Stavudine and zidovudine were associated with marked inflammation, which improved when these drugs were withdrawn; they also had a negative effect on differentiation and mitochondrial status. PIs were also associated with altered adipocyte differentiation and mitochondrial status. These data clearly show the detrimental effect of antiretroviral drugs, in particular thymidine analogues, on adipose tissue and argue for switch strategies sparing these drugs.
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He, Fang, Jie-Qiong Jin, Qing-Qing Qin, Yong-Qin Zheng, Ting-Ting Li, Yun Zhang, and Jun-Dong He. "Resistin Regulates Fatty Acid Β Oxidation by Suppressing Expression of Peroxisome Proliferator Activator Receptor Gamma-Coactivator 1α (PGC-1α)." Cellular Physiology and Biochemistry 46, no. 5 (2018): 2165–72. http://dx.doi.org/10.1159/000489546.
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Background/Aims: Abnormal fatty acid β oxidation has been associated with obesity and type 2 diabetes. Resistin is an adipokine that has been considered as a potential factor in obesity-mediated insulin resistance and type 2 diabetes. However, the effect of resistin on fatty acid β oxidation needs to be elucidated. Methods: We detected the effects of resistin on the expression of fatty acid oxidation (FAO) transcriptional regulatory genes, the fatty acid transport gene, and mitochondrial β-oxidation genes using real-time PCR. The rate of FAO was measured using 14C-palmitate. Immunofluorescence assay and western blot analysis were used to explore the underlying molecular mechanisms. Results: Resistin leads to a reduction in expression of the FAO transcriptional regulatory genes ERRα and NOR1, the fatty acid transport gene CD36, and the mitochondrial β-oxidation genes CPT1, MCAD, and ACO. Importantly, treatment with resistin led to a reduction in the rate of cellular fatty acid oxidation. In addition, treatment with resistin reduced phosphorylation of acetyl CoA carboxylase (ACC) (inhibitory). Mechanistically, resistin inhibited the activation of CREB, resulting in suppression of PGC-1α. Importantly, overexpressing PGC-1α can rescue the inhibitory effects of resistin on fatty acid β oxidation. Conclusions: Activating the transcriptional activity of CREB using small molecular chemicals is a potential pharmacological strategy for preventing the inhibitory effects of resistin on fatty acid β oxidation.
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McAdams, Natalie M., Michelle L. Ammerman, Julee Nanduri, Kaylen Lott, John C. Fisk, and Laurie K. Read. "An Arginine-Glycine-Rich RNA Binding Protein Impacts the Abundance of Specific mRNAs in the Mitochondria of Trypanosoma brucei." Eukaryotic Cell 14, no. 2 (December 5, 2014): 149–57. http://dx.doi.org/10.1128/ec.00232-14.
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ABSTRACT In kinetoplastid parasites, regulation of mitochondrial gene expression occurs posttranscriptionally via RNA stability and RNA editing. In addition to the 20S editosome that contains the enzymes required for RNA editing, a dynamic complex called the mitochondrial RNA binding 1 (MRB1) complex is also essential for editing. Trypanosoma brucei RGG3 (TbRGG3) was originally identified through its interaction with the guide RNA-associated proteins 1 and 2 (GAP1/2), components of the MRB1 complex. Both the arginine-glycine-rich character of TbRGG3, which suggests a function in RNA binding, and its interaction with MRB1 implicate TbRGG3 in mitochondrial gene regulation. Here, we report an in vitro and in vivo characterization of TbRGG3 function in T. brucei mitochondria. We show that in vitro TbRGG3 binds RNA with broad sequence specificity and has the capacity to modulate RNA-RNA interactions. In vivo , inducible RNA interference (RNAi) studies demonstrate that TbRGG3 is essential for proliferation of insect vector stage T. brucei . TbRGG3 ablation does not cause a defect in RNA editing but, rather, specifically affects the abundance of two preedited transcripts as well as their edited counterparts. Protein-protein interaction studies show that TbRGG3 associates with GAP1/2 apart from the remainder of the MRB1 complex, as well as with several non-MRB1 proteins that are required for mitochondrial RNA editing and/or stability. Together, these studies demonstrate that TbRGG3 is an essential mitochondrial gene regulatory factor that impacts the stabilities of specific RNAs.
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Prasad, Manoj, Anna N. Walker, Jasmeet Kaur, James L. Thomas, Shirley A. Powell, Amit V. Pandey, Randy M. Whittal, William E. Burak, Guy Petruzzelli, and Himangshu S. Bose. "Endoplasmic Reticulum Stress Enhances Mitochondrial Metabolic Activity in Mammalian Adrenals and Gonads." Molecular and Cellular Biology 36, no. 24 (October 3, 2016): 3058–74. http://dx.doi.org/10.1128/mcb.00411-16.
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The acute response to stress consists of a series of physiological programs to promote survival by generating glucocorticoids and activating stress response genes that increase the synthesis of many chaperone proteins specific to individual organelles. In the endoplasmic reticulum (ER), short-term stress triggers activation of the unfolded protein response (UPR) module that either leads to neutralization of the initial stress or adaptation to it; chronic stress favors cell death. UPR induces expression of the transcription factor, C/EBP homology protein (CHOP), and its deletion protects against the lethal consequences of prolonged UPR. Here, we show that stress-induced CHOP expression coincides with increased metabolic activity. During stress, the ER and mitochondria come close to each other, resulting in the formation of a complex consisting of the mitochondrial translocase, translocase of outer mitochondrial membrane 22 (Tom22), steroidogenic acute regulatory protein (StAR), and 3β-hydroxysteroid dehydrogenase type 2 (3βHSD2) via its intermembrane space (IMS)-exposed charged unstructured loop region. Stress increased the circulation of phosphates, which elevated pregnenolone synthesis by 2-fold by increasing the stability of 3βHSD2 and its association with the mitochondrion-associated ER membrane (MAM) and mitochondrial proteins. In summary, cytoplasmic CHOP plays a central role in coordinating the interaction of MAM proteins with the outer mitochondrial membrane translocase, Tom22, to activate metabolic activity in the IMS by enhanced phosphate circulation.
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Aranda-Rivera, Ana Karina, Alfredo Cruz-Gregorio, Omar Emiliano Aparicio-Trejo, Edilia Tapia, Laura Gabriela Sánchez-Lozada, Fernando Enrique García-Arroyo, Isabel Amador-Martínez, Marisol Orozco-Ibarra, Francisca Fernández-Valverde, and José Pedraza-Chaverri. "Sulforaphane Protects against Unilateral Ureteral Obstruction-Induced Renal Damage in Rats by Alleviating Mitochondrial and Lipid Metabolism Impairment." Antioxidants 11, no. 10 (September 20, 2022): 1854. http://dx.doi.org/10.3390/antiox11101854.
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Unilateral ureteral obstruction (UUO) is an animal rodent model that allows the study of obstructive nephropathy in an accelerated manner. During UUO, tubular damage is induced, and alterations such as oxidative stress, inflammation, lipid metabolism, and mitochondrial impairment favor fibrosis development, leading to chronic kidney disease progression. Sulforaphane (SFN), an isothiocyanate derived from green cruciferous vegetables, might improve mitochondrial functions and lipid metabolism; however, its role in UUO has been poorly explored. Therefore, we aimed to determine the protective effect of SFN related to mitochondria and lipid metabolism in UUO. Our results showed that in UUO SFN decreased renal damage, attributed to increased mitochondrial biogenesis. We showed that SFN augmented peroxisome proliferator-activated receptor γ co-activator 1α (PGC-1α) and nuclear respiratory factor 1 (NRF1). The increase in biogenesis augmented the mitochondrial mass marker voltage-dependent anion channel (VDAC) and improved mitochondrial structure, as well as complex III (CIII), aconitase 2 (ACO2) and citrate synthase activities in UUO. In addition, lipid metabolism was improved, observed by the downregulation of cluster of differentiation 36 (CD36), sterol regulatory-element binding protein 1 (SREBP1), fatty acid synthase (FASN), and diacylglycerol O-acyltransferase 1 (DGAT1), which reduces triglyceride (TG) accumulation. Finally, restoring the mitochondrial structure reduced excessive fission by decreasing the fission protein dynamin-related protein-1 (DRP1). Autophagy flux was further restored by reducing beclin and sequestosome (p62) and increasing B-cell lymphoma 2 (Bcl2) and the ratio of microtubule-associated proteins 1A/1B light chain 3 II and I (LC3II/LC3I). These results reveal that SFN confers protection against UUO-induced kidney injury by targeting mitochondrial biogenesis, which also improves lipid metabolism.
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Liu, Xin, Yuannyu Zhang, Feng Zhou, Zhen Shao, Robert Signer, Hui Cao, Zeping Hu, Ralph DeBerardinis, and Jian Xu. "Quantitative Proteomic and Transcriptomic Analysis Reveals Post-Transcriptional Regulation of Mitochondrial Biogenesis during Erythropoiesis." Blood 126, no. 23 (December 3, 2015): 47. http://dx.doi.org/10.1182/blood.v126.23.47.47.
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Abstract The differentiation and maturation of erythroid cells require highly regulated patterns of gene expression and metabolism. Mitochondria are critical for heme biosynthesis and iron metabolism in erythroid cells, yet their regulation during normal erythroid maturation remains largely unexplored. Here we measured global protein and mRNA expression in primary human fetal liver and adult bone marrow-derived CD34+ hematopoietic stem/progenitor cells (HSPCs) and differentiated erythroid precursors (proerythroblasts or ProEs) by mass-spectrometry-based quantitative proteomics and RNA-seq analysis, respectively. In-depth proteomic profiling resulted in identification and high-quality quantification of proteins encoded by 14,502 genes, accounting for 72.4% of the total annotated protein-coding genes in humans. Through unbiased and comprehensive comparison of the proteomic and transcriptomic dynamics between primary HSPCs and committed erythroid precursors, we discovered a number of previously unrecognized regulatory pathways essential for normal erythropoiesis. Importantly, we identified key pathways related to mitochondrial biogenesis, including ATP biosynthesis, electron transport chain, oxidative phosphorylation, and cellular respiration, whose protein expression was substantially induced during erythropoiesis. Strikingly, the increases in protein expression were not paralleled by changes in mRNA expression of these genes, suggesting that they are regulated through post-transcriptional mechanisms. Consistent with the enhanced mitochondrial protein expression, we observed substantial increases in mitochondrial membrane potential (MMP) and intracellular ATP level during early erythroid differentiation before clearance of mitochondria at terminal maturation stages. We next profiled metabolite levels in HSPCs and erythroid precursors at various differentiation stages, and observed progressive progressive alterations of metabolites from the tricarboxylic acid cycle and other mitochondrial pathways during erythroid maturation. Furthermore, we identified two principal mitochondria-associated transcription factors, mitochondrial transcription factor A (TFAM) and Prohibitin 2 (PHB2), whose protein but not mRNA expression was substantially increased during erythroid maturation. Depletion of TFAM or PHB2 expression markedly impaired erythroid differentiation from primary human CD34+ HSPCs. TFAM or PHB2-deficient cells displayed impaired erythroid differentiation, proliferation and hemoglobin expression, reduced mitochondrial mass, membrane potential and ATP synthesis, and increased apoptosis. Pharmacological inhibition of mitochondrial activities by targeting mitochondrial complex I (metformin, phenformin, and rotenone), complex III (antimycin A), or complex V (oligomycin) in CD34+ HSPCs impaired erythroid differentiation in a dose-dependent manner, consistent with an essential role of mitochondria for normal erythroid development. To elucidate the regulatory mechanisms underlying the developmental control of mitochondrial biogenesis, we measured protein synthesis rate in CD34+ HSPCs and differentiated erythroid cells by analyzing the incorporation of the methionine analogue HPG (L-homopropargylglycine). The rate of HPG incorporation was the lowest in undifferentiated CD34+, and increased by 1.8 and 2.5-fold in CD71+CD235a- and CD71+CD235a+ erythroid progenitor cells, respectively. Consistent with the progressive increase in protein synthesis, we observed a gradual increase of mTORC1 signaling, as measured by the phosphorylated eIF4-E binding protein (4E-BP1) and S6 kinase (p70S6K), during erythroid differentiation of CD34+ HSPCs. Inhibition of mTORC1 signaling by active-site mTOR inhibitors markedly impaired expression of mitochondria-associated proteins, mitochondrial mass and membrane potential, and erythroid differentiation of CD34+ HSPCs. Thus, our results support a model that mitochondrial biogenesis is highly regulated through mTORC1-mediated activation of protein translation during erythroid lineage specification. Our studies also suggest a novel mechanism for proper regulation of mitochondrial biogenesis by post-transcriptional machinery, and may have direct relevance to the hematological defects associated with human mitochondrial diseases and aging. Disclosures DeBerardinis: Agios Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Peloton Therapeutics: Membership on an entity's Board of Directors or advisory committees.
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D’Anna, Silvestro E., Mauro Maniscalco, Vitina Carriero, Isabella Gnemmi, Gaetano Caramori, Francesco Nucera, Luisella Righi, et al. "Evaluation of Innate Immune Mediators Related to Respiratory Viruses in the Lung of Stable COPD Patients." Journal of Clinical Medicine 9, no. 6 (June 10, 2020): 1807. http://dx.doi.org/10.3390/jcm9061807.
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Background: Little is known about the innate immune response to viral infections in stable Chronic Obstructive Pulmonary Disease (COPD). Objectives: To evaluate the innate immune mediators related to respiratory viruses in the bronchial biopsies and lung parenchyma of stable COPD patients. Methods: We evaluated the immunohistochemical (IHC) expression of Toll-like receptors 3-7-8-9 (TLR-3-7-8-9), TIR domain-containing adaptor inducing IFNβ (TRIF), Interferon regulatory factor 3 (IRF3), Phospho interferon regulatory factor 3 ( pIRF3), Interferon regulatory factor 7 (IRF7), Phospho interferon regulatory factor 7 (pIRF7), retinoic acid-inducible gene I (RIG1), melanoma differentiation-associated protein 5 (MDA5), Probable ATP-dependent RNA helicase DHX58 ( LGP2), Mitochondrial antiviral-signaling protein (MAVS), Stimulator of interferon genes (STING), DNA-dependent activator of IFN regulatory factors (DAI), forkhead box protein A3(FOXA3), Interferon alfa (IFNα), and Interferon beta (IFNβ) in the bronchial mucosa of patients with mild/moderate (n = 16), severe/very severe (n = 18) stable COPD, control smokers (CS) (n = 12), and control non-smokers (CNS) (n = 12). We performed similar IHC analyses in peripheral lung from COPD (n = 12) and CS (n = 12). IFNα and IFNβ were assessed in bronchoalveolar lavage (BAL) supernatant from CNS (n = 8), CS (n = 9) and mild/moderate COPD (n = 12). Viral load, including adenovirus-B, -C, Bocavirus, Respiratory syncytial Virus (RSV),Human Rhinovirus (HRV), Coronavirus, Influenza virus A (FLU-A), Influenza virus B (FLU-B), and Parainfluenzae-1 were measured in bronchial rings and lung parenchyma of COPD patients and the related control group (CS). Results: Among the viral-related innate immune mediators, RIG1, LGP2, MAVS, STING, and DAI resulted well expressed in the bronchial and lung tissues of COPD patients, although not in a significantly different mode from control groups. Compared to CS, COPD patients showed no significant differences of viral load in bronchial rings and lung parenchyma. Conclusions: Some virus-related molecules are well-expressed in the lung tissue and bronchi of stable COPD patients independently of the disease severity, suggesting a “primed” tissue environment capable of sensing the potential viral infections occurring in these patients.
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Sheng, Junqin, Hongyan Li, Qin Dai, Chang Lu, Min Xu, Jisheng Zhang, and Jianxun Feng. "NR4A1 Promotes Diabetic Nephropathy by Activating Mff-Mediated Mitochondrial Fission and Suppressing Parkin-Mediated Mitophagy." Cellular Physiology and Biochemistry 48, no. 4 (2018): 1675–93. http://dx.doi.org/10.1159/000492292.
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Background/Aims: Disrupted mitochondrial dynamics, including excessive mitochondrial fission and mitophagy arrest, has been identified as a pathogenic factor in diabetic nephropathy (DN), although the upstream regulatory signal for mitochondrial fission activation and mitophagy arrest in the setting of DN remains unknown. Methods: Wild-type (WT) mice and NR4A1 knockout (NR4A1-KO) mice were used to establish a DN model. Mitochondrial fission and mitophagy were evaluated by western blotting and immunofluorescence. Mitochondrial function was assessed by JC-1 staining, the mPTP opening assay, immunofluorescence and western blotting. Renal histopathology and morphometric analyses were conducted via H&E, Masson and PASM staining. Kidney function was evaluated via ELISA, western blotting and qPCR. Results: In the present study, we found that nuclear receptor subfamily 4 group A member 1 (NR4A1) was actually activated by a chronic hyperglycemic stimulus. Higher NR4A1 expression was associated with glucose metabolism disorder, renal dysfunction, kidney hypertrophy, renal fibrosis, and glomerular apoptosis. At the molecular level, increased NR4A1 expression activated p53, and the latter selectively stimulated mitochondrial fission and inhibited mitophagy by modulating Mff and Parkin transcription. Excessive Mff-related mitochondrial fission caused mitochondrial oxidative stress, promoted mPTP opening, exacerbated proapoptotic protein leakage into the cytoplasm, and finally initiated mitochondria-dependent cellular apoptosis in the setting of diabetes. In addition, defective Parkin-mediated mitophagy repressed cellular ATP production and failed to correct the uncontrolled mitochondrial fission. However, NR4A1 knockdown interrupted the Mff-related mitochondrial fission and recused Parkin-mediated mitophagy, reducing the hyperglycemia-mediated mitochondrial damage and thus improving renal function. Conclusion: Overall, we have shown that NR4A1 functions as a novel malefactor in diabetic renal damage and operates by synchronously enhancing Mff-related mitochondrial fission and repressing Parkin-mediated mitophagy. Thus, finding strategies to regulate the balance of the NR4A1-p53 signaling pathway and mitochondrial homeostasis may be a therapeutic option for treating diabetic nephropathy in clinical practice.
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Chang, Jae Seung, and Jun Namkung. "Effects of Exercise Intervention on Mitochondrial Stress Biomarkers in Metabolic Syndrome Patients: A Randomized Controlled Trial." International Journal of Environmental Research and Public Health 18, no. 5 (February 24, 2021): 2242. http://dx.doi.org/10.3390/ijerph18052242.
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Metabolic syndrome (MetS) pathogenesis involves oxidative stress associated with mitochondrial dysfunction, which triggers integrated stress responses via various compensatory metabolic modulators like mitokines and hepatokines. However, the regulatory mechanisms underlying the exercise-derived benefits with respect to mitokines and hepatokines (potential MetS biomarkers) are unknown. Thus, we investigated the effects of exercise training on MetS biomarkers and their associations with clinical parameters. In this single-center trial, 30 women with MetS were randomly assigned to 12-week supervised exercise or control groups (1:1) and compared with 12 age-matched healthy volunteers. All participants completed the study except one subject in the control group. Expectedly, serum levels of the mitokines, fibroblast growth factor-21 (FGF21), growth differentiation factor-15 (GDF15), and the hepatokine, angiopoietin-like 6 (ANGPTL6), were higher in MetS patients than in healthy volunteers. Moreover, their levels were markedly attenuated in the exercise group. Further, exercise-mediated changes in serum FGF21 and GDF15 correlated with changes in the homeostasis model of assessment of insulin resistance (HOMA-IR) and appendicular lean mass (ALM), respectively. Additionally, changes in serum triglycerides and ANGPTL6 were correlated with changes in leptin. Aberrant mitokine and hepatokine levels can be rectified by relieving metabolic stress burden. Therefore, exercise training may reduce the need for the compensatory upregulation of MetS metabolic modulators by improving gluco-lipid metabolism.