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Journal articles on the topic 'Bioenergetic pathways'
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Sandage, Mary J., and Audrey G. Smith. "Muscle Bioenergetic Considerations for Intrinsic Laryngeal Skeletal Muscle Physiology." Journal of Speech, Language, and Hearing Research 60, no. 5 (May 24, 2017): 1254–63. http://dx.doi.org/10.1044/2016_jslhr-s-16-0192.
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PurposeIntrinsic laryngeal skeletal muscle bioenergetics, the means by which muscles produce fuel for muscle metabolism, is an understudied aspect of laryngeal physiology with direct implications for voice habilitation and rehabilitation. The purpose of this review is to describe bioenergetic pathways identified in limb skeletal muscle and introduce bioenergetic physiology as a necessary parameter for theoretical models of laryngeal skeletal muscle function.MethodA comprehensive review of the human intrinsic laryngeal skeletal muscle physiology literature was conducted. Findings regarding intrinsic laryngeal muscle fiber complement and muscle metabolism in human models are summarized and exercise physiology methodology is applied to identify probable bioenergetic pathways used for voice function.ResultsIntrinsic laryngeal skeletal muscle fibers described in human models support the fast, high-intensity physiological requirements of these muscles for biological functions of airway protection. Inclusion of muscle bioenergetic constructs in theoretical modeling of voice training, detraining, fatigue, and voice loading have been limited.ConclusionsMuscle bioenergetics, a key component for muscle training, detraining, and fatigue models in exercise science, is a little-considered aspect of intrinsic laryngeal skeletal muscle physiology. Partnered with knowledge of occupation-specific voice requirements, application of bioenergetics may inform novel considerations for voice habilitation and rehabilitation.
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Cotter, David G., Rebecca C. Schugar, and Peter A. Crawford. "Ketone body metabolism and cardiovascular disease." American Journal of Physiology-Heart and Circulatory Physiology 304, no. 8 (April 15, 2013): H1060—H1076. http://dx.doi.org/10.1152/ajpheart.00646.2012.
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Ketone bodies are metabolized through evolutionarily conserved pathways that support bioenergetic homeostasis, particularly in brain, heart, and skeletal muscle when carbohydrates are in short supply. The metabolism of ketone bodies interfaces with the tricarboxylic acid cycle, β-oxidation of fatty acids, de novo lipogenesis, sterol biosynthesis, glucose metabolism, the mitochondrial electron transport chain, hormonal signaling, intracellular signal transduction pathways, and the microbiome. Here we review the mechanisms through which ketone bodies are metabolized and how their signals are transmitted. We focus on the roles this metabolic pathway may play in cardiovascular disease states, the bioenergetic benefits of myocardial ketone body oxidation, and prospective interactions among ketone body metabolism, obesity, metabolic syndrome, and atherosclerosis. Ketone body metabolism is noninvasively quantifiable in humans and is responsive to nutritional interventions. Therefore, further investigation of this pathway in disease models and in humans may ultimately yield tailored diagnostic strategies and therapies for specific pathological states.
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Bettinazzi, Stefano, Liliana Milani, Pierre U. Blier, and Sophie Breton. "Bioenergetic consequences of sex-specific mitochondrial DNA evolution." Proceedings of the Royal Society B: Biological Sciences 288, no. 1957 (August 18, 2021): 20211585. http://dx.doi.org/10.1098/rspb.2021.1585.
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Doubly uniparental inheritance (DUI) represents a notable exception to the general rule of strict maternal inheritance (SMI) of mitochondria in metazoans. This system entails the coexistence of two mitochondrial lineages (F- and M-type) transmitted separately through oocytes and sperm, thence providing an unprecedented opportunity for the mitochondrial genome to evolve adaptively for male functions. In this study, we explored the impact of a sex-specific mitochondrial evolution upon gamete bioenergetics of DUI and SMI bivalve species, comparing the activity of key enzymes of glycolysis, fermentation, fatty acid metabolism, tricarboxylic acid cycle, oxidative phosphorylation and antioxidant metabolism. Our findings suggest reorganized bioenergetic pathways in DUI gametes compared to SMI gametes. This generally results in a decreased enzymatic capacity in DUI sperm with respect to DUI oocytes, a limitation especially prominent at the terminus of the electron transport system. This bioenergetic remodelling fits a reproductive strategy that does not require high energy input and could potentially link with the preservation of the paternally transmitted mitochondrial genome in DUI species. Whether this phenotype may derive from positive or relaxed selection acting on DUI sperm is still uncertain.
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Protasoni, M., and J. W. Taanman. "Remodelling of bioenergetic pathways in human fibroblasts with carbohydrates." Neuromuscular Disorders 27 (March 2017): S19. http://dx.doi.org/10.1016/s0960-8966(17)30273-0.
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Busch, Karin B., Gabriele Deckers-Hebestreit, Guy T. Hanke, and Armen Y. Mulkidjanian. "Dynamics of bioenergetic microcompartments." Biological Chemistry 394, no. 2 (February 1, 2013): 163–88. http://dx.doi.org/10.1515/hsz-2012-0254.
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Abstract The vast majority of life on earth is dependent on harvesting electrochemical potentials over membranes for the synthesis of ATP. Generation of membrane potential often relies on electron transport through membrane protein complexes, which vary among the bioenergetic membranes found in living organisms. In order to maximize the efficient harvesting of the electrochemical potential, energy loss must be minimized, and this is achieved partly by restricting certain events to specific microcompartments, on bioenergetic membranes. In this review we will describe the characteristics of the energy-converting supramolecular structures involved in oxidative phosphorylation in mitochondria and bacteria, and photophosphorylation. Efficient function of electron transfer pathways requires regulation of electron flow, and we will also discuss how this is partly achieved through dynamic re-compartmentation of the membrane complexes into different supercomplexes. In addition to supercomplexes, the supramolecular structure of the membrane, and in particular the role of water layers on the surface of the membrane in the prevention of wasteful proton escape (and therefore energy loss), is discussed in detail. In summary, the restriction of energetic processes to specific microcompartments on bioenergetic membranes minimizes energy loss, and dynamic rearrangement of these structures allows for regulation.
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Hippler, Michael, Kevin Redding, and Jean-David Rochaix. "Chlamydomonas genetics, a tool for the study of bioenergetic pathways." Biochimica et Biophysica Acta (BBA) - Bioenergetics 1367, no. 1-3 (October 1998): 1–62. http://dx.doi.org/10.1016/s0005-2728(98)00136-4.
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Haq, Rizwan, David E. Fisher, and Hans R. Widlund. "Molecular Pathways: BRAF Induces Bioenergetic Adaptation by Attenuating Oxidative Phosphorylation." Clinical Cancer Research 20, no. 9 (March 7, 2014): 2257–63. http://dx.doi.org/10.1158/1078-0432.ccr-13-0898.
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Cheng, Gang, Jacek Zielonka, Joy Joseph, and Balaraman Kalyanaraman. "Synergistic Lethality of Inhibitors of Bioenergetic Pathways in Pancreatic Cells." Free Radical Biology and Medicine 51 (November 2011): S120. http://dx.doi.org/10.1016/j.freeradbiomed.2011.10.312.
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Maimouni, Sara, Mi-Hye Lee, and Stephen Byers. "2427." Journal of Clinical and Translational Science 1, S1 (September 2017): 9–10. http://dx.doi.org/10.1017/cts.2017.49.
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OBJECTIVES/SPECIFIC AIMS: The goal of this study is to examine bioenergetic phenotype of retinoic acid receptor responder 1 (RARRES1)-depleted epithelial cells and to facilitate the discovery of personalized metabo-therapeutics in the context of cancers characterized with loss of or low expression of RARRES1. METHODS/STUDY POPULATION: Anoikis assay and annexinV labeling were used to assess drug resistance and apoptotic phenotype in RARRES1-depleted epithelial cells. Metabolomics, AMP kinase activity, mito-tracker, and extracellular flux assays were used to examine the bioenergetic profile of RARRES1-depleted epithelial cells. Extracellular flux assays were used to assess the phenotype of RARRES1-depleted epithelial cells treated with or without metformin. RESULTS/ANTICIPATED RESULTS: RARRES1 is a major regulator of mitochondrial function. Its depletion in tumors induces an oxidative phosphorylation dependent phenotype and subsequently increases ATP abundance in the cell, enhances anabolic pathways and increases survival. Treatment with FDA approved mitochondrial respiration inhibitor, metformin, reversed the metabolic phenotype of RARRES1 depleted-epithelial cells. Metformin could be the ideal therapeutics to reduce tumor burden in cancers with loss of or low expression of RARRES1. DISCUSSION/SIGNIFICANCE OF IMPACT: Bioenergetic dynamics are emerging as a basis for understanding the pathology of cancer. The malignancy progresses as its metabolic pattern and mitochondrial respiration become more dysfunctional. The regulatory pathways of bioenergetic dynamics are currently poorly understood, and the characterization of proteins implicated in those processes must be assessed. One understudied protein and tumor suppressor is RARRES1. RARRES1 is induced by retinoic acid (a major metabolic regulator) and functions as a putative carboxypeptidase inhibitor. Understanding the connection between this carboxypeptidase inhibitor and intermediary metabolism will enlighten our understanding of the bioenergetic profile of cells and facilitate the discovery of personalized metabo-therapeutics in the context of cancer.
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Riddle, Ryan C., and Thomas L. Clemens. "Bone Cell Bioenergetics and Skeletal Energy Homeostasis." Physiological Reviews 97, no. 2 (April 2017): 667–98. http://dx.doi.org/10.1152/physrev.00022.2016.
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The rising incidence of metabolic diseases worldwide has prompted renewed interest in the study of intermediary metabolism and cellular bioenergetics. The application of modern biochemical methods for quantitating fuel substrate metabolism with advanced mouse genetic approaches has greatly increased understanding of the mechanisms that integrate energy metabolism in the whole organism. Examination of the intermediary metabolism of skeletal cells has been sparked by a series of unanticipated observations in genetically modified mice that suggest the existence of novel endocrine pathways through which bone cells communicate their energy status to other centers of metabolic control. The recognition of this expanded role of the skeleton has in turn led to new lines of inquiry directed at defining the fuel requirements and bioenergetic properties of bone cells. This article provides a comprehensive review of historical and contemporary studies on the metabolic properties of bone cells and the mechanisms that control energy substrate utilization and bioenergetics. Special attention is devoted to identifying gaps in our current understanding of this new area of skeletal biology that will require additional research to better define the physiological significance of skeletal cell bioenergetics in human health and disease.
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Vara-Perez, Monica, Blanca Felipe-Abrio, and Patrizia Agostinis. "Mitophagy in Cancer: A Tale of Adaptation." Cells 8, no. 5 (May 22, 2019): 493. http://dx.doi.org/10.3390/cells8050493.
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In the past years, we have learnt that tumors co-evolve with their microenvironment, and that the active interaction between cancer cells and stromal cells plays a pivotal role in cancer initiation, progression and treatment response. Among the players involved, the pathways regulating mitochondrial functions have been shown to be crucial for both cancer and stromal cells. This is perhaps not surprising, considering that mitochondria in both cancerous and non-cancerous cells are decisive for vital metabolic and bioenergetic functions and to elicit cell death. The central part played by mitochondria also implies the existence of stringent mitochondrial quality control mechanisms, where a specialized autophagy pathway (mitophagy) ensures the selective removal of damaged or dysfunctional mitochondria. Although the molecular underpinnings of mitophagy regulation in mammalian cells remain incomplete, it is becoming clear that mitophagy pathways are intricately linked to the metabolic rewiring of cancer cells to support the high bioenergetic demand of the tumor. In this review, after a brief introduction of the main mitophagy regulators operating in mammalian cells, we discuss emerging cell autonomous roles of mitochondria quality control in cancer onset and progression. We also discuss the relevance of mitophagy in the cellular crosstalk with the tumor microenvironment and in anti-cancer therapy responses.
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Murphy, Anne N., Gary Fiskum, and M. Flint Beal. "Mitochondria in Neurodegeneration: Bioenergetic Function in Cell Life and Death." Journal of Cerebral Blood Flow & Metabolism 19, no. 3 (March 1999): 231–45. http://dx.doi.org/10.1097/00004647-199903000-00001.
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The biochemical pathways to cell death in chronic and acute forms of neurodegeneration are poorly understood, limiting the ability to develop effective therapeutic approaches. As details of the apoptotic and necrotic pathways have been revealed, an appreciation for the decisive role that mitochondria play in life-death decisions for the cell has grown. As a result, the need has arisen to reevaluate the significance to cell viability of mitochondrial Ca2+ sequestration, reactive oxygen species generation, and the membrane permeability transition. This review provides basic information on these mitochondrial functions as they relate to control over cell death.
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Langley, Raymond J., Marie M. Migaud, D. Clark Files, and Peter Morris. "66942 Metabolomic endotype of bioenergetic dysfunction predicts mortality in critically ill patients with acute respiratory failure." Journal of Clinical and Translational Science 5, s1 (March 2021): 105. http://dx.doi.org/10.1017/cts.2021.669.
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ABSTRACT IMPACT: The pathophysiologic features of a metabolomic endotype that predicts patient outcomes due to sepsis have the potential to direct new therapies that target immune dysregulation and bioenergetic insufficiency. OBJECTIVES/GOALS: Acute respiratory failure (ARF) requiring mechanical ventilation is a frequent complication of sepsis and other disorders. It is associated with high morbidity and mortality. Despite its severity and prevalence, little is known about metabolic and bioenergetic changes that accompanying ARF. METHODS/STUDY POPULATION: In this study, semiquantitative and quantitative ultrahigh performance liquid chromatography mass spectrometry (UHPLC MS) analysis was performed on patient serum collected from the Trial with Acute Respiratory failure patients: evaluation of Global Exercise Therapies (TARGET). Serum from survivors (n=15) and nonsurvivors (n=15) was collected at day 1 and day 3 after admission to the medical intensive care unit as well as at discharge in survivors. Pathway analysis of the biochemical changes was performed to determine whether the disruption in specific metabolic pathways can identify the bioenergetic and metabolomic profile of these patients. RESULTS/ANTICIPATED RESULTS: Significant metabolomic differences were related to biosynthetic intermediates of redox cofactors nicotinamide adenine dinucleotide (NAD) and NAD phosphate (NADP), increased acyl-carnitines, and decreased acyl-glycerophosphocholines in nonsurvivors compared to survivors. The metabolites associated with poor outcomes are substrates of enzymatic processes dependent on NAD(P), while the abundance of NAD cofactors rely on the bioavailability of dietary vitamins B1, B2 and B6. Changes in the efficiency of the nicotinamide-derived cofactors’ biosynthetic pathways also associate with an alteration of the glutathione-dependent drug metabolism as characterized by the substantial differences observed in the acetaminophen metabolome. DISCUSSION/SIGNIFICANCE OF FINDINGS: This metabolomic endotype represents a previously unappreciated association between severity of outcomes and micronutrient deficiency, thus pointing to new pharmacologic targets and highlighting the need for nutritional remediation upon hospitalization to improve patient outcomes due to ARF.
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Simonetti, Giorgia, Antonella Padella, Ítalo Faria do Valle, Gabriele Fontanarosa, Elisa Zago, Marianna Garonzi, Cristina Papayannidis, et al. "Novel Genomic Patterns of Metabolic Remodeling in Acute Myeloid Leukemia." Blood 126, no. 23 (December 3, 2015): 3837. http://dx.doi.org/10.1182/blood.v126.23.3837.3837.
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Abstract Metabolic remodeling of cancer is controlled by metabolic enzymes having oncogenic or tumor suppressor functions, along with oncogenes and tumor suppressors, which cooperate with the tissue environment to define specific metabolic profiles (Yuneva et al. Cell met 2012). Dysregulated metabolic pathways contribute to the pathogenesis of Acute Myeloid Leukemia (AML), as demonstrated for IDH1/2 mutations, which force the production of the oncometabolite 2-Hydroxyglutarate (Ward et al. Cancer Cell 2010) and can be selectively targeted (Wang et al. Science 2013). However, the genetic determinants of leukemia metabolic plasticity are largely unexplored. To identify metabolism-related pathogenic mechanisms in AML, we screened 886 AML cases for targeted genomic alterations and performed Whole Exome Sequencing of 143 leukemia samples (100 bp paired-end, HiSeq2000, Illumina), focusing our analysis on 37 AML cases (34 at diagnosis and 3 at relapse). Mutations were called by MuTect and GATK. Moreover, transcriptional analysis was performed on bone marrow cells from 59 AML cases (≥80% blasts) and 7 healthy controls (HTA2.0, Affymetrix). By mapping the mutated genes into functional categories, we identified a previously undescribed class of mutations targeting metabolism-related genes, that we define metabolic acute leukemia genes (MALGs). MALG was the most represented category after signaling pathways (76/915 genomic alterations) and 29/37 patients carried at least one MALG mutation. MALG mutations mostly targeted biosynthesis and catabolism of lipids and of CoA (ACP2, PANK2), bioenergetic pathways, metabolism of amino acids and nucleotides (NUDT18, IMPDH2). Notably, IMPDH2 is a target of MYC, a known regulator of cancer cell metabolism, and balances the nucleotide pool required for DNA replication (Liu et al, Plos one 2008). IMPDH2 was not only mutated but also upregulated at mRNA level in AML compared with controls (p=0.0001), suggesting an oncogenic function of the gene in AML, which is under investigation. Moreover, MYC transcriptional network was affected by additional mutations targeting genes regulating MYC activity (HUWE1, ZBTB17, TRRAP) and degradation (HEPACAM). Mutations in amino acid metabolism affected the synthesis/degradation of serine (PHGDH), glycine (SHMT2), proline (PRODH), tryptophan(CYP1B1) and glutamate (OPLAH), with a glutamate-related metabolic signature being also enriched in AML. These results may be highly relevant to AML therapy, since they may identify patients suitable to glutaminase inhibitor treatment, which is under development by pharmaceutical companies. An additional subset of patients displayed mutations in glucose-dependent bioenergetic pathways: glycolysis (GPI), oxidative phosphorylation (ND1, ND4, ND5, CYTB) and pentose phosphate pathway (H6PD, PGLS). These mutations were mutually exclusive with KRAS/NRAS alterations, which were detected in 8/37 samples. Indeed, oncogenic KRAS stimulates glucose uptake and channeling of glucose intermediates into pentose phosphate pathway (Ying et al. Cell 2012). Mutations in the bioenergetic pathways occurred across different cytogenetic groups and were associated with a poor outcome in terms of overall survival (p=0.016 Fig.1) in our AML cohort. Along with mutations in KRAS- and MYC-oncogenic pathways, which are known to control metabolic processes, we identified a novel functional category of mutated genes involved in metabolism (MALG) in AML. Our results may suggest different types of metabolic remodeling across leukemia subgroups. Mutations targeting a common downstream metabolic pathway are mutually exclusive in our cohort, as shown by KRAS and genes involved in glucose-dependent bioenergetic processes. Glucose metabolism predicts clinical outcome and chemotherapy response in AML (Chen et al. Blood 2014). Our data further suggest that the mutational screening of glucose-related MALGs may define a new subgroup of patients, which could not be identified by cytogenetic analysis. These findings may have implication for AML treatment, since metabolic alterations and genomic determinants of metabolic remodeling are promising targets for tailored therapies, as recently shown for glutaminase and IDH1/2 inhibitors. Acknowledgments: EHA Research Fellowship award, FP7 NGS-PTL project, ELN, AIL, AIRC, progetto Regione-Università 2010-12 Disclosures Soverini: Novartis, Briston-Myers Squibb, ARIAD: Consultancy. Cavo:JANSSEN, CELGENE, AMGEN: Consultancy. Martinelli:Novartis: Consultancy, Speakers Bureau; Pfizer: Consultancy; MSD: Consultancy; Ariad: Consultancy; BMS: Consultancy, Speakers Bureau; ROCHE: Consultancy; AMGEN: Consultancy.
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Allmer, Jens, Bianca Naumann, Christine Markert, Monica Zhang, and Michael Hippler. "Mass spectrometric genomic data mining: Novel insights into bioenergetic pathways inChlamydomonas reinhardtii." PROTEOMICS 6, no. 23 (December 2006): 6207–20. http://dx.doi.org/10.1002/pmic.200600208.
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Swerdlow, Natalie S., and Heather M. Wilkins. "Mitophagy and the Brain." International Journal of Molecular Sciences 21, no. 24 (December 18, 2020): 9661. http://dx.doi.org/10.3390/ijms21249661.
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Stress mechanisms have long been associated with neuronal loss and neurodegenerative diseases. The origin of cell stress and neuronal loss likely stems from multiple pathways. These include (but are not limited to) bioenergetic failure, neuroinflammation, and loss of proteostasis. Cells have adapted compensatory mechanisms to overcome stress and circumvent death. One mechanism is mitophagy. Mitophagy is a form of macroautophagy, were mitochondria and their contents are ubiquitinated, engulfed, and removed through lysosome degradation. Recent studies have implicated mitophagy dysregulation in several neurodegenerative diseases and clinical trials are underway which target mitophagy pathways. Here we review mitophagy pathways, the role of mitophagy in neurodegeneration, potential therapeutics, and the need for further study.
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DeBerardinis, Ralph J., and Navdeep S. Chandel. "Fundamentals of cancer metabolism." Science Advances 2, no. 5 (May 2016): e1600200. http://dx.doi.org/10.1126/sciadv.1600200.
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Tumors reprogram pathways of nutrient acquisition and metabolism to meet the bioenergetic, biosynthetic, and redox demands of malignant cells. These reprogrammed activities are now recognized as hallmarks of cancer, and recent work has uncovered remarkable flexibility in the specific pathways activated by tumor cells to support these key functions. In this perspective, we provide a conceptual framework to understand how and why metabolic reprogramming occurs in tumor cells, and the mechanisms linking altered metabolism to tumorigenesis and metastasis. Understanding these concepts will progressively support the development of new strategies to treat human cancer.
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Iacobini, Carla, Martina Vitale, Giuseppe Pugliese, and Stefano Menini. "Normalizing HIF-1α Signaling Improves Cellular Glucose Metabolism and Blocks the Pathological Pathways of Hyperglycemic Damage." Biomedicines 9, no. 9 (September 2, 2021): 1139. http://dx.doi.org/10.3390/biomedicines9091139.
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Intracellular metabolism of excess glucose induces mitochondrial dysfunction and diversion of glycolytic intermediates into branch pathways, leading to cell injury and inflammation. Hyperglycemia-driven overproduction of mitochondrial superoxide was thought to be the initiator of these biochemical changes, but accumulating evidence indicates that mitochondrial superoxide generation is dispensable for diabetic complications development. Here we tested the hypothesis that hypoxia inducible factor (HIF)-1α and related bioenergetic changes (Warburg effect) play an initiating role in glucotoxicity. By using human endothelial cells and macrophages, we demonstrate that high glucose (HG) induces HIF-1α activity and a switch from oxidative metabolism to glycolysis and its principal branches. HIF1-α silencing, the carbonyl-trapping and anti-glycating agent ʟ-carnosine, and the glyoxalase-1 inducer trans-resveratrol reversed HG-induced bioenergetics/biochemical changes and endothelial-monocyte cell inflammation, pointing to methylglyoxal (MGO) as the non-hypoxic stimulus for HIF1-α induction. Consistently, MGO mimicked the effects of HG on HIF-1α induction and was able to induce a switch from oxidative metabolism to glycolysis. Mechanistically, methylglyoxal causes HIF1-α stabilization by inhibiting prolyl 4-hydroxylase domain 2 enzyme activity through post-translational glycation. These findings introduce a paradigm shift in the pathogenesis and prevention of diabetic complications by identifying HIF-1α as essential mediator of glucotoxicity, targetable with carbonyl-trapping agents and glyoxalase-1 inducers.
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Monk, Chandler H., and Kevin J. Zwezdaryk. "Host Mitochondrial Requirements of Cytomegalovirus Replication." Current Clinical Microbiology Reports 7, no. 4 (September 30, 2020): 115–23. http://dx.doi.org/10.1007/s40588-020-00153-5.
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Abstract Purpose of Review Metabolic rewiring of the host cell is required for optimal viral replication. Human cytomegalovirus (HCMV) has been observed to manipulate numerous mitochondrial functions. In this review, we describe the strategies and targets HCMV uses to control different aspects of mitochondrial function. Recent Findings The mitochondria are instrumental in meeting the biosynthetic and bioenergetic needs of HCMV replication. This is achieved through altered metabolism and signaling pathways. Morphological changes mediated through biogenesis and fission/fusion dynamics contribute to strategies to avoid cell death, overcome oxidative stress, and maximize the biosynthetic and bioenergetic outputs of mitochondria. Summary Emerging data suggests that cytomegalovirus relies on intact, functional host mitochondria for optimal replication. HCMV large size and slow replication kinetics create a dependency on mitochondria during replication. Targeting the host mitochondria is an attractive antiviral target.
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Forsberg, J., M. Rosenquist, L. Fraysse, and J. F. Allen. "Redox signalling in chloroplasts and mitochondria: genomic and biochemical evidence for two-component regulatory systems in bioenergetic organelles." Biochemical Society Transactions 29, no. 4 (August 1, 2001): 403–7. http://dx.doi.org/10.1042/bst0290403.
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Redox chemistry is central to the primary functions of chloroplasts and mitochondria, that is, to energy conversion in photosynthesis and respiration. However, these bioenergetic organelles always contain very small, specialized genetic systems, relics of their bacterial origin. At huge cost, organellar genomes contain, typically, a mere 0.1 % of the genetic information in a eukaryotic cell. There is evidence that chloroplast and mitochondrial genomes encode proteins whose function and biogenesis are particularly tightly governed by electron transfer. We have identified nuclear genes for ‘bacterial’ histidine sensor kinases and aspartate response regulators that seem to be targeted to chloroplast and mitochondrial membranes. Sequence similarities to cyano-bacterial redox signalling components indicate homology and suggest conserved sensory and signalling functions. Two-component redox signalling pathways might be ancient, conserved mechanisms that permit endogenous control over the biogenesis, in situ, of bioenergetic complexes of chloroplasts and mitochondria.
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McLaggan, D., M. Keyhan, and A. Matin. "Chloride transport pathways and their bioenergetic implications in the obligate acidophile Bacillus coagulans." Journal of Bacteriology 172, no. 3 (1990): 1485–90. http://dx.doi.org/10.1128/jb.172.3.1485-1490.1990.
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Dell'Antone, Paolo. "Metabolic pathways in Ehrlich ascites tumor cells recovering from a low bioenergetic status." FEBS Letters 350, no. 2-3 (August 22, 1994): 183–86. http://dx.doi.org/10.1016/0014-5793(94)00759-4.
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Gyllenhammer, Lauren E., Sonja Entringer, Claudia Buss, and Pathik D. Wadhwa. "Developmental programming of mitochondrial biology: a conceptual framework and review." Proceedings of the Royal Society B: Biological Sciences 287, no. 1926 (April 29, 2020): 20192713. http://dx.doi.org/10.1098/rspb.2019.2713.
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Research on mechanisms underlying the phenomenon of developmental programming of health and disease has focused primarily on processes that are specific to cell types, organs and phenotypes of interest. However, the observation that exposure to suboptimal or adverse developmental conditions concomitantly influences a broad range of phenotypes suggests that these exposures may additionally exert effects through cellular mechanisms that are common, or shared, across these different cell and tissue types. It is in this context that we focus on cellular bioenergetics and propose that mitochondria, bioenergetic and signalling organelles, may represent a key cellular target underlying developmental programming. In this review, we discuss empirical findings in animals and humans that suggest that key structural and functional features of mitochondrial biology exhibit developmental plasticity, and are influenced by the same physiological pathways that are implicated in susceptibility for complex, common age-related disorders, and that these targets of mitochondrial developmental programming exhibit long-term temporal stability. We conclude by articulating current knowledge gaps and propose future research directions to bridge these gaps.
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Kappler, Lisa, Miriam Hoene, Chunxiu Hu, Christine von Toerne, Jia Li, Daniel Bleher, Christoph Hoffmann, et al. "Linking bioenergetic function of mitochondria to tissue-specific molecular fingerprints." American Journal of Physiology-Endocrinology and Metabolism 317, no. 2 (August 1, 2019): E374—E387. http://dx.doi.org/10.1152/ajpendo.00088.2019.
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Mitochondria are dynamic organelles with diverse functions in tissues such as liver and skeletal muscle. To unravel the mitochondrial contribution to tissue-specific physiology, we performed a systematic comparison of the mitochondrial proteome and lipidome of mice and assessed the consequences hereof for respiration. Liver and skeletal muscle mitochondrial protein composition was studied by data-independent ultra-high-performance (UHP)LC-MS/MS-proteomics, and lipid profiles were compared by UHPLC-MS/MS lipidomics. Mitochondrial function was investigated by high-resolution respirometry in samples from mice and humans. Enzymes of pyruvate oxidation as well as several subunits of complex I, III, and ATP synthase were more abundant in muscle mitochondria. Muscle mitochondria were enriched in cardiolipins associated with higher oxidative phosphorylation capacity and flexibility, in particular CL(18:2)4 and 22:6-containing cardiolipins. In contrast, protein equipment of liver mitochondria indicated a shuttling of complex I substrates toward gluconeogenesis and ketogenesis and a higher preference for electron transfer via the flavoprotein quinone oxidoreductase pathway. Concordantly, muscle and liver mitochondria showed distinct respiratory substrate preferences. Muscle respired significantly more on the complex I substrates pyruvate and glutamate, whereas in liver maximal respiration was supported by complex II substrate succinate. This was a consistent finding in mouse liver and skeletal muscle mitochondria and human samples. Muscle mitochondria are tailored to produce ATP with a high capacity for complex I-linked substrates. Liver mitochondria are more connected to biosynthetic pathways, preferring fatty acids and succinate for oxidation. The physiologic diversity of mitochondria may help to understand tissue-specific disease pathologies and to develop therapies targeting mitochondrial function.
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Shen, Han, Cecilia Chang, Harriet Gee, Geraldine O’Neill, Victoria Prior, Anneke Blackburn, and Eric Hau. "DIPG-17. IMPROVING THE RADIOSENSITIVITY OF DIFFUSE INTRINSIC PONTINE GLIOMAS BY MODULATING BIOENERGETIC PATHWAYS." Neuro-Oncology 21, Supplement_2 (April 2019): ii72. http://dx.doi.org/10.1093/neuonc/noz036.038.
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Huang, Shih-Hao, and Yu-Wei Lin. "Bioenergetic Health Assessment of a Single Caenorhabditis elegans from Postembryonic Development to Aging Stages via Monitoring Changes in the Oxygen Consumption Rate within a Microfluidic Device." Sensors 18, no. 8 (July 28, 2018): 2453. http://dx.doi.org/10.3390/s18082453.
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Monitoring dynamic changes in oxygen consumption rates (OCR) of a living organism in real time provide an indirect method of monitoring changes in mitochondrial function during development, aging, or malfunctioning processes. In this study, we developed a microfluidic device integrated with an optical detection system to measure the OCR of a single developing Caenorhabditis elegans (C. elegans) from postembryonic development to aging stages in real time via phase-based phosphorescence lifetime measurement. The device consists of two components: an acrylic microwell deposited with an oxygen-sensitive luminescent layer for oxygen (O2) measurement and a microfluidic module with a pneumatically driven acrylic lid to controllably seal the microwell. We successfully measured the basal respiration (basal OCR, in pmol O2/min/worm) of a single C. elegans inside a microwell from the stages of postembryonic development (larval stages) through adulthood to aged adult. Sequentially adding metabolic inhibitors to block bioenergetic pathways allowed us to measure the metabolic profiles of a single C. elegans at key growth and aging stages, determining the following fundamental parameters: basal OCR, adenosine triphosphate (ATP)-linked OCR, maximal OCR, reserve respiratory capacity, OCR due to proton leak, and non-mitochondrial OCR. The bioenergetic health index (BHI) was calculated from these fundamental parameters to assess the bioenergetic health of a single developing C. elegans from the postembryonic development to aging stages. The changes in BHI are correlated to C. elegans development stage, with the highest BHI = 27.5 for 4-day-old adults, which possess well-developed bioenergetic functionality. Our proposed platform demonstrates for the first time the feasibility of assessing the BHI of a single C. elegans from postembryonic development to aging stages inside a microfluidic device and provides the potential for a wide variety of biomedical applications that relate mitochondrial malfunction and diseases.
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Parsons, Melissa J., and Douglas R. Green. "Mitochondria in cell death." Essays in Biochemistry 47 (June 14, 2010): 99–114. http://dx.doi.org/10.1042/bse0470099.
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Apoptosis can be thought of as a signalling cascade that results in the death of the cell. Properly executed apoptosis is critically important for both development and homoeostasis of most animals. Accordingly, defects in apoptosis can contribute to the development of autoimmune disorders, neurological diseases and cancer. Broadly speaking, there are two main pathways by which a cell can engage apoptosis: the extrinsic apoptotic pathway and the intrinsic apoptotic pathway. At the centre of the intrinsic apoptotic signalling pathway lies the mitochondrion, which, in addition to its role as the bioenergetic centre of the cell, is also the cell’s reservoir of pro-death factors which reside in the mitochondrial IMS (intermembrane space). During intrinsic apoptosis, pores are formed in the OMM (outer mitochondrial membrane) of the mitochondria in a process termed MOMP (mitochondrial outer membrane permeabilization). This allows for the release of IMS proteins; once released during MOMP, some IMS proteins, notably cytochrome c and Smac/DIABLO (Second mitochondria-derived activator of caspase/direct inhibitor of apoptosis-binding protein with low pI), promote caspase activation and subsequent cleavage of structural and regulatory proteins in the cytoplasm and the nucleus, leading to the demise of the cell. MOMP is achieved through the co-ordinated actions of pro-apoptotic members and inhibited by anti-apoptotic members of the Bcl-2 family of proteins. Other aspects of mitochondrial physiology, such as mitochondrial bioenergetics and dynamics, are also involved in processes of cell death that proceed through the mitochondria. Proper regulation of these mitochondrial functions is vitally important for the life and death of the cell and for the organism as a whole.
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Boyd, Eric S., Maximiliano J. Amenabar, Saroj Poudel, and Alexis S. Templeton. "Bioenergetic constraints on the origin of autotrophic metabolism." Philosophical Transactions of the Royal Society A: Mathematical, Physical and Engineering Sciences 378, no. 2165 (January 6, 2020): 20190151. http://dx.doi.org/10.1098/rsta.2019.0151.
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Autotrophs form the base of all complex food webs and seemingly have done so since early in Earth history. Phylogenetic evidence suggests that early autotrophs were anaerobic, used CO 2 as both an oxidant and carbon source, were dependent on H 2 as an electron donor, and used iron-sulfur proteins (termed ferredoxins) as a primary electron carrier. However, the reduction potential of H 2 is not typically low enough to efficiently reduce ferredoxin. Instead, in modern strictly anaerobic and H 2 -dependent autotrophs, ferredoxin reduction is accomplished using one of several recently evolved enzymatic mechanisms, including electron bifurcating and coupled ion translocating mechanisms. These observations raise the intriguing question of why anaerobic autotrophs adopted ferredoxins as central electron carriers only to have to evolve complex machinery to reduce them. Here, we report calculated reduction potentials for H 2 as a function of observed environmental H 2 concentration, pH and temperature. Results suggest that a combination of alkaline pH and high H 2 concentration yield H 2 reduction potentials low enough to efficiently reduce ferredoxins. Hyperalkaline, H 2 rich environments have existed in discrete locations throughout Earth history where ultramafic minerals are undergoing hydration through the process of serpentinization. These results suggest that serpentinizing systems, which would have been common on early Earth, naturally produced conditions conducive to the emergence of H 2 -dependent autotrophic life. The primitive process of hydrogenotrophic methanogenesis is used to examine potential changes in methanogenesis and Fd reduction pathways as these organisms diversified away from serpentinizing environments. This article is part of a discussion meeting issue ‘Serpentinite in the earth system’.
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Padhi, Abinash, Alexander H. Thomson, Justin B. Perry, Grace N. Davis, Ryan P. McMillan, Sandra Loesgen, Elizabeth N. Kaweesa, Rakesh Kapania, Amrinder S. Nain, and David A. Brown. "Bioenergetics underlying single-cell migration on aligned nanofiber scaffolds." American Journal of Physiology-Cell Physiology 318, no. 3 (March 1, 2020): C476—C485. http://dx.doi.org/10.1152/ajpcell.00221.2019.
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Cell migration is centrally involved in a myriad of physiological processes, including morphogenesis, wound healing, tissue repair, and metastatic growth. The bioenergetics that underlie migratory behavior are not fully understood, in part because of variations in cell culture media and utilization of experimental cell culture systems that do not model physiological connective extracellular fibrous networks. In this study, we evaluated the bioenergetics of C2C12 myoblast migration and force production on fibronectin-coated nanofiber scaffolds of controlled diameter and alignment, fabricated using a nonelectrospinning spinneret-based tunable engineered parameters (STEP) platform. The contribution of various metabolic pathways to cellular migration was determined using inhibitors of cellular respiration, ATP synthesis, glycolysis, or glucose uptake. Despite immediate effects on oxygen consumption, mitochondrial inhibition only modestly reduced cell migration velocity, whereas inhibitors of glycolysis and cellular glucose uptake led to striking decreases in migration. The migratory metabolic sensitivity was modifiable based on the substrates present in cell culture media. Cells cultured in galactose (instead of glucose) showed substantial migratory sensitivity to mitochondrial inhibition. We used nanonet force microscopy to determine the bioenergetic factors responsible for single-cell force production and observed that neither mitochondrial nor glycolytic inhibition altered single-cell force production. These data suggest that myoblast migration is heavily reliant on glycolysis in cells grown in conventional media. These studies have wide-ranging implications for the causes, consequences, and putative therapeutic treatments aimed at cellular migration.
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Chevalier, Robert L. "Bioenergetic Evolution Explains Prevalence of Low Nephron Number at Birth: Risk Factor for CKD." Kidney360 1, no. 8 (July 7, 2020): 863–79. http://dx.doi.org/10.34067/kid.0002012020.
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There is greater than tenfold variation in nephron number of the human kidney at birth. Although low nephron number is a recognized risk factor for CKD, its determinants are poorly understood. Evolutionary medicine represents a new discipline that seeks evolutionary explanations for disease, broadening perspectives on research and public health initiatives. Evolution of the kidney, an organ rich in mitochondria, has been driven by natural selection for reproductive fitness constrained by energy availability. Over the past 2 million years, rapid growth of an energy-demanding brain in Homo sapiens enabled hominid adaptation to environmental extremes through selection for mutations in mitochondrial and nuclear DNA epigenetically regulated by allocation of energy to developing organs. Maternal undernutrition or hypoxia results in intrauterine growth restriction or preterm birth, resulting in low birth weight and low nephron number. Regulated through placental transfer, environmental oxygen and nutrients signal nephron progenitor cells to reprogram metabolism from glycolysis to oxidative phosphorylation. These processes are modulated by counterbalancing anabolic and catabolic metabolic pathways that evolved from prokaryote homologs and by hypoxia-driven and autophagy pathways that evolved in eukaryotes. Regulation of nephron differentiation by histone modifications and DNA methyltransferases provide epigenetic control of nephron number in response to energy available to the fetus. Developmental plasticity of nephrogenesis represents an evolved life history strategy that prioritizes energy to early brain growth with adequate kidney function through reproductive years, the trade-off being increasing prevalence of CKD delayed until later adulthood. The research implications of this evolutionary analysis are to identify regulatory pathways of energy allocation directing nephrogenesis while accounting for the different life history strategies of animal models such as the mouse. The clinical implications are to optimize nutrition and minimize hypoxic/toxic stressors in childbearing women and children in early postnatal development.
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Naumann, Bianca, Andreas Busch, Jens Allmer, Elisabeth Ostendorf, Martin Zeller, Helmut Kirchhoff, and Michael Hippler. "Comparative quantitative proteomics to investigate the remodeling of bioenergetic pathways under iron deficiency inChlamydomonas reinhardtii." PROTEOMICS 7, no. 21 (November 2007): 3964–79. http://dx.doi.org/10.1002/pmic.200700407.
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Yin, Fei, Tianyi Jiang, and Enrique Cadenas. "Metabolic triad in brain aging: mitochondria, insulin/IGF-1 signalling and JNK signalling." Biochemical Society Transactions 41, no. 1 (January 29, 2013): 101–5. http://dx.doi.org/10.1042/bst20120260.
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Mitochondria generate second messengers, such as H2O2, that are involved in the redox regulation of cell signalling and their function is regulated by several cytosolic signalling pathways. IIS [insulin/IGF1 (insulin-like growth factor 1) signalling] in the brain proceeds mainly through the PI3K (phosphatidylinositol 3-kinase)–Akt (protein kinase B) pathway, which is involved in the regulation of synaptic plasticity and neuronal survival via the maintenance of the bioenergetic and metabolic capacities of mitochondria. Conversely, the JNK (c-Jun N-terminal kinase) pathway is induced by increased oxidative stress and JNK translocation to the mitochondrion results in impairment of energy metabolism. Moreover, IIS and JNK signalling interact with and antagonize each other. This review focuses on functional outcomes of a metabolic triad that entails the co-ordination of mitochondrial function (energy transducing and redox regulation), IIS and JNK signalling, in the aging brain and in neurodegenerative disorders, such as Alzheimer's disease.
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Tamarindo, Guilherme H., Daniele L. Ribeiro, Marina G. Gobbo, Luiz H. A. Guerra, Paula Rahal, Sebastião R. Taboga, Fernanda R. Gadelha, and Rejane M. Góes. "Melatonin and Docosahexaenoic Acid Decrease Proliferation of PNT1A Prostate Benign Cells via Modulation of Mitochondrial Bioenergetics and ROS Production." Oxidative Medicine and Cellular Longevity 2019 (January 9, 2019): 1–15. http://dx.doi.org/10.1155/2019/5080798.
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Prostate cancer development has been associated with changes in mitochondrial activity and reactive oxygen species (ROS) production. Melatonin (MLT) and docosahexaenoic acid (DHA) have properties to modulate both, but their protective role, mainly at early stages of prostate cancer, remains unclear. In this study, the effects of MLT and DHA, combined or not, on PNT1A cells with regard to mitochondria bioenergetics, ROS production, and proliferation-related pathways were examined. Based on dose response and lipid accumulation assays, DHA at 100 μM and MLT at 1 μM for 48 h were chosen. DHA doubled and MLT reduced (40%) superoxide anion production, but coincubation (DM) did not normalize to control. Hydrogen peroxide production decreased after MLT incubation only (p<0.01). These alterations affected the area and perimeter of mitochondria, since DHA increased whereas MLT decreased, but such hormone has no effect on coincubation. DHA isolated did not change the oxidative phosphorylation rate (OXPHOS), but decreased (p<0.001) the mitochondrial bioenergetic reserve capacity (MBRC) which is closely related to cell responsiveness to stress conditions. MLT, regardless of DHA, ameliorated OXPHOS and recovered MBRC after coincubation. All incubations decreased AKT phosphorylation; however, only MLT alone inhibited p-mTOR. MLT increased p-ERK1/2 and, when combined to DHA, increased GSTP1 expression (p<0.01). DHA did not change the testosterone levels in the medium, whereas MLT alone or coincubated decreased by about 20%; however, any incubation affected AR expression. Moreover, incubation with luzindole revealed that MLT effects were MTR1/2-independent. In conclusion, DHA increased ROS production and impaired mitochondrial function which was probably related to AKT inactivation; MLT improved OXPHOS and decreased ROS which was related to AKT/mTOR dephosphorylation, and when coincubated, the antiproliferative action was related to mitochondrial bioenergetic modulation associated to AKT and ERK1/2 regulation. Together, these findings point to the potential application of DHA and MLT towards the prevention of proliferative prostate diseases.
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Filipe, Anne, Alexander Chernorudskiy, Sandrine Arbogast, Ersilia Varone, Rocío-Nur Villar-Quiles, Diego Pozzer, Maryline Moulin, et al. "Defective endoplasmic reticulum-mitochondria contacts and bioenergetics in SEPN1-related myopathy." Cell Death & Differentiation 28, no. 1 (July 13, 2020): 123–38. http://dx.doi.org/10.1038/s41418-020-0587-z.
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AbstractSEPN1-related myopathy (SEPN1-RM) is a muscle disorder due to mutations of the SEPN1 gene, which is characterized by muscle weakness and fatigue leading to scoliosis and life-threatening respiratory failure. Core lesions, focal areas of mitochondria depletion in skeletal muscle fibers, are the most common histopathological lesion. SEPN1-RM underlying mechanisms and the precise role of SEPN1 in muscle remained incompletely understood, hindering the development of biomarkers and therapies for this untreatable disease. To investigate the pathophysiological pathways in SEPN1-RM, we performed metabolic studies, calcium and ATP measurements, super-resolution and electron microscopy on in vivo and in vitro models of SEPN1 deficiency as well as muscle biopsies from SEPN1-RM patients. Mouse models of SEPN1 deficiency showed marked alterations in mitochondrial physiology and energy metabolism, suggesting that SEPN1 controls mitochondrial bioenergetics. Moreover, we found that SEPN1 was enriched at the mitochondria-associated membranes (MAM), and was needed for calcium transients between ER and mitochondria, as well as for the integrity of ER-mitochondria contacts. Consistently, loss of SEPN1 in patients was associated with alterations in body composition which correlated with the severity of muscle weakness, and with impaired ER-mitochondria contacts and low ATP levels. Our results indicate a role of SEPN1 as a novel MAM protein involved in mitochondrial bioenergetics. They also identify a systemic bioenergetic component in SEPN1-RM and establish mitochondria as a novel therapeutic target. This role of SEPN1 contributes to explain the fatigue and core lesions in skeletal muscle as well as the body composition abnormalities identified as part of the SEPN1-RM phenotype. Finally, these results point out to an unrecognized interplay between mitochondrial bioenergetics and ER homeostasis in skeletal muscle. They could therefore pave the way to the identification of biomarkers and therapeutic drugs for SEPN1-RM and for other disorders in which muscle ER-mitochondria cross-talk are impaired.
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Mayeur, Sylvain, Steve Lancel, Nicolas Theys, Marie-Amélie Lukaszewski, Sophie Duban-Deweer, Bruno Bastide, Johan Hachani, et al. "Maternal calorie restriction modulates placental mitochondrial biogenesis and bioenergetic efficiency: putative involvement in fetoplacental growth defects in rats." American Journal of Physiology-Endocrinology and Metabolism 304, no. 1 (January 1, 2013): E14—E22. http://dx.doi.org/10.1152/ajpendo.00332.2012.
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Low birth weight is associated with an increased risk for developing type 2 diabetes and metabolic diseases. The placental capacity to supply nutrients and oxygen to the fetus represents the main determiner of fetal growth. However, few studies have investigated the effects of maternal diet on the placenta. We explored placental adaptive proteomic processes implicated in response to maternal undernutrition. Rat term placentas from 70% food-restricted (FR30) mothers were used for a proteomic screen. Placental mitochondrial functions were evaluated using molecular and functional approaches, and ATP production was measured. FR30 drastically reduced placental and fetal weights. FR30 placentas displayed 14 proteins that were differentially expressed, including several mitochondrial proteins. FR30 induced a marked increase in placental mtDNA content and changes in mitochondrial functions, including modulation of the expression of genes implicated in biogenesis and bioenergetic pathways. FR30 mitochondria showed higher oxygen consumption but failed to maintain their ATP production. Maternal undernutrition induces placental mitochondrial abnormalities. Although an increase in biogenesis and bioenergetic efficiency was noted, placental ATP level was reduced. Our data suggest that placental mitochondrial defects may be implicated in fetoplacental pathologies.
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LeMoine, Christophe M. R., Grant B. McClelland, Carrie N. Lyons, Odile Mathieu-Costello, and Christopher D. Moyes. "Control of mitochondrial gene expression in the aging rat myocardium." Biochemistry and Cell Biology 84, no. 2 (April 1, 2006): 191–98. http://dx.doi.org/10.1139/o05-169.
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Aging induces complex changes in myocardium bioenergetic and contractile properties. Using F344BNF1rats, we examined age-dependent changes in myocardial bioenergetic enzymes (catalytic activities and transcript levels) and mRNA levels of putative transcriptional regulators of bioenergetic genes. Very old rats (35 months) showed a 22% increase in ventricular mass with no changes in DNA or RNA per gram. Age-dependent cardiac hypertrophy was accompanied by complex changes in mitochondrial enzymes. Enzymes of the Krebs cycle and electron transport system remained within 15% of the values measured in adult heart, significant decreases occurring in citrate synthase (10%) and aconitase (15%). Transcripts for these enzymes were largely unaffected by aging, although mRNA levels of putative transcriptional regulators of the enzymes (nuclear respiratory factor (NRF) 1 and 2 α subunit) increased by about 30%–50%. In contrast, enzymes of fatty acid oxidation exhibited a more diverse pattern, with a 50% decrease in β-hydroxyacyl-CoA dehydrogenase (HOAD) and no change in long-chain acyl-CoA dehydrogenase or carnitine palmitoyltransferase. Transcript levels for fatty acid oxidizing enzymes covaried with HOAD, which declined significantly by 30%. There were no significant changes in the relative transcript levels of regulators of genes for fatty acid oxidizing enzymes: peroxisome proliferator-activated receptor-α (PPARα), PPARβ, or PPARγ coactivator-1α (PGC-1α). There were no changes in the mRNA levels of Sirt1, a histone-modifying enzyme that interacts with PGC-1α. Collectively, these data suggest that aging causes complex changes in the enzymes of myocardial energy metabolism, triggered in part by NRF-independent pathways as well as post-transcriptional regulation.Key words: PGC-1a, fatty acid oxidation, nuclear respiratory factor (NRF), PPAR, coactivator, transcriptional regulation.
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Moro, Loredana. "Mitochondria at the Crossroads of Physiology and Pathology." Journal of Clinical Medicine 9, no. 6 (June 24, 2020): 1971. http://dx.doi.org/10.3390/jcm9061971.
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Mitochondria play a crucial role in cell life and death by regulating bioenergetic and biosynthetic pathways. They are able to adapt rapidly to different microenvironmental stressors by accommodating the metabolic and biosynthetic needs of the cell. Mounting evidence places mitochondrial dysfunction at the core of several diseases, notably in the context of pathologies of the cardiovascular and central nervous system. In addition, mutations in some mitochondrial proteins are bona fide cancer drivers. Better understanding of the functions of these multifaceted organelles and their components may finetune our knowledge on the molecular bases of certain diseases and suggest new therapeutic avenues.
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Basco, Davide, Grazia Paola Nicchia, Angelo D'Alessandro, Lello Zolla, Maria Svelto, and Antonio Frigeri. "Absence of Aquaporin-4 in Skeletal Muscle Alters Proteins Involved in Bioenergetic Pathways and Calcium Handling." PLoS ONE 6, no. 4 (April 28, 2011): e19225. http://dx.doi.org/10.1371/journal.pone.0019225.
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Valença, Isabel, Ana Rita Ferreira, Marcelo Correia, Sandra Kühl, Carlo van Roermund, Hans R. Waterham, Valdemar Máximo, Markus Islinger, and Daniela Ribeiro. "Prostate Cancer Proliferation Is Affected by the Subcellular Localization of MCT2 and Accompanied by Significant Peroxisomal Alterations." Cancers 12, no. 11 (October 27, 2020): 3152. http://dx.doi.org/10.3390/cancers12113152.
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Reprogramming of lipid metabolism directly contributes to malignant transformation and progression. The increased uptake of circulating lipids, the transfer of fatty acids from stromal adipocytes to cancer cells, the de novo fatty acid synthesis, and the fatty acid oxidation support the central role of lipids in many cancers, including prostate cancer (PCa). Fatty acid β-oxidation is the dominant bioenergetic pathway in PCa and recent evidence suggests that PCa takes advantage of the peroxisome transport machinery to target monocarboxylate transporter 2 (MCT2) to peroxisomes in order to increase β-oxidation rates and maintain the redox balance. Here we show evidence suggesting that PCa streamlines peroxisome metabolism by upregulating distinct pathways involved in lipid metabolism. Moreover, we show that MCT2 is required for PCa cell proliferation and, importantly, that its specific localization at the peroxisomal membranes is essential for this role. Our results highlight the importance of peroxisomes in PCa development and uncover different cellular mechanisms that may be further explored as possible targets for PCa therapy.
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Murphy, Anne N., and Gary Fiskum. "Bcl-2 and Ca2+-mediated mitochondrial dysfunction in neural cell death." Biochemical Society Symposia 66 (September 1, 1999): 33–41. http://dx.doi.org/10.1042/bss0660033.
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Although altered Ca2+ homoeostasis is believed to be a primary cause of death for many cell types in response to toxic insults, the specific Ca2+-stimulated event responsible for directing cells down the death pathway has remained elusive. Recent publications support the hypothesis that mitochondrial Ca2+ sequestration is the critical event in induction of excitotoxic neuronal death. If similar pathways are involved in the induction of Ca2+-induced necrotic and apoptotic death, then agents that mimic the action of the anti-apoptotic protein Bcl-2 should be particularly useful. Our previous results provide evidence that Bcl-2 increases the maximal capacity of mitochondria to accumulate Ca2+ while providing resistance to Ca2+-induced respiratory damage. In addition, we have found that Bcl-2 can block Ca2+-ionophore-induced delayed cell death. These data predict that in response to a challenging mitochondrial Ca2+ load, Bcl-2-containing mitochondria would be capable of continuing bioenergetic function, potentially avoiding a catastrophic death signalling event.
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Cherak, Stephana J., and Raymond J. Turner. "Assembly pathway of a bacterial complex iron sulfur molybdoenzyme." Biomolecular Concepts 8, no. 3-4 (September 26, 2017): 155–67. http://dx.doi.org/10.1515/bmc-2017-0011.
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AbstractProtein folding and assembly into macromolecule complexes within the living cell are complex processes requiring intimate coordination. The biogenesis of complex iron sulfur molybdoenzymes (CISM) requires use of a system specific chaperone – a redox enzyme maturation protein (REMP) – to help mediate final folding and assembly. The CISM dimethyl sulfoxide (DMSO) reductase is a bacterial oxidoreductase that utilizes DMSO as a final electron acceptor for anaerobic respiration. The REMP DmsD strongly interacts with DMSO reductase to facilitate folding, cofactor-insertion, subunit assembly and targeting of the multi-subunit enzyme prior to membrane translocation and final assembly and maturation into a bioenergetic catalytic unit. In this article, we discuss the biogenesis of DMSO reductase as an example of the participant network for bacterial CISM maturation pathways.
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Doughty, Cheryl A., Blair F. Bleiman, Dean J. Wagner, Fay J. Dufort, Jennifer M. Mataraza, Mary F. Roberts, and Thomas C. Chiles. "Antigen receptor–mediated changes in glucose metabolism in B lymphocytes: role of phosphatidylinositol 3-kinase signaling in the glycolytic control of growth." Blood 107, no. 11 (June 1, 2006): 4458–65. http://dx.doi.org/10.1182/blood-2005-12-4788.
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AbstractThe bioenergetic response of B lymphocytes is subject to rapid changes following antigen encounter in order to provide ATP and anabolic precursors necessary to support growth. However, the pathways involved in glucose acquisition and metabolism are unknown. We find that B lymphocytes rapidly increase glucose uptake and glycolysis following B-cell antigen receptor (BCR) crosslinking. Inhibition of glycolysis blocks BCR-mediated growth. Prior to S-phase entry, glucose metabolism shifts from primarily glycolytic to include the pentose phosphate pathway. BCR-induced glucose utilization is dependent upon phosphatidylinositol 3-kinase (PI-3K) activity as evidenced by inhibition of glucose uptake and glycolysis with LY294002 treatment of normal B cells and impaired glucose utilization in B cells deficient in the PI-3K regulatory subunit p85α. Activation of Akt is sufficient to increase glucose utilization in B cells. We find that glucose utilization is inhibited by coengagement of the BCR and FcγRIIB, suggesting that limiting glucose metabolism may represent an important mechanism underlying FcγRIIB-mediated growth arrest. Taken together, these findings demonstrate that both growth-promoting BCR signaling and growth-inhibitory FcγRIIB signaling modulate glucose energy metabolism. Manipulation of these pathways may prove to be useful in the treatment of lymphoproliferative disorders, wherein clonal expansion of B lymphocytes plays a role.
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Al-Habib, Hasan, and Margaret Ashcroft. "CHCHD4 (MIA40) and the mitochondrial disulfide relay system." Biochemical Society Transactions 49, no. 1 (February 18, 2021): 17–27. http://dx.doi.org/10.1042/bst20190232.
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Mitochondria are pivotal for normal cellular physiology, as they perform a crucial role in diverse cellular functions and processes, including respiration and the regulation of bioenergetic and biosynthetic pathways, as well as regulating cellular signalling and transcriptional networks. In this way, mitochondria are central to the cell's homeostatic machinery, and as such mitochondrial dysfunction underlies the pathology of a diverse range of diseases including mitochondrial disease and cancer. Mitochondrial import pathways and targeting mechanisms provide the means to transport into mitochondria the hundreds of nuclear-encoded mitochondrial proteins that are critical for the organelle's many functions. One such import pathway is the highly evolutionarily conserved disulfide relay system (DRS) within the mitochondrial intermembrane space (IMS), whereby proteins undergo a form of oxidation-dependent protein import. A central component of the DRS is the oxidoreductase coiled-coil-helix-coiled-coil-helix (CHCH) domain-containing protein 4 (CHCHD4, also known as MIA40), the human homologue of yeast Mia40. Here, we summarise the recent advances made to our understanding of the role of CHCHD4 and the DRS in physiology and disease, with a specific focus on the emerging importance of CHCHD4 in regulating the cellular response to low oxygen (hypoxia) and metabolism in cancer.
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Kuffner, Kerstin, Julian Triebelhorn, Katrin Meindl, Christoph Benner, André Manook, Daniel Sudria-Lopez, Ramona Siebert, et al. "Major Depressive Disorder is Associated with Impaired Mitochondrial Function in Skin Fibroblasts." Cells 9, no. 4 (April 4, 2020): 884. http://dx.doi.org/10.3390/cells9040884.
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Mitochondrial malfunction is supposed to be involved in the etiology and pathology of major depressive disorder (MDD). Here, we aimed to identify and characterize the molecular pathomechanisms related to mitochondrial dysfunction in adult human skin fibroblasts, which were derived from MDD patients or non-depressive control subjects. We found that MDD fibroblasts showed significantly impaired mitochondrial functioning: basal and maximal respiration, spare respiratory capacity, non-mitochondrial respiration and adenosine triphosphate (ATP)-related oxygen consumption was lower. Moreover, MDD fibroblasts harbor lower ATP levels and showed hyperpolarized mitochondrial membrane potential. To investigate cellular resilience, we challenged both groups of fibroblasts with hormonal (dexamethasone) or metabolic (galactose) stress for one week, and found that both stressors increased oxygen consumption but lowered ATP content in MDD as well as in non-depressive control fibroblasts. Interestingly, the bioenergetic differences between fibroblasts from MDD or non-depressed subjects, which were observed under non-treated conditions, could not be detected after stress. Our findings support the hypothesis that altered mitochondrial function causes a bioenergetic imbalance, which is associated with the molecular pathophysiology of MDD. The observed alterations in the oxidative phosphorylation system (OXPHOS) and other mitochondria-related properties represent a basis for further investigations of pathophysiological mechanisms and might open new ways to gain insight into antidepressant signaling pathways.
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Cirilli, Ilenia, Elisabetta Damiani, Phiwayinkosi Vusi Dludla, Iain Hargreaves, Fabio Marcheggiani, Lauren Elizabeth Millichap, Patrick Orlando, Sonia Silvestri, and Luca Tiano. "Role of Coenzyme Q10 in Health and Disease: An Update on the Last 10 Years (2010–2020)." Antioxidants 10, no. 8 (August 23, 2021): 1325. http://dx.doi.org/10.3390/antiox10081325.
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The present review focuses on preclinical and clinical studies conducted in the last decade that contribute to increasing knowledge on Coenzyme Q10’s role in health and disease. Classical antioxidant and bioenergetic functions of the coenzyme have been taken into consideration, as well as novel mechanisms of action involving the redox-regulated activation of molecular pathways associated with anti-inflammatory activities. Cardiovascular research and fertility remain major fields of application of Coenzyme Q10, although novel applications, in particular in relation to topical application, are gaining considerable interest. In this respect, bioavailability represents a major challenge and the innovation in formulation aspects is gaining critical importance.
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Higdon, Ashlee, Anne R. Diers, Joo Yeun Oh, Aimee Landar, and Victor M. Darley-Usmar. "Cell signalling by reactive lipid species: new concepts and molecular mechanisms." Biochemical Journal 442, no. 3 (February 24, 2012): 453–64. http://dx.doi.org/10.1042/bj20111752.
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The process of lipid peroxidation is widespread in biology and is mediated through both enzymatic and non-enzymatic pathways. A significant proportion of the oxidized lipid products are electrophilic in nature, the RLS (reactive lipid species), and react with cellular nucleophiles such as the amino acids cysteine, lysine and histidine. Cell signalling by electrophiles appears to be limited to the modification of cysteine residues in proteins, whereas non-specific toxic effects involve modification of other nucleophiles. RLS have been found to participate in several physiological pathways including resolution of inflammation, cell death and induction of cellular antioxidants through the modification of specific signalling proteins. The covalent modification of proteins endows some unique features to this signalling mechanism which we have termed the ‘covalent advantage’. For example, covalent modification of signalling proteins allows for the accumulation of a signal over time. The activation of cell signalling pathways by electrophiles is hierarchical and depends on a complex interaction of factors such as the intrinsic chemical reactivity of the electrophile, the intracellular domain to which it is exposed and steric factors. This introduces the concept of electrophilic signalling domains in which the production of the lipid electrophile is in close proximity to the thiol-containing signalling protein. In addition, we propose that the role of glutathione and associated enzymes is to insulate the signalling domain from uncontrolled electrophilic stress. The persistence of the signal is in turn regulated by the proteasomal pathway which may itself be subject to redox regulation by RLS. Cell death mediated by RLS is associated with bioenergetic dysfunction, and the damaged proteins are probably removed by the lysosome-autophagy pathway.
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Baker, Simon C., Stuart J. Ferguson, Bernd Ludwig, M. Dudley Page, Oliver-Matthias H. Richter, and Rob J. M. van Spanning. "Molecular Genetics of the GenusParacoccus: Metabolically Versatile Bacteria with Bioenergetic Flexibility." Microbiology and Molecular Biology Reviews 62, no. 4 (December 1, 1998): 1046–78. http://dx.doi.org/10.1128/mmbr.62.4.1046-1078.1998.
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SUMMARY Paracoccus denitrificans and its near relative Paracoccus versutus (formerly known as Thiobacilllus versutus) have been attracting increasing attention because the aerobic respiratory system of P. denitrificans has long been regarded as a model for that of the mitochondrion, with which there are many components (e.g., cytochrome aa3 oxidase) in common. Members of the genus exhibit a great range of metabolic flexibility, particularly with respect to processes involving respiration. Prominent examples of flexibility are the use in denitrification of nitrate, nitrite, nitrous oxide, and nitric oxide as alternative electron acceptors to oxygen and the ability to use C1 compounds (e.g., methanol and methylamine) as electron donors to the respiratory chains. The proteins required for these respiratory processes are not constitutive, and the underlying complex regulatory systems that regulate their expression are beginning to be unraveled. There has been uncertainty about whether transcription in a member of the alpha-3 Proteobacteria such as P. denitrificans involves a conventional ς70-type RNA polymerase, especially since canonical −35 and −10 DNA binding sites have not been readily identified. In this review, we argue that many genes, in particular those encoding constitutive proteins, may be under the control of a ς70 RNA polymerase very closely related to that of Rhodobacter capsulatus. While the main focus is on the structure and regulation of genes coding for products involved in respiratory processes in Paracoccus, the current state of knowledge of the components of such respiratory pathways, and their biogenesis, is also reviewed.
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Pecze, Laszlo, and Csaba Szabo. "Meta-analysis of gene expression patterns in Down syndrome highlights significant alterations in mitochondrial and bioenergetic pathways." Mitochondrion 57 (March 2021): 163–72. http://dx.doi.org/10.1016/j.mito.2020.12.017.
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Chang, Louis K., Robert E. Schmidt, and Eugene M. Johnson. "Alternating metabolic pathways in NGF-deprived sympathetic neurons affect caspase-independent death." Journal of Cell Biology 162, no. 2 (July 21, 2003): 245–56. http://dx.doi.org/10.1083/jcb.200302109.
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Mitochondrial release of cytochrome c in apoptotic cells activates caspases, which execute apoptotic cell death. However, the events themselves that culminate in caspase activation can have deleterious effects because caspase inhibitor–saved cells ultimately die in a caspase-independent manner. To determine what events may underlie this form of cell death, we examined bioenergetic changes in sympathetic neurons deprived of NGF in the presence of a broad-spectrum caspase inhibitor, boc-aspartyl-(OMe)-fluoromethylketone. Here, we report that NGF-deprived, boc-aspartyl-(OMe)-fluoromethylketone–saved neurons rely heavily on glycolysis for ATP generation and for survival. Second, the activity of F0F1 contributes to caspase-independent death, but has only a minor role in the maintenance of mitochondrial membrane potential, which is maintained primarily by electron transport. Third, permeability transition pore inhibition by cyclosporin A attenuates NGF deprivation–induced loss of mitochondrial proteins, suggesting that permeability transition pore opening may have a function in regulating the degradation of mitochondria after cytochrome c release. Identification of changes in caspase inhibitor–saved cells may provide the basis for rational strategies to augment the effectiveness of the therapeutic use of postmitochondrial interventions.
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Zhang, Hanwen, Yanshuo Ye, and Wei Li. "Perspectives of Molecular Therapy-Targeted Mitochondrial Fission in Hepatocellular Carcinoma." BioMed Research International 2020 (December 29, 2020): 1–7. http://dx.doi.org/10.1155/2020/1039312.
Full textAbstract:
Current advances of molecular-targeting therapies for hepatocellular carcinoma (HCC) have improved the overall survival significantly, whereas the results still remain unsatisfied. Recently, much attention has been focused on organelles, such as the mitochondria, to reveal novel strategies to control the cancers. The mitochondria are vital organelles which supply energy and maintain metabolism in most of the eukaryotic cells. They not only execute critical bioenergetic and biosynthetic functions but also regulate ROS homeostasis and apoptosis. Existing in a dynamic equilibrium state, mitochondria constantly undergo the fission and fusion processes in normal situation. Increasing evidences have showed that mitochondrial fission is highly related to the diseases and cancers. Distinctive works have proved the significant effects of mitochondrial fission on HCC behaviors and the crosstalks with other molecular pathways. Here, we provide an overview of the mitochondrial fission and the link with HCC, emphasizing on the underlying molecular pathways and several novel materials that modulate HCC behaviors.