Journal articles on the topic 'Mitochondria, mitochondrial diseases, Opa1, therapies'
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1
Xia, Yi, Xu Zhang, Peng An, Junjie Luo, and Yongting Luo. "Mitochondrial Homeostasis in VSMCs as a Central Hub in Vascular Remodeling." International Journal of Molecular Sciences 24, no. 4 (February 9, 2023): 3483. http://dx.doi.org/10.3390/ijms24043483.
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Vascular remodeling is a common pathological hallmark of many cardiovascular diseases. Vascular smooth muscle cells (VSMCs) are the predominant cell type lining the tunica media and play a crucial role in maintaining aortic morphology, integrity, contraction and elasticity. Their abnormal proliferation, migration, apoptosis and other activities are tightly associated with a spectrum of structural and functional alterations in blood vessels. Emerging evidence suggests that mitochondria, the energy center of VSMCs, participate in vascular remodeling through multiple mechanisms. For example, peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α)-mediated mitochondrial biogenesis prevents VSMCs from proliferation and senescence. The imbalance between mitochondrial fusion and fission controls the abnormal proliferation, migration and phenotypic transformation of VSMCs. Guanosine triphosphate-hydrolyzing enzymes, including mitofusin 1 (MFN1), mitofusin 2 (MFN2), optic atrophy protein 1 (OPA1) and dynamin-related protein 1 (DRP1), are crucial for mitochondrial fusion and fission. In addition, abnormal mitophagy accelerates the senescence and apoptosis of VSMCs. PINK/Parkin and NIX/BINP3 pathways alleviate vascular remodeling by awakening mitophagy in VSMCs. Mitochondrial DNA (mtDNA) damage destroys the respiratory chain of VSMCs, resulting in excessive ROS production and decreased ATP levels, which are related to the proliferation, migration and apoptosis of VSMCs. Thus, maintaining mitochondrial homeostasis in VSMCs is a possible way to relieve pathologic vascular remodeling. This review aims to provide an overview of the role of mitochondria homeostasis in VSMCs during vascular remodeling and potential mitochondria-targeted therapies.
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Samant, Sadhana A., Hannah J. Zhang, Zhigang Hong, Vinodkumar B. Pillai, Nagalingam R. Sundaresan, Donald Wolfgeher, Stephen L. Archer, David C. Chan, and Mahesh P. Gupta. "SIRT3 Deacetylates and Activates OPA1 To Regulate Mitochondrial Dynamics during Stress." Molecular and Cellular Biology 34, no. 5 (December 16, 2013): 807–19. http://dx.doi.org/10.1128/mcb.01483-13.
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Mitochondrial morphology is regulated by the balance between two counteracting mitochondrial processes of fusion and fission. There is significant evidence suggesting a stringent association between morphology and bioenergetics of mitochondria. Morphological alterations in mitochondria are linked to several pathological disorders, including cardiovascular diseases. The consequences of stress-induced acetylation of mitochondrial proteins on the organelle morphology remain largely unexplored. Here we report that OPA1, a mitochondrial fusion protein, was hyperacetylated in hearts under pathological stress and this posttranslational modification reduced the GTPase activity of the protein. The mitochondrial deacetylase SIRT3 was capable of deacetylating OPA1 and elevating its GTPase activity. Mass spectrometry and mutagenesis analyses indicated that in SIRT3-deficient cells OPA1 was acetylated at lysine 926 and 931 residues. Overexpression of a deacetylation-mimetic version of OPA1 recovered the mitochondrial functions of OPA1-null cells, thus demonstrating the functional significance of K926/931 acetylation in regulating OPA1 activity. Moreover, SIRT3-dependent activation of OPA1 contributed to the preservation of mitochondrial networking and protection of cardiomyocytes from doxorubicin-mediated cell death. In summary, these data indicated that SIRT3 promotes mitochondrial function not only by regulating activity of metabolic enzymes, as previously reported, but also by regulating mitochondrial dynamics by targeting OPA1.
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Ranieri, Michela, Simona Brajkovic, Giulietta Riboldi, Dario Ronchi, Federica Rizzo, Nereo Bresolin, Stefania Corti, and Giacomo P. Comi. "Mitochondrial Fusion Proteins and Human Diseases." Neurology Research International 2013 (2013): 1–11. http://dx.doi.org/10.1155/2013/293893.
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Mitochondria are highly dynamic, complex organelles that continuously alter their shape, ranging between two opposite processes, fission and fusion, in response to several stimuli and the metabolic demands of the cell. Alterations in mitochondrial dynamics due to mutations in proteins involved in the fusion-fission machinery represent an important pathogenic mechanism of human diseases. The most relevant proteins involved in the mitochondrial fusion process are three GTPase dynamin-like proteins: mitofusin 1 (MFN1) and 2 (MFN2), located in the outer mitochondrial membrane, and optic atrophy protein 1 (OPA1), in the inner membrane. An expanding number of degenerative disorders are associated with mutations in the genes encoding MFN2 and OPA1, including Charcot-Marie-Tooth disease type 2A and autosomal dominant optic atrophy. While these disorders can still be considered rare, defective mitochondrial dynamics seem to play a significant role in the molecular and cellular pathogenesis of more common neurodegenerative diseases, for example, Alzheimer’s and Parkinson’s diseases. This review provides an overview of the basic molecular mechanisms involved in mitochondrial fusion and focuses on the alteration in mitochondrial DNA amount resulting from impairment of mitochondrial dynamics. We also review the literature describing the main disorders associated with the disruption of mitochondrial fusion.
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Wu, Bangwei, Jian Li, Huanchun Ni, Xinyu Zhuang, Zhiyong Qi, Qiying Chen, Zhichao Wen, Haiming Shi, Xinping Luo, and Bo Jin. "TLR4 Activation Promotes the Progression of Experimental Autoimmune Myocarditis to Dilated Cardiomyopathy by Inducing Mitochondrial Dynamic Imbalance." Oxidative Medicine and Cellular Longevity 2018 (June 26, 2018): 1–15. http://dx.doi.org/10.1155/2018/3181278.
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Mitochondrial dynamic imbalance associates with several cardiovascular diseases. However, the role of mitochondrial dynamics in TLR4 activation-mediated dilated cardiomyopathy (DCM) progress remains unknown. A model of experimental autoimmune myocarditis (EAM) was established in BALB/c mice on which TLR4 activation by LPS-EB or TLR4 inhibition by LPS-RS was performed to induce chronic inflammation for 5 weeks. TLR4 activation promoted the transition of EAM to DCM as demonstrated by increased cardiomyocyte apoptosis, myocardial fibrosis, ventricular dilatation, and declined heart function. TLR4 inhibition mitigated the above DCM changes. Transmission electron microscope study showed that mitochondria became fragmented, also with damaged crista in ultrastructure in EAM mice. TLR4 activation aggravated the above mitochondrial aberration, and TLR4 inhibition alleviated it. The mitochondrial dynamic imbalance and damage in DCM development were mainly associated with OPA1 downregulation, which may be caused by elevated TNF-α level and ROS stress after TLR4 activation. Furthermore, OMA1/YME1L abnormal degradation was involved in the OPA1 dysfunction, and intervening OMA1/YME1L in H9C2 significantly alleviated mitochondrial fission, ultrastructure damage, and cell apoptosis induced by TNF-α and ROS. These data indicate that TLR4 activation resulted in OPA1 dysfunction, promoting mitochondrial dynamic imbalance and damage, which may involve in the progress of EAM to DCM.
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Markin, Alexander M., Viktoria A. Khotina, Xenia G. Zabudskaya, Anastasia I. Bogatyreva, Antonina V. Starodubova, Ekaterina Ivanova, Nikita G. Nikiforov, and Alexander N. Orekhov. "Disturbance of Mitochondrial Dynamics and Mitochondrial Therapies in Atherosclerosis." Life 11, no. 2 (February 20, 2021): 165. http://dx.doi.org/10.3390/life11020165.
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Mitochondrial dysfunction is associated with a wide range of chronic human disorders, including atherosclerosis and diabetes mellitus. Mitochondria are dynamic organelles that undergo constant turnover in living cells. Through the processes of mitochondrial fission and fusion, a functional population of mitochondria is maintained, that responds to the energy needs of the cell. Damaged or excessive mitochondria are degraded by mitophagy, a specialized type of autophagy. These processes are orchestrated by a number of proteins and genes, and are tightly regulated. When one or several of these processes are affected, it can lead to the accumulation of dysfunctional mitochondria, deficient energy production, increased oxidative stress and cell death—features that are described in many human disorders. While severe mitochondrial dysfunction is known to cause specific and mitochondrial disorders in humans, progressing damage of the mitochondria is also observed in a wide range of other chronic diseases, including cancer and atherosclerosis, and appears to play an important role in disease development. Therefore, correction of mitochondrial dynamics can help in developing new therapies for the treatment of these conditions. In this review, we summarize the recent knowledge on the processes of mitochondrial turnover and the proteins and genes involved in it. We provide a list of known mutations that affect mitochondrial function, and discuss the emerging therapeutic approaches.
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Carelli, Valerio, Chiara La Morgia, Luisa Iommarini, Rosanna Carroccia, Marina Mattiazzi, Simonetta Sangiorgi, Sabrina Farne', et al. "Mitochondrial Optic Neuropathies: How Two Genomes may Kill the Same Cell Type?" Bioscience Reports 27, no. 1-3 (June 13, 2007): 173–84. http://dx.doi.org/10.1007/s10540-007-9045-0.
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Ocular involvement is a prevalent feature in mitochondrial diseases. Leber's hereditary optic neuropathy (LHON) and dominant optic atrophy (DOA) are both non-syndromic optic neuropathies with a mitochondrial etiology. LHON is associated with point mutations in the mitochondrial DNA (mtDNA), which affect subunit genes of complex I. The majority of DOA patients harbor mutations in the nuclear-encoded protein OPA1, which is targeted to mitochondria and participates to cristae organization and mitochondrial network dynamics. In both disorders the retinal ganglion cells (RGCs) are specific cellular targets of the degenerative process. We here review the clinical features and the genetic bases, and delineate the possible common pathomechanism for both these disorders.
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Liesa, Marc, Manuel Palacín, and Antonio Zorzano. "Mitochondrial Dynamics in Mammalian Health and Disease." Physiological Reviews 89, no. 3 (July 2009): 799–845. http://dx.doi.org/10.1152/physrev.00030.2008.
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The meaning of the word mitochondrion (from the Greek mitos, meaning thread, and chondros, grain) illustrates that the heterogeneity of mitochondrial morphology has been known since the first descriptions of this organelle. Such a heterogeneous morphology is explained by the dynamic nature of mitochondria. Mitochondrial dynamics is a concept that includes the movement of mitochondria along the cytoskeleton, the regulation of mitochondrial architecture (morphology and distribution), and connectivity mediated by tethering and fusion/fission events. The relevance of these events in mitochondrial and cell physiology has been partially unraveled after the identification of the genes responsible for mitochondrial fusion and fission. Furthermore, during the last decade, it has been identified that mutations in two mitochondrial fusion genes ( MFN2 and OPA1) cause prevalent neurodegenerative diseases (Charcot-Marie Tooth type 2A and Kjer disease/autosomal dominant optic atrophy). In addition, other diseases such as type 2 diabetes or vascular proliferative disorders show impaired MFN2 expression. Altogether, these findings have established mitochondrial dynamics as a consolidated area in cellular physiology. Here we review the most significant findings in the field of mitochondrial dynamics in mammalian cells and their implication in human pathologies.
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Zhong, Gang, Jagadeesh K. Venkatesan, Henning Madry, and Magali Cucchiarini. "Advances in Human Mitochondria-Based Therapies." International Journal of Molecular Sciences 24, no. 1 (December 29, 2022): 608. http://dx.doi.org/10.3390/ijms24010608.
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Mitochondria are the key biological generators of eukaryotic cells, controlling the energy supply while providing many important biosynthetic intermediates. Mitochondria act as a dynamic, functionally and structurally interconnected network hub closely integrated with other cellular compartments via biomembrane systems, transmitting biological information by shuttling between cells and tissues. Defects and dysregulation of mitochondrial functions are critically involved in pathological mechanisms contributing to aging, cancer, inflammation, neurodegenerative diseases, and other severe human diseases. Mediating and rejuvenating the mitochondria may therefore be of significant benefit to prevent, reverse, and even treat such pathological conditions in patients. The goal of this review is to present the most advanced strategies using mitochondria to manage such disorders and to further explore innovative approaches in the field of human mitochondria-based therapies.
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Yang, Yanyan, Min Li, Yan Liu, Zhibin Wang, Xiuxiu Fu, Xingqiang He, Qi Wang, et al. "The lncRNA Punisher Regulates Apoptosis and Mitochondrial Homeostasis of Vascular Smooth Muscle Cells via Targeting miR-664a-5p and OPA1." Oxidative Medicine and Cellular Longevity 2022 (May 25, 2022): 1–21. http://dx.doi.org/10.1155/2022/5477024.
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Long noncoding RNAs (lncRNAs) are important regulators of various cellular functions. Recent studies have shown that a novel lncRNA termed Punisher is highly expressed in cardiovascular progenitors and has potential role in cardiovascular diseases. However, its role, especially in molecular mechanism, is unclear. In our present study, we observed that Punisher was obviously downregulated in atherosclerotic plaques. Further research proved that it can suppress the apoptosis of VSMCs potentially contributing to the progression of atherosclerosis. Intriguingly, Punisher revealed to regulate mitochondria fission as well as mitochondrial functions induced by hydrogen peroxide (H2O2) in VSMCs. Mechanistically, Punisher was further proved to serve as a ceRNA which directly binds to miR-664a-5p and consequently regulates its target OPA1, and finally contributes to the biological function of VSMCs. Particularly, Punisher overexpression distinctly suppressed neointima formation and VSMC apoptosis in vivo. Encouragingly, these results were in accordance with findings obtained with the clinical evaluation of patients with atherosclerosis. Our data provides the significant relationship among OPA1, mitochondrial homeostasis, VSMC apoptosis, and atherosclerosis. And lncRNA Punisher and miR-664a-5p could serve as the novel and potential targets in the diagnosis and treatment of cardiovascular diseases.
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Che, Ruochen, Yanggang Yuan, Songming Huang, and Aihua Zhang. "Mitochondrial dysfunction in the pathophysiology of renal diseases." American Journal of Physiology-Renal Physiology 306, no. 4 (February 15, 2014): F367—F378. http://dx.doi.org/10.1152/ajprenal.00571.2013.
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Mitochondrial dysfunction has gained recognition as a contributing factor in many diseases. The kidney is a kind of organ with high energy demand, rich in mitochondria. As such, mitochondrial dysfunction in the kidney plays a critical role in the pathogenesis of kidney diseases. Despite the recognized importance mitochondria play in the pathogenesis of the diseases, there is limited understanding of various aspects of mitochondrial biology. This review examines the physiology and pathophysiology of mitochondria. It begins by discussing mitochondrial structure, mitochondrial DNA, mitochondrial reactive oxygen species production, mitochondrial dynamics, and mitophagy, before turning to inherited mitochondrial cytopathies in kidneys (inherited or sporadic mitochondrial DNA or nuclear DNA mutations in genes that affect mitochondrial function). Glomerular diseases, tubular defects, and other renal diseases are then discussed. Next, acquired mitochondrial dysfunction in kidney diseases is discussed, emphasizing the role of mitochondrial dysfunction in the pathogenesis of chronic kidney disease and acute kidney injury, as their prevalence is increasing. Finally, it summarizes the possible beneficial effects of mitochondrial-targeted therapeutic agents for treatment of mitochondrial dysfunction-mediated kidney injury-genetic therapies, antioxidants, thiazolidinediones, sirtuins, and resveratrol-as mitochondrial-based drugs may offer potential treatments for renal diseases.
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Méndez-López, Iago, Francisco J. Sancho-Bielsa, Tobias Engel, Antonio G. G. García, and Juan Fernando Padín. "Progressive Mitochondrial SOD1G93A Accumulation Causes Severe Structural, Metabolic and Functional Aberrations through OPA1 Down-Regulation in a Mouse Model of Amyotrophic Lateral Sclerosis." International Journal of Molecular Sciences 22, no. 15 (July 30, 2021): 8194. http://dx.doi.org/10.3390/ijms22158194.
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In recent years, the “non-autonomous motor neuron death” hypothesis has become more consolidated behind amyotrophic lateral sclerosis (ALS). It postulates that cells other than motor neurons participate in the pathology. In fact, the involvement of the autonomic nervous system is fundamental since patients die of sudden death when they become unable to compensate for cardiorespiratory arrest. Mitochondria are thought to play a fundamental role in the physiopathology of ALS, as they are compromised in multiple ALS models in different cell types, and it also occurs in other neurodegenerative diseases. Our study aimed to uncover mitochondrial alterations in the sympathoadrenal system of a mouse model of ALS, from a structural, bioenergetic and functional perspective during disease instauration. We studied the adrenal chromaffin cell from mutant SOD1G93A mouse at pre-symptomatic and symptomatic stages. The mitochondrial accumulation of the mutated SOD1G93A protein and the down-regulation of optic atrophy protein-1 (OPA1) provoke mitochondrial ultrastructure alterations prior to the onset of clinical symptoms. These changes affect mitochondrial fusion dynamics, triggering mitochondrial maturation impairment and cristae swelling, with increased size of cristae junctions. The functional consequences are a loss of mitochondrial membrane potential and changes in the bioenergetics profile, with reduced maximal respiration and spare respiratory capacity of mitochondria, as well as enhanced production of reactive oxygen species. This study identifies mitochondrial dynamics regulator OPA1 as an interesting therapeutic target in ALS. Additionally, our findings in the adrenal medulla gland from presymptomatic stages highlight the relevance of sympathetic impairment in this disease. Specifically, we show new SOD1G93A toxicity pathways affecting cellular energy metabolism in non-motor neurons, which offer a possible link between cell specific metabolic phenotype and the progression of ALS.
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Al Ojaimi, Mode, Azza Salah, and Ayman W. El-Hattab. "Mitochondrial Fission and Fusion: Molecular Mechanisms, Biological Functions, and Related Disorders." Membranes 12, no. 9 (September 16, 2022): 893. http://dx.doi.org/10.3390/membranes12090893.
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Mitochondria are dynamic organelles that undergo fusion and fission. These active processes occur continuously and simultaneously and are mediated by nuclear-DNA-encoded proteins that act on mitochondrial membranes. The balance between fusion and fission determines the mitochondrial morphology and adapts it to the metabolic needs of the cells. Therefore, these two processes are crucial to optimize mitochondrial function and its bioenergetics abilities. Defects in mitochondrial proteins involved in fission and fusion due to pathogenic variants in the genes encoding them result in disruption of the equilibrium between fission and fusion, leading to a group of mitochondrial diseases termed disorders of mitochondrial dynamics. In this review, the molecular mechanisms and biological functions of mitochondrial fusion and fission are first discussed. Then, mitochondrial disorders caused by defects in fission and fusion are summarized, including disorders related to MFN2, MSTO1, OPA1, YME1L1, FBXL4, DNM1L, and MFF genes.
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Mohamud, Yasir, Boaz Li, Amirhossein Bahreyni, and Honglin Luo. "Mitochondria Dysfunction at the Heart of Viral Myocarditis: Mechanistic Insights and Therapeutic Implications." Viruses 15, no. 2 (January 26, 2023): 351. http://dx.doi.org/10.3390/v15020351.
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The myocardium/heart is the most mitochondria-rich tissue in the human body with mitochondria comprising approximately 30% of total cardiomyocyte volume. As the resident “powerhouse” of cells, mitochondria help to fuel the high energy demands of a continuously beating myocardium. It is no surprise that mitochondrial dysfunction underscores the pathogenesis of many cardiovascular ailments, including those of viral origin such as virus-induced myocarditis. Enteroviruses have been especially linked to injuries of the myocardium and its sequelae dilated cardiomyopathy for which no effective therapies currently exist. Intriguingly, recent mechanistic insights have demonstrated viral infections to directly damage mitochondria, impair the mitochondrial quality control processes of the cell, such as disrupting mitochondrial antiviral innate immune signaling, and promoting mitochondrial-dependent pathological inflammation of the infected myocardium. In this review, we briefly highlight recent insights on the virus-mitochondria crosstalk and discuss the therapeutic implications of targeting mitochondria to preserve heart function and ultimately combat viral myocarditis.
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Mokhtari, Behnaz, Rana Yavari, Reza Badalzadeh, and Ata Mahmoodpoor. "An Overview on Mitochondrial-Based Therapies in Sepsis-Related Myocardial Dysfunction: Mitochondrial Transplantation as a Promising Approach." Canadian Journal of Infectious Diseases and Medical Microbiology 2022 (June 6, 2022): 1–17. http://dx.doi.org/10.1155/2022/3277274.
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Sepsis is defined as a life-threatening organ failure due to dysregulated host response to infection. Despite current advances in our knowledge about sepsis, it is still considered as a major global health challenge. Myocardial dysfunction is a well-defined manifestation of sepsis which is related to worse outcomes in septic patients. Given that the heart is a mitochondria-rich organ and the normal function of mitochondria is essential for successful modulation of septic response, the contribution of mitochondrial damage in sepsis-related myocardial dysfunction has attracted the attention of many scientists. It is widely accepted that mitochondrial damage is involved in sepsis-related myocardial dysfunction; however, effective and potential treatment modalities in clinical setting are still lacking. Mitochondrial-based therapies are potential approaches in sepsis treatment. Although various therapeutic strategies have been used for mitochondrial function improvement, their effects are limited when mitochondria undergo irreversible alterations under septic challenge. Therefore, application of more effective approaches such as mitochondrial transplantation has been suggested. This review highlights the crucial role of mitochondrial damage in sepsis-related myocardial dysfunction, then provides an overview on mitochondrial-based therapies and current approaches to mitochondrial transplantation as a novel strategy, and proposes future directions for more researches in this field.
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Prasuhn, Jannik, and Norbert Brüggemann. "Gene Therapeutic Approaches for the Treatment of Mitochondrial Dysfunction in Parkinson’s Disease." Genes 12, no. 11 (November 22, 2021): 1840. http://dx.doi.org/10.3390/genes12111840.
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Background: Mitochondrial dysfunction has been identified as a pathophysiological hallmark of disease onset and progression in patients with Parkinsonian disorders. Besides the overall emergence of gene therapies in treating these patients, this highly relevant molecular concept has not yet been defined as a target for gene therapeutic approaches. Methods: This narrative review will discuss the experimental evidence suggesting mitochondrial dysfunction as a viable treatment target in patients with monogenic and idiopathic Parkinson’s disease. In addition, we will focus on general treatment strategies and crucial challenges which need to be overcome. Results: Our current understanding of mitochondrial biology in parkinsonian disorders opens up the avenue for viable treatment strategies in Parkinsonian disorders. Insights can be obtained from primary mitochondrial diseases. However, substantial knowledge gaps and unique challenges of mitochondria-targeted gene therapies need to be addressed to provide innovative treatments in the future. Conclusions: Mitochondria-targeted gene therapies are a potential strategy to improve an important primary disease mechanism in Parkinsonian disorders. However, further studies are needed to address the unique design challenges for mitochondria-targeted gene therapies.
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D’Amato, Marco, Francesca Morra, Ivano Di Di Meo, and Valeria Tiranti. "Mitochondrial Transplantation in Mitochondrial Medicine: Current Challenges and Future Perspectives." International Journal of Molecular Sciences 24, no. 3 (January 19, 2023): 1969. http://dx.doi.org/10.3390/ijms24031969.
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Mitochondrial diseases (MDs) are inherited genetic conditions characterized by pathogenic mutations in nuclear DNA (nDNA) or mitochondrial DNA (mtDNA). Current therapies are still far from being fully effective and from covering the broad spectrum of mutations in mtDNA. For example, unlike heteroplasmic conditions, MDs caused by homoplasmic mtDNA mutations do not yet benefit from advances in molecular approaches. An attractive method of providing dysfunctional cells and/or tissues with healthy mitochondria is mitochondrial transplantation. In this review, we discuss what is known about intercellular transfer of mitochondria and the methods used to transfer mitochondria both in vitro and in vivo, and we provide an outlook on future therapeutic applications. Overall, the transfer of healthy mitochondria containing wild-type mtDNA copies could induce a heteroplasmic shift even when homoplasmic mtDNA variants are present, with the aim of attenuating or preventing the progression of pathological clinical phenotypes. In summary, mitochondrial transplantation is a challenging but potentially ground-breaking option for the treatment of various mitochondrial pathologies, although several questions remain to be addressed before its application in mitochondrial medicine.
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James, Rachel, Helena Chaytow, Leire M. Ledahawsky, and Thomas H. Gillingwater. "Revisiting the role of mitochondria in spinal muscular atrophy." Cellular and Molecular Life Sciences 78, no. 10 (April 5, 2021): 4785–804. http://dx.doi.org/10.1007/s00018-021-03819-5.
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AbstractSpinal muscular atrophy (SMA) is an autosomal recessive motor neuron disease of variable clinical severity that is caused by mutations in the survival motor neuron 1 (SMN1) gene. Despite its name, SMN is a ubiquitous protein that functions within and outside the nervous system and has multiple cellular roles in transcription, translation, and proteostatic mechanisms. Encouragingly, several SMN-directed therapies have recently reached the clinic, albeit this has highlighted the increasing need to develop combinatorial therapies for SMA to achieve full clinical efficacy. As a subcellular site of dysfunction in SMA, mitochondria represents a relevant target for a combinatorial therapy. Accordingly, we will discuss our current understanding of mitochondrial dysfunction in SMA, highlighting mitochondrial-based pathways that offer further mechanistic insights into the involvement of mitochondria in SMA. This may ultimately facilitate translational development of targeted mitochondrial therapies for SMA. Due to clinical and mechanistic overlaps, such strategies may also benefit other motor neuron diseases and related neurodegenerative disorders.
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Sita, Giulia, Patrizia Hrelia, Agnese Graziosi, and Fabiana Morroni. "Back to The Fusion: Mitofusin-2 in Alzheimer’s Disease." Journal of Clinical Medicine 9, no. 1 (January 2, 2020): 126. http://dx.doi.org/10.3390/jcm9010126.
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Mitochondria are dynamic organelles that undergo constant fission and fusion. Mitochondria dysfunction underlies several human disorders, including Alzheimer’s disease (AD). Preservation of mitochondrial dynamics is fundamental for regulating the organelle’s functions. Several proteins participate in the regulation of mitochondrial morphology and networks, and among these, Mitofusin 2 (Mfn2) has been extensively studied. This review focuses on the role of Mfn2 in mitochondrial dynamics and in the crosstalk between mitochondria and the endoplasmic reticulum, in particular in AD. Understanding how this protein may be related to AD pathogenesis will provide essential information for the development of therapies for diseases linked to disturbed mitochondrial dynamics, as in AD.
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Martel, Cécile, Le Ha Huynh, Anne Garnier, Renée Ventura-Clapier, and Catherine Brenner. "Inhibition of the Mitochondrial Permeability Transition for Cytoprotection: DirectversusIndirect Mechanisms." Biochemistry Research International 2012 (2012): 1–13. http://dx.doi.org/10.1155/2012/213403.
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Mitochondria are fascinating organelles, which fulfill multiple cellular functions, as diverse as energy production, fatty acidβoxidation, reactive oxygen species (ROS) production and detoxification, and cell death regulation. The coordination of these functions relies on autonomous mitochondrial processes as well as on sustained cross-talk with other organelles and/or the cytosol. Therefore, this implies a tight regulation of mitochondrial functions to ensure cell homeostasis. In many diseases (e.g., cancer, cardiopathies, nonalcoholic fatty liver diseases, and neurodegenerative diseases), mitochondria can receive harmful signals, dysfunction and then, participate to pathogenesis. They can undergo either a decrease of their bioenergetic function or a process called mitochondrial permeability transition (MPT) that can coordinate cell death execution. Many studies present evidence that protection of mitochondria limits disease progression and severity. Here, we will review recent strategies to preserve mitochondrial functions via direct or indirect mechanisms of MPT inhibition. Thus, several mitochondrial proteins may be considered for cytoprotective-targeted therapies.
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Maycotte, Paola, Alvaro Marín-Hernández, Miriam Goyri-Aguirre, Maricruz Anaya-Ruiz, Julio Reyes-Leyva, and Paulina Cortés-Hernández. "Mitochondrial dynamics and cancer." Tumor Biology 39, no. 5 (May 2017): 101042831769839. http://dx.doi.org/10.1177/1010428317698391.
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Cancer is among the leading causes of death worldwide, and the number of new cases continues to rise. Despite recent advances in diagnosis and therapeutic strategies, millions of cancer-related deaths occur, indicating the need for better therapies and diagnostic strategies. Mitochondria and metabolic alterations have been recognized as important for cancer progression. However, a more precise understanding of how to manipulate mitochondria-related processes for cancer therapy remains to be established. Mitochondria are highly dynamic organelles which continually fuse and divide in response to diverse stimuli. Participation in the aforementioned processes requires a precise regulation at many levels that allows the cell to couple mitochondrial activity to nutrient availability, biosynthetic demands, proliferation rates, and external stimuli. The many functions of these organelles are intimately linked to their morphology. Recent evidence suggests an important link between mitochondrial morphology and disease, including neurodegenerative, inflammatory diseases and cancer. Here, we review recent advances in the understanding of mitochondrial dynamics with a special focus on its relationship to tumor progression.
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Blagov, Alexander V., Sergey Kozlov, Tatiana Blokhina, Vasily N. Sukhorukov, and Aleksander N. Orekhov. "Targeting Mitochondrial Dynamics Proteins for the Development of Therapies for Cardiovascular Diseases." International Journal of Molecular Sciences 23, no. 23 (November 25, 2022): 14741. http://dx.doi.org/10.3390/ijms232314741.
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Cardiovascular diseases are one of the leading causes of death worldwide. The identification of new pathogenetic targets contributes to more efficient development of new types of drugs for the treatment of cardiovascular diseases. This review highlights the problem of mitochondrial dynamics disorders, in the context of cardiovascular diseases. A change in the normal function of mitochondrial dynamics proteins is one of the reasons for the development of the pathological state of cardiomyocytes. Based on this, therapeutic targeting of these proteins may be a promising strategy in the development of cardiac drugs. Here we will consider changes for each process of mitochondrial dynamics in cardiovascular diseases: fission and fusion of mitochondria, mitophagy, mitochondrial transport and biogenesis, and also analyze the prospects of the considered protein targets based on existing drug developments.
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Kochar Kaur, Kulvinder. "Role of Mitochondrial Unfolding Protein Response in Reproduction and Aging with Utilization of Autologous Mitochondrial Injections in Mitochondrial Diseases along with in Aging Oocytes." Open Access Journal of Gynecology 5, no. 1 (2020): 1–10. http://dx.doi.org/10.23880/oajg-16000187.
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There is a very essential role that mitochondria play in controlling energy metabolism with respect to oocytes maturation as well as Preimplantation embryos in which both quantity as well as morphology of mitochondria along with mitochondrial DNA amount get very closely controlled. Lot of mouse experimental kinds having impaired mitochondrial function cause infertility that validates the crucial part played by mitochondria in female reproduction. On finding abnormalities of mitochondrial action both cells as well as organisms utilize methods that are aimed at recuperating or help in get the mitochondria rescued and delete mitochondria which can’t in anyway be salvaged. Of these methods Mitochondrial Unfolded Protein Response (mtUPR) has been associated with ageing avoidance recently, since mitochondrial aids in age associated collection of injured proteins, decreased oxidative phosphorylation as well as reactive oxygen species (ROS) synthesis. Importance of these lies in female reproduction since if mtUPR genes like Clpp are removed following specific targeting it causes female infertility, causing problems in maturing of oocyte along with 2 cell embryo generation and inability to develop blastocyst. Additionally if CLPP is missing it results in exaggerated follicular removal with a phenotype mimic long premature ovarian failure. More studies will give understanding of both physiological and pathological regulation of oocyte as well as initial embryonic mitochondrial action that workers are trying to use in generating therapies that are innovative in aging oocytes and in women presenting with mitochondrial inheritent abnormalities and thus treating female infertility with elderly females.
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Middleton, Paul, and Nikhil Vergis. "Mitochondrial dysfunction and liver disease: role, relevance, and potential for therapeutic modulation." Therapeutic Advances in Gastroenterology 14 (January 2021): 175628482110313. http://dx.doi.org/10.1177/17562848211031394.
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Mitochondria are key organelles involved in energy production as well as numerous metabolic processes. There is a growing interest in the role of mitochondrial dysfunction in the pathogenesis of common chronic diseases as well as in cancer development. This review will examine the role mitochondria play in the pathophysiology of common liver diseases, including alcohol-related liver disease, non-alcoholic fatty liver disease, chronic hepatitis B and hepatocellular carcinoma. Mitochondrial dysfunction is described widely in the literature in studies examining patient tissue and in disease models. Despite significant differences in pathophysiology between chronic liver diseases, common mitochondrial defects are described, including increased mitochondrial reactive oxygen species production and impaired oxidative phosphorylation. We review the current literature on mitochondrial-targeted therapies, which have the potential to open new therapeutic avenues in the management of patients with chronic liver disease.
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Braga, Patrícia C., Marco G. Alves, Anabela S. Rodrigues, and Pedro F. Oliveira. "Mitochondrial Pathophysiology on Chronic Kidney Disease." International Journal of Molecular Sciences 23, no. 3 (February 4, 2022): 1776. http://dx.doi.org/10.3390/ijms23031776.
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In healthy kidneys, interstitial fibroblasts are responsible for the maintenance of renal architecture. Progressive interstitial fibrosis is thought to be a common pathway for chronic kidney diseases (CKD). Diabetes is one of the boosters of CKD. There is no effective treatment to improve kidney function in CKD patients. The kidney is a highly demanding organ, rich in redox reactions occurring in mitochondria, making it particularly vulnerable to oxidative stress (OS). A dysregulation in OS leads to an impairment of the Electron transport chain (ETC). Gene deficiencies in the ETC are closely related to the development of kidney disease, providing evidence that mitochondria integrity is a key player in the early detection of CKD. The development of novel CKD therapies is needed since current methods of treatment are ineffective. Antioxidant targeted therapies and metabolic approaches revealed promising results to delay the progression of some markers associated with kidney disease. Herein, we discuss the role and possible origin of fibroblasts and the possible potentiators of CKD. We will focus on the important features of mitochondria in renal cell function and discuss their role in kidney disease progression. We also discuss the potential of antioxidants and pharmacologic agents to delay kidney disease progression.
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Protasoni, Margherita, and Manuel Serrano. "Targeting Mitochondria to Control Ageing and Senescence." Pharmaceutics 15, no. 2 (January 20, 2023): 352. http://dx.doi.org/10.3390/pharmaceutics15020352.
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Ageing is accompanied by a progressive impairment of cellular function and a systemic deterioration of tissues and organs, resulting in increased vulnerability to multiple diseases. Here, we review the interplay between two hallmarks of ageing, namely, mitochondrial dysfunction and cellular senescence. The targeting of specific mitochondrial features in senescent cells has the potential of delaying or even reverting the ageing process. A deeper and more comprehensive understanding of mitochondrial biology in senescent cells is necessary to effectively face this challenge. Here, we discuss the main alterations in mitochondrial functions and structure in both ageing and cellular senescence, highlighting the differences and similarities between the two processes. Moreover, we describe the treatments available to target these pathways and speculate on possible future directions of anti-ageing and anti-senescence therapies targeting mitochondria.
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Ahuja, Abhimanyu S. "Understanding mitochondrial myopathies: a review." PeerJ 6 (May 21, 2018): e4790. http://dx.doi.org/10.7717/peerj.4790.
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Mitochondria are small, energy-producing structures vital to the energy needs of the body. Genetic mutations cause mitochondria to fail to produce the energy needed by cells and organs which can cause severe disease and death. These genetic mutations are likely to be in the mitochondrial DNA (mtDNA), or possibly in the nuclear DNA (nDNA). The goal of this review is to assess the current understanding of mitochondrial diseases. This review focuses on the pathology, causes, risk factors, symptoms, prevalence data, symptomatic treatments, and new research aimed at possible preventions and/or treatments of mitochondrial diseases. Mitochondrial myopathies are mitochondrial diseases that cause prominent muscular symptoms such as muscle weakness and usually present with a multitude of symptoms and can affect virtually all organ systems. There is no cure for these diseases as of today. Treatment is generally supportive and emphasizes symptom management. Mitochondrial diseases occur infrequently and hence research funding levels tend to be low in comparison with more common diseases. On the positive side, quite a few genetic defects responsible for mitochondrial diseases have been identified, which are in turn being used to investigate potential treatments. Speech therapy, physical therapy, and respiratory therapy have been used in mitochondrial diseases with variable results. These therapies are not curative and at best help with maintaining a patient’s current abilities to move and function.
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Doblado, Laura, Claudia Lueck, Claudia Rey, Alejandro K. Samhan-Arias, Ignacio Prieto, Alessandra Stacchiotti, and Maria Monsalve. "Mitophagy in Human Diseases." International Journal of Molecular Sciences 22, no. 8 (April 9, 2021): 3903. http://dx.doi.org/10.3390/ijms22083903.
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Mitophagy is a selective autophagic process, essential for cellular homeostasis, that eliminates dysfunctional mitochondria. Activated by inner membrane depolarization, it plays an important role during development and is fundamental in highly differentiated post-mitotic cells that are highly dependent on aerobic metabolism, such as neurons, muscle cells, and hepatocytes. Both defective and excessive mitophagy have been proposed to contribute to age-related neurodegenerative diseases, such as Parkinson’s and Alzheimer’s diseases, metabolic diseases, vascular complications of diabetes, myocardial injury, muscle dystrophy, and liver disease, among others. Pharmacological or dietary interventions that restore mitophagy homeostasis and facilitate the elimination of irreversibly damaged mitochondria, thus, could serve as potential therapies in several chronic diseases. However, despite extraordinary advances in this field, mainly derived from in vitro and preclinical animal models, human applications based on the regulation of mitochondrial quality in patients have not yet been approved. In this review, we summarize the key selective mitochondrial autophagy pathways and their role in prevalent chronic human diseases and highlight the potential use of specific interventions.
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Morciano, Giampaolo, Simone Patergnani, Massimo Bonora, Gaia Pedriali, Anna Tarocco, Esmaa Bouhamida, Saverio Marchi, et al. "Mitophagy in Cardiovascular Diseases." Journal of Clinical Medicine 9, no. 3 (March 24, 2020): 892. http://dx.doi.org/10.3390/jcm9030892.
Full textAbstract:
Cardiovascular diseases are one of the leading causes of death. Increasing evidence has shown that pharmacological or genetic targeting of mitochondria can ameliorate each stage of these pathologies, which are strongly associated with mitochondrial dysfunction. Removal of inefficient and dysfunctional mitochondria through the process of mitophagy has been reported to be essential for meeting the energetic requirements and maintaining the biochemical homeostasis of cells. This process is useful for counteracting the negative phenotypic changes that occur during cardiovascular diseases, and understanding the molecular players involved might be crucial for the development of potential therapies. Here, we summarize the current knowledge on mitophagy (and autophagy) mechanisms in the context of heart disease with an important focus on atherosclerosis, ischemic heart disease, cardiomyopathies, heart failure, hypertension, arrhythmia, congenital heart disease and peripheral vascular disease. We aim to provide a complete background on the mechanisms of action of this mitochondrial quality control process in cardiology and in cardiac surgery by also reviewing studies on the use of known compounds able to modulate mitophagy for cardioprotective purposes.
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Stamerra, Cosimo Andrea, Paolo Di Giosia, Paolo Giorgini, Claudio Ferri, Vasily N. Sukhorukov, and Amirhossein Sahebkar. "Mitochondrial Dysfunction and Cardiovascular Disease: Pathophysiology and Emerging Therapies." Oxidative Medicine and Cellular Longevity 2022 (August 2, 2022): 1–16. http://dx.doi.org/10.1155/2022/9530007.
Full textAbstract:
Mitochondria ensure the supply of cellular energy through the production of ATP via oxidative phosphorylation. The alteration of this process, called mitochondrial dysfunction, leads to a reduction in ATP and an increase in the production of reactive oxygen species (ROS). Mitochondrial dysfunction can be caused by mitochondrial/nuclear DNA mutations, or it can be secondary to pathological conditions such as cardiovascular disease, aging, and environmental stress. The use of therapies aimed at the prevention/correction of mitochondrial dysfunction, in the context of the specific treatment of cardiovascular diseases, is a topic of growing interest. In this context, the data are conflicting since preclinical studies are numerous, but there are no large randomized studies.
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Marra, Federica, Paola Lunetti, Rosita Curcio, Francesco Massimo Lasorsa, Loredana Capobianco, Vito Porcelli, Vincenza Dolce, Giuseppe Fiermonte, and Pasquale Scarcia. "An Overview of Mitochondrial Protein Defects in Neuromuscular Diseases." Biomolecules 11, no. 11 (November 4, 2021): 1633. http://dx.doi.org/10.3390/biom11111633.
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Neuromuscular diseases (NMDs) are dysfunctions that involve skeletal muscle and cause incorrect communication between the nerves and muscles. The specific causes of NMDs are not well known, but most of them are caused by genetic mutations. NMDs are generally progressive and entail muscle weakness and fatigue. Muscular impairments can differ in onset, severity, prognosis, and phenotype. A multitude of possible injury sites can make diagnosis of NMDs difficult. Mitochondria are crucial for cellular homeostasis and are involved in various metabolic pathways; for this reason, their dysfunction can lead to the development of different pathologies, including NMDs. Most NMDs due to mitochondrial dysfunction have been associated with mutations of genes involved in mitochondrial biogenesis and metabolism. This review is focused on some mitochondrial routes such as the TCA cycle, OXPHOS, and β-oxidation, recently found to be altered in NMDs. Particular attention is given to the alterations found in some genes encoding mitochondrial carriers, proteins of the inner mitochondrial membrane able to exchange metabolites between mitochondria and the cytosol. Briefly, we discuss possible strategies used to diagnose NMDs and therapies able to promote patient outcome.
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Agrawal, Anurag, and Ulaganathan Mabalirajan. "Rejuvenating cellular respiration for optimizing respiratory function: targeting mitochondria." American Journal of Physiology-Lung Cellular and Molecular Physiology 310, no. 2 (January 15, 2016): L103—L113. http://dx.doi.org/10.1152/ajplung.00320.2015.
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Altered bioenergetics with increased mitochondrial reactive oxygen species production and degradation of epithelial function are key aspects of pathogenesis in asthma and chronic obstructive pulmonary disease (COPD). This motif is not unique to obstructive airway disease, reported in related airway diseases such as bronchopulmonary dysplasia and parenchymal diseases such as pulmonary fibrosis. Similarly, mitochondrial dysfunction in vascular endothelium or skeletal muscles contributes to the development of pulmonary hypertension and systemic manifestations of lung disease. In experimental models of COPD or asthma, the use of mitochondria-targeted antioxidants, such as MitoQ, has substantially improved mitochondrial health and restored respiratory function. Modulation of noncoding RNA or protein regulators of mitochondrial biogenesis, dynamics, or degradation has been found to be effective in models of fibrosis, emphysema, asthma, and pulmonary hypertension. Transfer of healthy mitochondria to epithelial cells has been associated with remarkable therapeutic efficacy in models of acute lung injury and asthma. Together, these form a 3R model—repair, reprogramming, and replacement—for mitochondria-targeted therapies in lung disease. This review highlights the key role of mitochondrial function in lung health and disease, with a focus on asthma and COPD, and provides an overview of mitochondria-targeted strategies for rejuvenating cellular respiration and optimizing respiratory function in lung diseases.
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Gruosso, Francesco, Vincenzo Montano, Costanza Simoncini, Gabriele Siciliano, and Michelangelo Mancuso. "Therapeutical Management and Drug Safety in Mitochondrial Diseases—Update 2020." Journal of Clinical Medicine 10, no. 1 (December 29, 2020): 94. http://dx.doi.org/10.3390/jcm10010094.
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Mitochondrial diseases (MDs) are a group of genetic disorders that may manifest with vast clinical heterogeneity in childhood or adulthood. These diseases are characterized by dysfunctional mitochondria and oxidative phosphorylation deficiency. Patients are usually treated with supportive and symptomatic therapies due to the absence of a specific disease-modifying therapy. Management of patients with MDs is based on different therapeutical strategies, particularly the early treatment of organ-specific complications and the avoidance of catabolic stressors or toxic medication. In this review, we discuss the therapeutic management of MDs, supported by a revision of the literature, and provide an overview of the drugs that should be either avoided or carefully used both for the specific treatment of MDs and for the management of comorbidities these subjects may manifest. We finally discuss the latest therapies approved for the management of MDs and some ongoing clinical trials.
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Matuz-Mares, Deyamira, Martin González-Andrade, Minerva Georgina Araiza-Villanueva, María Magdalena Vilchis-Landeros, and Héctor Vázquez-Meza. "Mitochondrial Calcium: Effects of Its Imbalance in Disease." Antioxidants 11, no. 5 (April 20, 2022): 801. http://dx.doi.org/10.3390/antiox11050801.
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Calcium is used in many cellular processes and is maintained within the cell as free calcium at low concentrations (approximately 100 nM), compared with extracellular (millimolar) concentrations, to avoid adverse effects such as phosphate precipitation. For this reason, cells have adapted buffering strategies by compartmentalizing calcium into mitochondria and the endoplasmic reticulum (ER). In mitochondria, the calcium concentration is in the millimolar range, as it is in the ER. Mitochondria actively contribute to buffering cellular calcium, but if matrix calcium increases beyond physiological demands, it can promote the opening of the mitochondrial permeability transition pore (mPTP) and, consequently, trigger apoptotic or necrotic cell death. The pathophysiological implications of mPTP opening in ischemia-reperfusion, liver, muscle, and lysosomal storage diseases, as well as those affecting the central nervous system, for example, Parkinson’s disease (PD), Alzheimer’s disease (AD), Huntington’s disease (HD), and amyotrophic lateral sclerosis (ALS) have been reported. In this review, we present an updated overview of the main cellular mechanisms of mitochondrial calcium regulation. We specially focus on neurodegenerative diseases related to imbalances in calcium homeostasis and summarize some proposed therapies studied to attenuate these diseases.
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Tian, Rong, Wilson S. Colucci, Zoltan Arany, Markus M. Bachschmid, Scott W. Ballinger, Sihem Boudina, James E. Bruce, et al. "Unlocking the Secrets of Mitochondria in the Cardiovascular System." Circulation 140, no. 14 (October 2019): 1205–16. http://dx.doi.org/10.1161/circulationaha.119.040551.
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Mitochondria have emerged as a central factor in the pathogenesis and progression of heart failure, and other cardiovascular diseases, as well, but no therapies are available to treat mitochondrial dysfunction. The National Heart, Lung, and Blood Institute convened a group of leading experts in heart failure, cardiovascular diseases, and mitochondria research in August 2018. These experts reviewed the current state of science and identified key gaps and opportunities in basic, translational, and clinical research focusing on the potential of mitochondria-based therapeutic strategies in heart failure. The workshop provided short- and long-term recommendations for moving the field toward clinical strategies for the prevention and treatment of heart failure and cardiovascular diseases by using mitochondria-based approaches.
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Li, Danni, Fenghua Tao, and Lin Jin. "Mitochondrial Dysfunction in Intervertebral Disc Degeneration: From Pathogenesis to Therapeutic Target." Oxidative Medicine and Cellular Longevity 2020 (November 27, 2020): 1–13. http://dx.doi.org/10.1155/2020/8880320.
Full textAbstract:
Mitochondria are cytosolic organelles essential for cellular function and survival. The function of mitochondria is maintained by mitochondrial quality control systems including mitochondrial fission and fusion to adapt the altered environment and mitophagy for removal of damaged mitochondria. Mitochondrial dysfunction is closely involved in aging-related diseases. Intervertebral disc (IVD) degeneration, an aging-associated process, is the major contributor to low back pain. Growing evidence has suggested that the mitochondrial function in IVD cells is severely compromised during the degenerative process of IVD, and dysfunctional mitochondria along with impaired mitochondrial dynamics and mitophagy cause a series of cascade reactions that have been implicated in increased oxidative stress, senescence, matrix catabolism, and apoptosis of IVD cells, thereby contributing to the degeneration of IVD. Accordingly, therapies that target mitochondrial dysfunction and related mechanisms, such as ROS generation, mitophagy, and specific molecules and signaling, hold great promise. The present review summarizes the current state of the role of mitochondrial dysfunction in the pathophysiology of IVD degeneration and potential therapeutic strategies that could be developed.
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Protasoni, Margherita, and Massimo Zeviani. "Mitochondrial Structure and Bioenergetics in Normal and Disease Conditions." International Journal of Molecular Sciences 22, no. 2 (January 8, 2021): 586. http://dx.doi.org/10.3390/ijms22020586.
Full textAbstract:
Mitochondria are ubiquitous intracellular organelles found in almost all eukaryotes and involved in various aspects of cellular life, with a primary role in energy production. The interest in this organelle has grown stronger with the discovery of their link to various pathologies, including cancer, aging and neurodegenerative diseases. Indeed, dysfunctional mitochondria cannot provide the required energy to tissues with a high-energy demand, such as heart, brain and muscles, leading to a large spectrum of clinical phenotypes. Mitochondrial defects are at the origin of a group of clinically heterogeneous pathologies, called mitochondrial diseases, with an incidence of 1 in 5000 live births. Primary mitochondrial diseases are associated with genetic mutations both in nuclear and mitochondrial DNA (mtDNA), affecting genes involved in every aspect of the organelle function. As a consequence, it is difficult to find a common cause for mitochondrial diseases and, subsequently, to offer a precise clinical definition of the pathology. Moreover, the complexity of this condition makes it challenging to identify possible therapies or drug targets.
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Protasoni, Margherita, and Massimo Zeviani. "Mitochondrial Structure and Bioenergetics in Normal and Disease Conditions." International Journal of Molecular Sciences 22, no. 2 (January 8, 2021): 586. http://dx.doi.org/10.3390/ijms22020586.
Full textAbstract:
Mitochondria are ubiquitous intracellular organelles found in almost all eukaryotes and involved in various aspects of cellular life, with a primary role in energy production. The interest in this organelle has grown stronger with the discovery of their link to various pathologies, including cancer, aging and neurodegenerative diseases. Indeed, dysfunctional mitochondria cannot provide the required energy to tissues with a high-energy demand, such as heart, brain and muscles, leading to a large spectrum of clinical phenotypes. Mitochondrial defects are at the origin of a group of clinically heterogeneous pathologies, called mitochondrial diseases, with an incidence of 1 in 5000 live births. Primary mitochondrial diseases are associated with genetic mutations both in nuclear and mitochondrial DNA (mtDNA), affecting genes involved in every aspect of the organelle function. As a consequence, it is difficult to find a common cause for mitochondrial diseases and, subsequently, to offer a precise clinical definition of the pathology. Moreover, the complexity of this condition makes it challenging to identify possible therapies or drug targets.
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Lee, Yun Haeng, Ji Yun Park, Haneur Lee, Eun Seon Song, Myeong Uk Kuk, Junghyun Joo, Sekyung Oh, Hyung Wook Kwon, Joon Tae Park, and Sang Chul Park. "Targeting Mitochondrial Metabolism as a Strategy to Treat Senescence." Cells 10, no. 11 (November 3, 2021): 3003. http://dx.doi.org/10.3390/cells10113003.
Full textAbstract:
Mitochondria are one of organelles that undergo significant changes associated with senescence. An increase in mitochondrial size is observed in senescent cells, and this increase is ascribed to the accumulation of dysfunctional mitochondria that generate excessive reactive oxygen species (ROS). Such dysfunctional mitochondria are prime targets for ROS-induced damage, which leads to the deterioration of oxidative phosphorylation and increased dependence on glycolysis as an energy source. Based on findings indicating that senescent cells exhibit mitochondrial metabolic alterations, a strategy to induce mitochondrial metabolic reprogramming has been proposed to treat aging and age-related diseases. In this review, we discuss senescence-related mitochondrial changes and consequent mitochondrial metabolic alterations. We assess the significance of mitochondrial metabolic reprogramming for senescence regulation and propose the appropriate control of mitochondrial metabolism to ameliorate senescence. Learning how to regulate mitochondrial metabolism will provide knowledge for the control of aging and age-related pathologies. Further research focusing on mitochondrial metabolic reprogramming will be an important guide for the development of anti-aging therapies, and will provide novel strategies for anti-aging interventions.
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Angale, Ruth. "The Role of Mitochondria in Alzheimer's disease: Neurodegenerative Disease and Future Therapeutic Options." Neuroscience and Neurological Surgery 2, no. 1 (February 19, 2018): 01–03. http://dx.doi.org/10.31579/2578-8868/026.
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Mitochondria are cytoplasmic organelles responsible for life and death. Extensive evidence from animal and clinical studies suggests that mitochondria play a critical role in aging, cancer, diabetes and neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and Huntington's disease. Several lines of research suggest that mitochondrial oxidative damage is an important cellular change in most late-onset neurodegenerative diseases. Further, emerging evidence suggests that structural changes in mitochondria, including increased mitochondrial fragmentation and decreased mitochondrial fusion, are critical factors associated with mitochondrial dysfunction and cell death in aging and age-related diseases. In addition, epigenetic factors and lifestyle activities may contribute to selective disease susceptibility for each of these diseases. This paper discusses research that has elucidated features of mitochondria that are associated with cellular dysfunction in aging and neurodegenerative diseases. This paper also discusses mitochondrial abnormalities and potential mitochondrial therapeutics in AD. Alzheimer's disease (AD) is characterized by neuronal loss and gradual cognitive impairment. AD is the leading cause of dementia worldwide and the incidence is increasing rapidly, with diagnoses expected to triple by the year 2050. Impaired cholinergic transmission is a major role player in the rapid deterioration associated with AD, primarily as a result of increased acetylcholinesterase (AChE) in the AD brain, responsible for reducing the amount of acetylcholine (ACh). Current drug therapies, known as AChE inhibitors (AChEIs), target this heightened level of AChE in an attempt to slow disease progression. AChEIs have only showed success in the treatment of mild to moderate AD symptoms, with the glutamate inhibitor memantine being the most common drug prescribed for the management of severe AD.
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López, Sònia, Òscar Miró, Esteban Martínez, Enric Pedrol, Benjamín Rodríguez-Santiago, Ana Milinkovic, Anna Soler, et al. "Mitochondrial Effects of Antiretroviral Therapies in Asymptomatic Patients." Antiviral Therapy 9, no. 1 (January 2004): 47–55. http://dx.doi.org/10.1177/135965350400900109.
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Background A decrease in the mitochondrial (mt) DNA to nuclear DNA ratio has gained acceptance as a marker of mitochondrial toxicity in treated HIV-infected patients, but the functional meaning of this alteration is unclear. Methods We assessed mtDNA content, mitochondrial content and function in peripheral blood mononuclear cells (PBMCs) of consecutive asymptomatic HIV-infected patients. Patients selected had been receiving a first-line highly active antiretroviral therapy (HAART) regimen for at least 6 months, consisting of zidovudine plus lamivudine or stavudine plus didanosine plus either nelfinavir or nevirapine, or were antiretroviral-naive. The mtDNA content was assessed by quantitative real-time PCR, mitochondrial content by citrate synthase activity, enzyme activity of complexes III and IV (both partially encoded by mtDNA) of the electron transport chain by spectrophotometry, oxygen consumption by polarography, and oxidative damage in cell membranes by monitoring cis-parinaric acid fluorescence. Results Mitochondrial content was significantly lower in all treated groups. Patients receiving stavudine plus didanosine had mtDNA depletion and a decrease in complex IV activity. However, oxygen consumption capacity and lipid peroxidation were unaffected in all groups. Conclusion Long-term HAART may induce mitochondrial abnormalities in PBMC mitochondria, which do not necessarily translate into functional abnormalities, at least in asymptomatic patients. This study was presented in the 4th International Workshop on Adverse Drug Reactions & Lipodystrophy in HIV (San Diego, Calif., USA, September 2002) and in ‘Late Breakers & Hot Topics’ session in the 6th International Congress on Drug Therapy in HIV Infection (Glasgow, UK, November 2002).
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Peterman, E. M., C. Sullivan, M. F. Goody, I. Rodriguez-Nunez, J. A. Yoder, and C. H. Kim. "Neutralization of Mitochondrial Superoxide by Superoxide Dismutase 2 Promotes Bacterial Clearance and Regulates Phagocyte Numbers in Zebrafish." Infection and Immunity 83, no. 1 (November 10, 2014): 430–40. http://dx.doi.org/10.1128/iai.02245-14.
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Mitochondria are known primarily as the location of the electron transport chain and energy production in cells. More recently, mitochondria have been shown to be signaling centers for apoptosis and inflammation. Reactive oxygen species (ROS) generated as by-products of the electron transport chain within mitochondria significantly impact cellular signaling pathways. Because of the toxic nature of ROS, mitochondria possess an antioxidant enzyme, superoxide dismutase 2 (SOD2), to neutralize ROS. If mitochondrial antioxidant enzymes are overwhelmed during severe infections, mitochondrial dysfunction can occur and lead to multiorgan failure or death.Pseudomonas aeruginosais an opportunistic pathogen that can infect immunocompromised patients. Infochemicals and exotoxins associated withP. aeruginosaare capable of causing mitochondrial dysfunction. In this work, we describe the roles of SOD2 and mitochondrial ROS regulation in the zebrafish innate immune response toP. aeruginosainfection.sod2is upregulated in mammalian macrophages and neutrophils in response to lipopolysaccharidein vitro, andsod2knockdown in zebrafish results in an increased bacterial burden. Further investigation revealed that phagocyte numbers are compromised in Sod2-deficient zebrafish. Addition of the mitochondrion-targeted ROS-scavenging chemical MitoTEMPO rescues neutrophil numbers and reduces the bacterial burden in Sod2-deficient zebrafish. Our work highlights the importance of mitochondrial ROS regulation by SOD2 in the context of innate immunity and supports the use of mitochondrion-targeted ROS scavengers as potential adjuvant therapies during severe infections.
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Fields, Matteo, Annalisa Marcuzzi, Arianna Gonelli, Claudio Celeghini, Natalia Maximova, and Erika Rimondi. "Mitochondria-Targeted Antioxidants, an Innovative Class of Antioxidant Compounds for Neurodegenerative Diseases: Perspectives and Limitations." International Journal of Molecular Sciences 24, no. 4 (February 13, 2023): 3739. http://dx.doi.org/10.3390/ijms24043739.
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Neurodegenerative diseases comprise a wide spectrum of pathologies characterized by progressive loss of neuronal functions and structures. Despite having different genetic backgrounds and etiology, in recent years, many studies have highlighted a point of convergence in the mechanisms leading to neurodegeneration: mitochondrial dysfunction and oxidative stress have been observed in different pathologies, and their detrimental effects on neurons contribute to the exacerbation of the pathological phenotype at various degrees. In this context, increasing relevance has been acquired by antioxidant therapies, with the purpose of restoring mitochondrial functions in order to revert the neuronal damage. However, conventional antioxidants were not able to specifically accumulate in diseased mitochondria, often eliciting harmful effects on the whole body. In the last decades, novel, precise, mitochondria-targeted antioxidant (MTA) compounds have been developed and studied, both in vitro and in vivo, to address the need to counter the oxidative stress in mitochondria and restore the energy supply and membrane potentials in neurons. In this review, we focus on the activity and therapeutic perspectives of MitoQ, SkQ1, MitoVitE and MitoTEMPO, the most studied compounds belonging to the class of MTA conjugated to lipophilic cations, in order to reach the mitochondrial compartment.
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Su, Xin, Mingyang Zhou, Yingjian Li, Na An, Fan Yang, Guoxia Zhang, Lianjiang Xu, Hengwen Chen, Hongjin Wu, and Yanwei Xing. "Mitochondrial Damage in Myocardial Ischemia/Reperfusion Injury and Application of Natural Plant Products." Oxidative Medicine and Cellular Longevity 2022 (May 16, 2022): 1–19. http://dx.doi.org/10.1155/2022/8726564.
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Ischemic heart disease (IHD) is currently one of the leading causes of death among cardiovascular diseases worldwide. In addition, blood reflow and reperfusion paradoxically also lead to further death of cardiomyocytes and increase the infarct size. Multiple evidences indicated that mitochondrial function and structural disorders were the basic driving force of IHD. We summed up the latest evidence of the basic associations and underlying mechanisms of mitochondrial damage in the event of ischemia/reperfusion (I/R) injury. This review then reviewed natural plant products (NPPs) which have been demonstrated to mitochondria-targeted therapeutic effects during I/R injury and the potential pathways involved. We realized that NPPs mainly maintained the integrality of mitochondria membrane and ameliorated dysfunction, such as improving abnormal mitochondrial calcium handling and inhibiting oxidative stress, so as to protect cardiomyocytes during I/R injury. This information will improve our knowledge of mitochondrial biology and I/R-induced injury’s pathogenesis and exhibit that NPPs hold promise for translation into potential therapies that target mitochondria.
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Molenaars, Marte, Eileen G. Daniels, Amber Meurs, Georges E. Janssens, and Riekelt H. Houtkooper. "Mitochondrial cross-compartmental signalling to maintain proteostasis and longevity." Philosophical Transactions of the Royal Society B: Biological Sciences 375, no. 1801 (May 4, 2020): 20190414. http://dx.doi.org/10.1098/rstb.2019.0414.
Full textAbstract:
Lifespan in eukaryotic species can be prolonged by shifting from cellular states favouring growth to those favouring maintenance and stress resistance. For instance, perturbations in mitochondrial oxidative phosphorylation (OXPHOS) can shift cells into this latter state and extend lifespan. Because mitochondria rely on proteins synthesized from nuclear as well as mitochondrial DNA, they need to constantly send and receive messages from other compartments of the cell in order to function properly and maintain homeostasis, and lifespan extension is often dependent on this cross-compartmental signalling. Here, we describe the mechanisms of bi-directional mitochondrial cross-compartmental signalling resulting in proteostasis and longevity. These proteostasis mechanisms are highly context-dependent, governed by the origin and extent of stress. Furthermore, we discuss the translatability of these mechanisms and explore therapeutic developments, such as the antibiotic studies targeting mitochondria or mitochondria-derived peptides as therapies for age-related diseases such as neurodegeneration and cancer. This article is part of the theme issue ‘Retrograde signalling from endosymbiotic organelles’.
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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.
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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.
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Mazur, Monika, Hanna Kmita, and Małgorzata Wojtkowska. "The Diversity of the Mitochondrial Outer Membrane Protein Import Channels: Emerging Targets for Modulation." Molecules 26, no. 13 (July 4, 2021): 4087. http://dx.doi.org/10.3390/molecules26134087.
Full textAbstract:
The functioning of mitochondria and their biogenesis are largely based on the proper function of the mitochondrial outer membrane channels, which selectively recognise and import proteins but also transport a wide range of other molecules, including metabolites, inorganic ions and nucleic acids. To date, nine channels have been identified in the mitochondrial outer membrane of which at least half represent the mitochondrial protein import apparatus. When compared to the mitochondrial inner membrane, the presented channels are mostly constitutively open and consequently may participate in transport of different molecules and contribute to relevant changes in the outer membrane permeability based on the channel conductance. In this review, we focus on the channel structure, properties and transported molecules as well as aspects important to their modulation. This information could be used for future studies of the cellular processes mediated by these channels, mitochondrial functioning and therapies for mitochondria-linked diseases.
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Baek, Lily, Junegoo Lee, Mariah J. Berner, Katherine E. Pendleton, Emily B. Goff, Karen Wang, James P. Barrish, et al. "Abstract 6384: Morphological and functional plasticity of mitochondria promotes chemotherapy resistance in triple negative breast cancer." Cancer Research 82, no. 12_Supplement (June 15, 2022): 6384. http://dx.doi.org/10.1158/1538-7445.am2022-6384.
Full textAbstract:
Abstract Mitochondrial metabolism plays a key role in triple negative breast cancer (TNBC) aggressiveness. As TNBC has limited targeted therapy options, chemotherapies remain the mainstay treatment. Nearly 50% of TNBC patients harbor substantial residual cancer following chemotherapy, leading to high rates of recurrence. Using longitudinal biopsies from orthotopic patient-derived xenograft (PDX) models and TNBC patients, we found residual tumors following chemotherapy transitioned to a unique metabolic state characterized by high mitochondrial oxidative phosphorylation (oxphos). This state was transient, with tumors reverting to their baseline glycolysis-high phenotype when they were allowed to regrow in the absence of treatment. Using genomic sequencing and cellular barcode-mediated clonal tracking, we found this mechanism of chemoresistance arose in the absence of clonal selection, suggesting chemotherapy induced plastic (i.e., non-genomic) programs enabling cell survival following treatment. Blocking oxphos with an inhibitor of electron transport chain Complex I (IACS010759; PMID:29892070) was significantly more efficacious against residual than pre-treated tumors (PMID:30996079), providing evidence that dynamic metabolic phenotypes represent targetable therapeutic vulnerabilities for TNBC. Using longitudinal samples collected from PDX models undergoing treatments with anthracyclines, platinums, and/or taxanes, we visualized and quantified mitochondrial structure in two- and three-dimensions by electron microscopy. These studies revealed extensive alteration of mitochondrial structure and number in residual tumor cells, and these changes reverted when residual tumors were allowed to regrow in the absence of treatment. We then administered chemotherapeutics to human TNBC cells, revealing that DNA-damaging chemotherapeutics increased mitochondrial elongation, but microtubule poisons increased mitochondrial fragmentation. These findings suggested chemotherapeutics may alter the dynamics of mitochondrial fission and fusion in TNBC cells. These structural changes were accompanied by increased or decreased oxphos rates, glucose-driven TCA cycle flux, and mitochondrial content, respectively. Driving mitochondrial fusion by genetic or pharmacologic inhibition of the mitochondrial fission factor Drp1 increased oxphos and chemoresistance, whereas driving mitochondrial fission by genetic or pharmacologic inhibition of the mitochondrial fusion protein Opa1 decreased oxphos and chemoresistance. These findings provide evidence that modulating mitochondrial fission and fusion may be a promising strategy to overcome metabolic states contributing to chemoresistance in TNBC. Our ongoing investigations are aimed at rational targeted therapies and scheduling approaches to overcome chemoresistance in in vivo models of TNBC. Citation Format: Lily Baek, Junegoo Lee, Mariah J. Berner, Katherine E. Pendleton, Emily B. Goff, Karen Wang, James P. Barrish, Bora Lim, Philip J. Lorenzi, Weston Porter, Michael T. Lewis, Gloria V. Echeverria. Morphological and functional plasticity of mitochondria promotes chemotherapy resistance in triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6384.
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ROSS, Meredith F., Aleksandra FILIPOVSKA, Robin A. J. SMITH, Michael J. GAIT, and Michael P. MURPHY. "Cell-penetrating peptides do not cross mitochondrial membranes even when conjugated to a lipophilic cation: evidence against direct passage through phospholipid bilayers." Biochemical Journal 383, no. 3 (October 26, 2004): 457–68. http://dx.doi.org/10.1042/bj20041095.
Full textAbstract:
CPPs (cell-penetrating peptides) facilitate the cellular uptake of covalently attached oligonucleotides, proteins and other macromolecules, but the mechanism of their uptake is disputed. Two models are proposed: direct movement through the phospholipid bilayer and endocytic uptake. Mitochondria are a good model system to distinguish between these possibilities, since they have no vesicular transport systems. Furthermore, CPP-mediated delivery of macromolecules to the mitochondrial matrix would be a significant breakthrough in the study of mitochondrial function and dysfunction, and could also lead to new therapies for diseases caused by mitochondrial damage. Therefore we investigated whether two CPPs, penetratin and Tat, could act as mitochondrial delivery vectors. We also determined whether conjugation of the lipophilic cation TPP (triphenylphosphonium) to penetratin or Tat facilitated their uptake into mitochondria, since TPP leads to uptake of attached molecules into mitochondria driven by the membrane potential. Neither penetratin nor Tat, nor their TPP conjugates, are internalized by isolated mitochondria, indicating that these CPPs cannot cross mitochondrial phospholipid bilayers. Tat and TPP–Tat are taken up by cells, but they accumulate in endosomes and do not reach mitochondria. We conclude that CPPs cannot cross mitochondrial phospholipid bilayers, and therefore cannot deliver macromolecules directly to mitochondria. Our findings shed light on the mechanism of uptake of CPPs by cells. The lack of direct movement of CPPs through mitochondrial phospholipid bilayers, along with the observed endosomal accumulation of Tat and TPP–Tat in cells, makes it unlikely that CPPs enter cells by direct membrane passage, and instead favours cellular uptake via an endocytic pathway.
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Albert, Manuel, Martina Bécares, Michela Falqui, Carlos Fernández-Lozano, and Susana Guerra. "ISG15, a Small Molecule with Huge Implications: Regulation of Mitochondrial Homeostasis." Viruses 10, no. 11 (November 13, 2018): 629. http://dx.doi.org/10.3390/v10110629.
Full textAbstract:
Viruses are responsible for the majority of infectious diseases, from the common cold to HIV/AIDS or hemorrhagic fevers, the latter with devastating effects on the human population. Accordingly, the development of efficient antiviral therapies is a major goal and a challenge for the scientific community, as we are still far from understanding the molecular mechanisms that operate after virus infection. Interferon-stimulated gene 15 (ISG15) plays an important antiviral role during viral infection. ISG15 catalyzes a ubiquitin-like post-translational modification termed ISGylation, involving the conjugation of ISG15 molecules to de novo synthesized viral or cellular proteins, which regulates their stability and function. Numerous biomedically relevant viruses are targets of ISG15, as well as proteins involved in antiviral immunity. Beyond their role as cellular powerhouses, mitochondria are multifunctional organelles that act as signaling hubs in antiviral responses. In this review, we give an overview of the biological consequences of ISGylation for virus infection and host defense. We also compare several published proteomic studies to identify and classify potential mitochondrial ISGylation targets. Finally, based on our recent observations, we discuss the essential functions of mitochondria in the antiviral response and examine the role of ISG15 in the regulation of mitochondrial processes, specifically OXPHOS and mitophagy.
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Shemiakova, Taisiia, Ekaterina Ivanova, Andrey V. Grechko, Elena V. Gerasimova, Igor A. Sobenin, and Alexander N. Orekhov. "Mitochondrial Dysfunction and DNA Damage in the Context of Pathogenesis of Atherosclerosis." Biomedicines 8, no. 6 (June 18, 2020): 166. http://dx.doi.org/10.3390/biomedicines8060166.
Full textAbstract:
Atherosclerosis is a multifactorial disease of the cardiovascular system associated with aging, inflammation, and oxidative stress. An important role in the development of atherosclerosis play elevated plasma lipoproteins. A number of external factors (smoking, diabetes, infections) can also contribute to the development of the disease. For a long time, atherosclerosis remains asymptomatic, therefore, the search for early markers of the disease is critical for the timely management and better outcomes for patients. Mitochondrial dysfunction and mitochondrial DNA (mtDNA) damage appear to connect different aspects of atherosclerosis pathogenesis. To date, multiple lines of research have demonstrated the strong association of mitochondrial dysfunction with the development of various human diseases. Therapies aimed at restoring the mitochondrial function are being actively developed, and are expected to broaden the therapeutic possibilities for several chronic human diseases. The development of such therapies depends on our understanding of the functional roles of different mtDNA variants associated with one or another disorder, and the molecular mechanisms linking mitochondrial dysfunction with a given pathological feature. These questions are, however, challenging and require future intensive research. This review summarizes the recent studies and describes the central processes of the development of atherosclerosis, and shows their relationship with mitochondrial dysfunction. One of the promising therapeutic approaches for future atherosclerosis treatments is the use of mitochondria-targeted antioxidants. Future studies should focus on characterizing the mechanisms of mitochondrial involvement in cardiovascular pathologies to better direct the search for novel therapies.