Journal articles on the topic 'Mitochondrial defects'
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1
Gorsich, Steven W., and Janet M. Shaw. "Importance of Mitochondrial Dynamics During Meiosis and Sporulation." Molecular Biology of the Cell 15, no. 10 (October 2004): 4369–81. http://dx.doi.org/10.1091/mbc.e03-12-0875.
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Opposing fission and fusion events maintain the yeast mitochondrial network. Six proteins regulate these membrane dynamics during mitotic growth—Dnm1p, Mdv1p, and Fis1p mediate fission; Fzo1p, Mgm1p, and Ugo1p mediate fusion. Previous studies established that mitochondria fragment and rejoin at distinct stages during meiosis and sporulation, suggesting that mitochondrial fission and fusion are required during this process. Here we report that strains defective for mitochondrial fission alone, or both fission and fusion, complete meiosis and sporulation. However, visualization of mitochondria in sporulating cultures reveals morphological defects associated with the loss of fusion and/or fission proteins. Specifically, mitochondria collapse to one side of the cell and fail to fragment during presporulation. In addition, mitochondria are not inherited equally by newly formed spores, and mitochondrial DNA nucleoid segregation defects give rise to spores lacking nucleoids. This nucleoid inheritance defect is correlated with an increase in petite spore colonies. Unexpectedly, mitochondria fragment in mature tetrads lacking fission proteins. The latter finding suggests either that novel fission machinery operates during sporulation or that mechanical forces generate the mitochondrial fragments observed in mature spores. These results provide evidence of fitness defects caused by fission mutations and reveal new phenotypes associated with fission and fusion mutations.
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Weidling, Ian, and Russell H. Swerdlow. "Mitochondrial Dysfunction and Stress Responses in Alzheimer’s Disease." Biology 8, no. 2 (May 11, 2019): 39. http://dx.doi.org/10.3390/biology8020039.
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Alzheimer’s disease (AD) patients display widespread mitochondrial defects. Brain hypometabolism occurs alongside mitochondrial defects, and correlates well with cognitive decline. Numerous theories attempt to explain AD mitochondrial dysfunction. Groups propose AD mitochondrial defects stem from: (1) mitochondrial-nuclear DNA interactions/variations; (2) amyloid and neurofibrillary tangle interactions with mitochondria, and (3) mitochondrial quality control defects and oxidative damage. Cells respond to mitochondrial dysfunction through numerous retrograde responses including the Integrated Stress Response (ISR) involving eukaryotic initiation factor 2α (eIF2α), activating transcription factor 4 (ATF4) and C/EBP homologous protein (CHOP). AD brains activate the ISR and we hypothesize mitochondrial defects may contribute to ISR activation. Here we review current recognized contributions of the mitochondria to AD, with an emphasis on their potential contribution to brain stress responses.
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Ciceri, E., I. Moroni, G. Uziel, and M. Savoiardo. "Le encefalomiopatie mitocondriali." Rivista di Neuroradiologia 9, no. 6 (December 1996): 775–80. http://dx.doi.org/10.1177/197140099600900623.
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The mitochondrial encephalomyopathies are relatively rare neuromuscular diseases clinically characterised by myopathy and encephalopathy caused by structurally or functionally impaired mitochondria. The biochemical hallmark of this group of disorders is impaired mitochondrial energy production: Kreb's cycle, respiratory chain, oxidative phosphorylation and beta-oxidation of fatty acids. The presence of lactic acidosis and ragged red fibres, i.e. subsarcolemmal accumulations of abnormally sized mitochondria are highly indicative findings for mitochondrial disease. Classification and diagnostic criteria are based on biochemical findings with a search for specific enzyme deficit and molecular genetic information. Molecular genetic studies aim to identify the mitochondrial DNA changes responsible for the enzyme defect. Ragged red fibres are not essential for diagnosis as they are not present in some diseases. In rare cases, mitochondrial diseases are caused by nuclear DNA defects or, more commonly a mitochondrial DNA deficit. Diagnosis may prove difficult given the pathogenetic complexity and clinical and phenotypical variability of these conditions. Despite indirect symptoms of mitochondrial disease, the enzyme defect and genetic alteration cannot be identified in some cases. The mitochondrial encephalopathies can be classified according to the metabolic pathways involved into impaired transport ot uptake of energy, impaired Kreb's cycle or respiratory chain complexes or complex defects due to mitochondrial DNA changes.
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Chen, Tsung-Hsien, Kok-Yean Koh, Kurt Ming-Chao Lin, and Chu-Kuang Chou. "Mitochondrial Dysfunction as an Underlying Cause of Skeletal Muscle Disorders." International Journal of Molecular Sciences 23, no. 21 (October 26, 2022): 12926. http://dx.doi.org/10.3390/ijms232112926.
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Mitochondria are an important energy source in skeletal muscle. A main function of mitochondria is the generation of ATP for energy through oxidative phosphorylation (OXPHOS). Mitochondrial defects or abnormalities can lead to muscle disease or multisystem disease. Mitochondrial dysfunction can be caused by defective mitochondrial OXPHOS, mtDNA mutations, Ca2+ imbalances, mitochondrial-related proteins, mitochondrial chaperone proteins, and ultrastructural defects. In addition, an imbalance between mitochondrial fusion and fission, lysosomal dysfunction due to insufficient biosynthesis, and/or defects in mitophagy can result in mitochondrial damage. In this review, we explore the association between impaired mitochondrial function and skeletal muscle disorders. Furthermore, we emphasize the need for more research to determine the specific clinical benefits of mitochondrial therapy in the treatment of skeletal muscle disorders.
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Salgado, Josefa, Beatriz Honorato, and Jesús García-Foncillas. "Review: Mitochondrial Defects in Breast Cancer." Clinical medicine. Oncology 2 (January 2008): CMO.S524. http://dx.doi.org/10.4137/cmo.s524.
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Mitochondria play important roles in cellular energy metabolism, free radical generation, and apoptosis. Mitochondrial DNA has been proposed to be involved in carcinogenesis because of its high susceptibility to mutations and limited repair mechanisms in comparison to nuclear DNA. Breast cancer is the most frequent cancer type among women in the world and, although exhaustive research has been done on nuclear DNA changes, several studies describe a variety of mitochondrial DNA alterations present in breast cancer. In this review article, we to provide a summary of the mitochondrial genomic alterations reported in breast cancer and their functional consequences.
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PAL, ARUNA, and SAMIDDHA BANERJEE. "Mitochondrial replacement therapy - a new remedy for defects in reproduction." Indian Journal of Animal Sciences 88, no. 6 (June 22, 2018): 637–44. http://dx.doi.org/10.56093/ijans.v88i6.80860.
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Mitochondria is an important subcellular organelle with the prime function being energy metabolism and supply of energy to the body cells for carrying out the vital functions. Energy is the primary requisite for the reproductive organs of both male and female for carrying out the normal functions. In the present article, we have described how mutation in mitochondrial DNA lead to defects in male and female reproduction. Mitochondria is an integral part of the mid-piece of sperm and also has role in other parts of male reproductive system. Similarly, mitochondrial DNA has role in female reproductive system including ovulation, zygote activation, fertilization, oocyte maturation and embryo development. Mitochondrial defect are collectively named as "mystondria" (mysterious diseases of mitochondria) and may be corrected through mitochondrial replacement therapy, popularly known as three parent baby concept, since there are no other scope for cure or treatment. Two approaches for mitochondrial replacement therapy are pronuclear transfer and spindle transfer. The first three parent baby was developed in April 2016 through mitochondrial replacement therapy. The present review is aimed at functional relevance of three-parent baby concept in animal reproduction.
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Lenzi, Paola, Rosangela Ferese, Francesca Biagioni, Federica Fulceri, Carla L. Busceti, Alessandra Falleni, Stefano Gambardella, Alessandro Frati, and Francesco Fornai. "Rapamycin Ameliorates Defects in Mitochondrial Fission and Mitophagy in Glioblastoma Cells." International Journal of Molecular Sciences 22, no. 10 (May 20, 2021): 5379. http://dx.doi.org/10.3390/ijms22105379.
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Glioblastoma (GBM) cells feature mitochondrial alterations, which are documented and quantified in the present study, by using ultrastructural morphometry. Mitochondrial impairment, which roughly occurs in half of the organelles, is shown to be related to mTOR overexpression and autophagy suppression. The novelty of the present study consists of detailing an mTOR-dependent mitophagy occlusion, along with suppression of mitochondrial fission. These phenomena contribute to explain the increase in altered mitochondria reported here. Administration of the mTOR inhibitor rapamycin rescues mitochondrial alterations. In detail, rapamycin induces the expression of genes promoting mitophagy (PINK1, PARKIN, ULK1, AMBRA1) and mitochondrial fission (FIS1, DRP1). This occurs along with over-expression of VPS34, an early gene placed upstream in the autophagy pathway. The topographic stoichiometry of proteins coded by these genes within mitochondria indicates that, a remarkable polarization of proteins involved in fission and mitophagy within mitochondria including LC3 takes place. Co-localization of these proteins within mitochondria, persists for weeks following rapamycin, which produces long-lasting mitochondrial plasticity. Thus, rapamycin restores mitochondrial status in GBM cells. These findings add novel evidence about mitochondria and GBM, while fostering a novel therapeutic approach to restore healthy mitochondria through mTOR inhibition.
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Bakare, Ajibola B., Julienne Daniel, Joshua Stabach, Anapaula Rojas, Austin Bell, Brooke Henry, and Shilpa Iyer. "Quantifying Mitochondrial Dynamics in Patient Fibroblasts with Multiple Developmental Defects and Mitochondrial Disorders." International Journal of Molecular Sciences 22, no. 12 (June 10, 2021): 6263. http://dx.doi.org/10.3390/ijms22126263.
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Mitochondria are dynamic organelles that undergo rounds of fission and fusion and exhibit a wide range of morphologies that contribute to the regulation of different signaling pathways and various cellular functions. It is important to understand the differences between mitochondrial structure in health and disease so that therapies can be developed to maintain the homeostatic balance of mitochondrial dynamics. Mitochondrial disorders are multisystemic and characterized by complex and variable clinical pathologies. The dynamics of mitochondria in mitochondrial disorders is thus worthy of investigation. Therefore, in this study, we performed a comprehensive analysis of mitochondrial dynamics in ten patient-derived fibroblasts containing different mutations and deletions associated with various mitochondrial disorders. Our results suggest that the most predominant morphological signature for mitochondria in the diseased state is fragmentation, with eight out of the ten cell lines exhibiting characteristics consistent with fragmented mitochondria. To our knowledge, this is the first comprehensive study that quantifies mitochondrial dynamics in cell lines with a wide array of developmental and mitochondrial disorders. A more thorough analysis of the correlations between mitochondrial dynamics, mitochondrial genome perturbations, and bioenergetic dysfunction will aid in identifying unique morphological signatures of various mitochondrial disorders in the future.
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Murata, Daisuke, Kenta Arai, Miho Iijima, and Hiromi Sesaki. "Mitochondrial division, fusion and degradation." Journal of Biochemistry 167, no. 3 (December 4, 2019): 233–41. http://dx.doi.org/10.1093/jb/mvz106.
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Abstract The mitochondrion is an essential organelle for a wide range of cellular processes, including energy production, metabolism, signal transduction and cell death. To execute these functions, mitochondria regulate their size, number, morphology and distribution in cells via mitochondrial division and fusion. In addition, mitochondrial division and fusion control the autophagic degradation of dysfunctional mitochondria to maintain a healthy population. Defects in these dynamic membrane processes are linked to many human diseases that include metabolic syndrome, myopathy and neurodegenerative disorders. In the last several years, our fundamental understanding of mitochondrial fusion, division and degradation has been significantly advanced by high resolution structural analyses, protein-lipid biochemistry, super resolution microscopy and in vivo analyses using animal models. Here, we summarize and discuss this exciting recent progress in the mechanism and function of mitochondrial division and fusion.
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Sonn, Seong Keun, Seungwoon Seo, Jaemoon Yang, Ki Sook Oh, Hsiuchen Chen, David C. Chan, Kunsoo Rhee, Kyung S. Lee, Young Yang, and Goo Taeg Oh. "ER-associated CTRP1 regulates mitochondrial fission via interaction with DRP1." Experimental & Molecular Medicine 53, no. 11 (November 2021): 1769–80. http://dx.doi.org/10.1038/s12276-021-00701-z.
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AbstractC1q/TNF-related protein 1 (CTRP1) is a CTRP family member that has collagenous and globular C1q-like domains. The secreted form of CTRP1 is known to be associated with cardiovascular and metabolic diseases, but its cellular roles have not yet been elucidated. Here, we showed that cytosolic CTRP1 localizes to the endoplasmic reticulum (ER) membrane and that knockout or depletion of CTRP1 leads to mitochondrial fission defects, as demonstrated by mitochondrial elongation. Mitochondrial fission events are known to occur through an interaction between mitochondria and the ER, but we do not know whether the ER and/or its associated proteins participate directly in the entire mitochondrial fission event. Interestingly, we herein showed that ablation of CTRP1 suppresses the recruitment of DRP1 to mitochondria and provided evidence suggesting that the ER–mitochondrion interaction is required for the proper regulation of mitochondrial morphology. We further report that CTRP1 inactivation-induced mitochondrial fission defects induce apoptotic resistance and neuronal degeneration, which are also associated with ablation of DRP1. These results demonstrate for the first time that cytosolic CTRP1 is an ER transmembrane protein that acts as a key regulator of mitochondrial fission, providing new insight into the etiology of metabolic and neurodegenerative disorders.
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Dürr, Mark, Mafalda Escobar-Henriques, Sandra Merz, Stefan Geimer, Thomas Langer, and Benedikt Westermann. "Nonredundant Roles of Mitochondria-associated F-Box Proteins Mfb1 and Mdm30 in Maintenance of Mitochondrial Morphology in Yeast." Molecular Biology of the Cell 17, no. 9 (September 2006): 3745–55. http://dx.doi.org/10.1091/mbc.e06-01-0053.
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Mitochondria constantly fuse and divide to adapt organellar morphology to the cell’s ever-changing physiological conditions. Little is known about the molecular mechanisms regulating mitochondrial dynamics. F-box proteins are subunits of both Skp1-Cullin-F-box (SCF) ubiquitin ligases and non-SCF complexes that regulate a large number of cellular processes. Here, we analyzed the roles of two yeast F-box proteins, Mfb1 and Mdm30, in mitochondrial dynamics. Mfb1 is a novel mitochondria-associated F-box protein. Mitochondria in mutants lacking Mfb1 are fusion competent, but they form aberrant aggregates of interconnected tubules. In contrast, mitochondria in mutants lacking Mdm30 are highly fragmented due to a defect in mitochondrial fusion. Fragmented mitochondria are docked but nonfused in Δmdm30 cells. Mitochondrial fusion is also blocked during sporulation of homozygous diploid mutants lacking Mdm30, leading to a mitochondrial inheritance defect in ascospores. Mfb1 and Mdm30 exert nonredundant functions and likely have different target proteins. Because defects in F-box protein mutants could not be mimicked by depletion of SCF complex and proteasome core subunits, additional yet unknown factors are likely involved in regulating mitochondrial dynamics. We propose that mitochondria-associated F-box proteins Mfb1 and Mdm30 are key components of a complex machinery that regulates mitochondrial dynamics throughout yeast’s entire life cycle.
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Zhu, Yiyi, Weiwei Gui, Bowen Tan, Ying Du, Jiaqiang Zhou, Fang Wu, Hong Li, and Xihua Lin. "IGF2 deficiency causes mitochondrial defects in skeletal muscle." Clinical Science 135, no. 7 (April 2021): 979–90. http://dx.doi.org/10.1042/cs20210128.
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Abstract Exercise training improves muscle fitness in many aspects, including induction of mitochondrial biogenesis and maintenance of mitochondrial dynamics. The insulin-like growth factors were recently proposed as key regulators of myogenic factors to regulate muscle development. The present study aimed to investigate the physical exercise impact on insulin-like growth factor 2 (IGF2) and analyzed its functions on skeletal muscle cells in vitro. Using online databases, we stated that IGF2 was relatively highly expressed in skeletal muscle cells and increased after exercise training. Then, IGF2 deficiency in myotubes from C2C12 and primary skeletal muscle cells (PMSCs) led to impaired mitochondrial function, reduced mitochondria-related protein content, and decreased mitochondrial biogenesis. Furthermore, we explored the possible regulatory pathway and found that mitochondrial regulation in skeletal muscle cells might occur through IGF2-Sirtuin 1 (SIRT1)-peroxisome proliferator-activated receptor-γ co-activator-1α (PGC1α) signaling pathway. Therefore, the present study first demonstrated the relationship between IGF2 and mitochondria in skeletal muscle.
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Jensen, Per Bo. "Measuring Mitochondrial Defects." Genetic Engineering & Biotechnology News 34, no. 10 (May 15, 2014): 19. http://dx.doi.org/10.1089/gen.34.10.10.
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Almannai, Mohammed, Azza Salah, and Ayman W. El-Hattab. "Mitochondrial Membranes and Mitochondrial Genome: Interactions and Clinical Syndromes." Membranes 12, no. 6 (June 15, 2022): 625. http://dx.doi.org/10.3390/membranes12060625.
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Mitochondria are surrounded by two membranes; the outer mitochondrial membrane and the inner mitochondrial membrane. They are unique organelles since they have their own DNA, the mitochondrial DNA (mtDNA), which is replicated continuously. Mitochondrial membranes have direct interaction with mtDNA and are therefore involved in organization of the mitochondrial genome. They also play essential roles in mitochondrial dynamics and the supply of nucleotides for mtDNA synthesis. In this review, we will discuss how the mitochondrial membranes interact with mtDNA and how this interaction is essential for mtDNA maintenance. We will review different mtDNA maintenance disorders that result from defects in this crucial interaction. Finally, we will review therapeutic approaches relevant to defects in mitochondrial membranes.
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Wang, Sheng-Fan, Shiuan Chen, Ling-Ming Tseng, and Hsin-Chen Lee. "Role of the mitochondrial stress response in human cancer progression." Experimental Biology and Medicine 245, no. 10 (April 23, 2020): 861–78. http://dx.doi.org/10.1177/1535370220920558.
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Mitochondria are important organelles that are responsible for cellular energy metabolism, cellular redox/calcium homeostasis, and cell death regulation in mammalian cells. Mitochondrial dysfunction is involved in various diseases, such as neurodegenerative diseases, cardiovascular diseases, immune disorders, and cancer. Defective mitochondria and metabolism remodeling are common characteristics in cancer cells. Several factors, such as mitochondrial DNA copy number changes, mitochondrial DNA mutations, mitochondrial enzyme defects, and mitochondrial dynamic changes, may contribute to mitochondrial dysfunction in cancer cells. Some lines of evidence have shown that mitochondrial dysfunction may promote cancer progression. Here, several mitochondrial stress responses, including the mitochondrial unfolded protein response and the integrated stress response, and several mitochondrion-derived molecules (reactive oxygen species, calcium, oncometabolites, and others) are reviewed; these pathways and molecules are considered to act as retrograde signaling regulators in the development and progression of cancer. Targeting these components of the mitochondrial stress response may be an important strategy for cancer treatment. Impact statement Dysregulated mitochondria often occurred in cancers. Mitochondrial dysfunction might contribute to cancer progression. We reviewed several mitochondrial stresses in cancers. Mitochondrial stress responses might contribute to cancer progression. Several mitochondrion-derived molecules (ROS, Ca2+, oncometabolites, exported mtDNA, mitochondrial double-stranded RNA, humanin, and MOTS-c), integrated stress response, and mitochondrial unfolded protein response act as retrograde signaling pathways and might be critical in the development and progression of cancer. Targeting these mitochondrial stress responses may be an important strategy for cancer treatment.
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Bailey, Shannon M., Gloria Robinson, Anita Pinner, Laura Chamlee, Elena Ulasova, Melissa Pompilius, Grier P. Page, et al. "S-adenosylmethionine prevents chronic alcohol-induced mitochondrial dysfunction in the rat liver." American Journal of Physiology-Gastrointestinal and Liver Physiology 291, no. 5 (November 2006): G857—G867. http://dx.doi.org/10.1152/ajpgi.00044.2006.
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An early event that occurs in response to alcohol consumption is mitochondrial dysfunction, which is evident in changes to the mitochondrial proteome, respiration defects, and mitochondrial DNA (mtDNA) damage. S-adenosylmethionine (SAM) has emerged as a potential therapeutic for treating alcoholic liver disease through mechanisms that appear to involve decreases in oxidative stress and proinflammatory cytokine production as well as the alleviation of steatosis. Because mitochondria are a source of reactive oxygen/nitrogen species and a target for oxidative damage, we tested the hypothesis that SAM treatment during alcohol exposure preserves organelle function. Mitochondria were isolated from livers of rats fed control and ethanol diets with and without SAM for 5 wk. Alcohol feeding caused a significant decrease in state 3 respiration and the respiratory control ratio, whereas SAM administration prevented these alcohol-mediated defects and preserved hepatic SAM levels. SAM treatment prevented alcohol-associated increases in mitochondrial superoxide production, mtDNA damage, and inducible nitric oxide synthase induction, without a significant lessening of steatosis. Accompanying these indexes of oxidant damage, SAM prevented alcohol-mediated losses in cytochrome c oxidase subunits as shown using blue native PAGE proteomics and immunoblot analysis, which resulted in partial preservation of complex IV activity. SAM treatment attenuated the upregulation of the mitochondrial stress chaperone prohibitin. Although SAM supplementation did not alleviate steatosis by itself, SAM prevented several key alcohol-mediated defects to the mitochondria genome and proteome that contribute to the bioenergetic defect in the liver after alcohol consumption. These findings reveal new molecular targets through which SAM may work to alleviate one critical component of alcohol-induced liver injury: mitochondria dysfunction.
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Tilokani, Lisa, Shun Nagashima, Vincent Paupe, and Julien Prudent. "Mitochondrial dynamics: overview of molecular mechanisms." Essays in Biochemistry 62, no. 3 (July 20, 2018): 341–60. http://dx.doi.org/10.1042/ebc20170104.
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Mitochondria are highly dynamic organelles undergoing coordinated cycles of fission and fusion, referred as ‘mitochondrial dynamics’, in order to maintain their shape, distribution and size. Their transient and rapid morphological adaptations are crucial for many cellular processes such as cell cycle, immunity, apoptosis and mitochondrial quality control. Mutations in the core machinery components and defects in mitochondrial dynamics have been associated with numerous human diseases. These dynamic transitions are mainly ensured by large GTPases belonging to the Dynamin family. Mitochondrial fission is a multi-step process allowing the division of one mitochondrion in two daughter mitochondria. It is regulated by the recruitment of the GTPase Dynamin-related protein 1 (Drp1) by adaptors at actin- and endoplasmic reticulum-mediated mitochondrial constriction sites. Drp1 oligomerization followed by mitochondrial constriction leads to the recruitment of Dynamin 2 to terminate membrane scission. Inner mitochondrial membrane constriction has been proposed to be an independent process regulated by calcium influx. Mitochondrial fusion is driven by a two-step process with the outer mitochondrial membrane fusion mediated by mitofusins 1 and 2 followed by inner membrane fusion, mediated by optic atrophy 1. In addition to the role of membrane lipid composition, several members of the machinery can undergo post-translational modifications modulating these processes. Understanding the molecular mechanisms controlling mitochondrial dynamics is crucial to decipher how mitochondrial shape meets the function and to increase the knowledge on the molecular basis of diseases associated with morphology defects. This article will describe an overview of the molecular mechanisms that govern mitochondrial fission and fusion in mammals.
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Fuchs, Florian, and Benedikt Westermann. "Role of Unc104/KIF1-related Motor Proteins in Mitochondrial Transport in Neurospora crassa." Molecular Biology of the Cell 16, no. 1 (January 2005): 153–61. http://dx.doi.org/10.1091/mbc.e04-05-0413.
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Eukaryotic cells use diverse cytoskeleton-dependent machineries to control inheritance and intracellular positioning of mitochondria. In particular, microtubules play a major role in mitochondrial motility in the filamentous fungus Neurospora crassa and in mammalian cells. We examined the role of two novel Unc104/KIF1-related members of the kinesin family, Nkin2 and Nkin3, in mitochondrial motility in Neurospora. The Nkin2 protein is required for mitochondrial interactions with microtubules in vitro. Mutant hyphae lacking Nkin2 show mitochondrial motility defects in vivo early after germination of conidiospores. Nkin3, a member of a unique fungal-specific subgroup of small Unc104/KIF1-related proteins, is not associated with mitochondria in wild-type cells. However, it is highly expressed and recruited to mitochondria in Δnkin-2 mutants. Mitochondria lacking Nkin2 require Nkin3 for binding to microtubules in vitro, and mitochondrial motility defects in Δnkin-2 mutants disappear with up-regulation of Nkin3 in vivo. We propose that mitochondrial transport is mediated by Nkin2 in Neurospora, and organelle motility defects in Δnkin-2 mutants are rescued by Nkin3. Apparently, a highly versatile complement of organelle motors allows the cell to efficiently respond to exogenous challenges, a process that might also account for the great variety of different mitochondrial transport systems that have evolved in eukaryotic cells.
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Campbell, C. L., and P. E. Thorsness. "Escape of mitochondrial DNA to the nucleus in yme1 yeast is mediated by vacuolar-dependent turnover of abnormal mitochondrial compartments." Journal of Cell Science 111, no. 16 (August 15, 1998): 2455–64. http://dx.doi.org/10.1242/jcs.111.16.2455.
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Inactivation of Yme1p, a mitochondrially-localized ATP-dependent metallo-protease in the yeast Saccharomyces cerevisiae, causes a high rate of DNA escape from mitochondria to the nucleus as well as pleiotropic functional and morphological mitochondrial defects. The evidence presented here suggests that the abnormal mitochondria of a yme1 strain are degraded by the vacuole. First, electron microscopy of Yme1p-deficient strains revealed mitochondria physically associated with the vacuole via electron dense structures. Second, disruption of vacuolar function affected the frequency of mitochondrial DNA escape from yme1 and wild-type strains. Both PEP4 or PRC1 gene disruptions resulted in a lower frequency of mitochondrial DNA escape. Third, an in vivo assay that monitors vacuole-dependent turnover of the mitochondrial compartment demonstrated an increased rate of mitochondrial turnover in yme1 yeast when compared to the rate found in wild-type yeast. In this assay, vacuolar alkaline phosphatase, encoded by PHO8, was targeted to mitochondria in a strain bearing disruption to the genomic PHO8 locus. Maturation of the mitochondrially localized alkaline phosphatase pro-enzyme requires proteinase A, which is localized in the vacuole. Therefore, alkaline phosphatase activity reflects vacuole-dependent turnover of mitochondria. This assay reveals that mitochondria of a yme1 strain are taken up by the vacuole more frequently than mitochondria of an isogenic wild-type strain when these yeast are cultured in medium necessitating respiratory growth. Degradation of abnormal mitochondria is one pathway by which mitochondrial DNA escapes and migrates to the nucleus.
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Cagin, Umut, Olivia F. Duncan, Ariana P. Gatt, Marc S. Dionne, Sean T. Sweeney, and Joseph M. Bateman. "Mitochondrial retrograde signaling regulates neuronal function." Proceedings of the National Academy of Sciences 112, no. 44 (October 21, 2015): E6000—E6009. http://dx.doi.org/10.1073/pnas.1505036112.
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Mitochondria are key regulators of cellular homeostasis, and mitochondrial dysfunction is strongly linked to neurodegenerative diseases, including Alzheimer’s and Parkinson’s. Mitochondria communicate their bioenergetic status to the cell via mitochondrial retrograde signaling. To investigate the role of mitochondrial retrograde signaling in neurons, we induced mitochondrial dysfunction in the Drosophila nervous system. Neuronal mitochondrial dysfunction causes reduced viability, defects in neuronal function, decreased redox potential, and reduced numbers of presynaptic mitochondria and active zones. We find that neuronal mitochondrial dysfunction stimulates a retrograde signaling response that controls the expression of several hundred nuclear genes. We show that the Drosophila hypoxia inducible factor alpha (HIFα) ortholog Similar (Sima) regulates the expression of several of these retrograde genes, suggesting that Sima mediates mitochondrial retrograde signaling. Remarkably, knockdown of Sima restores neuronal function without affecting the primary mitochondrial defect, demonstrating that mitochondrial retrograde signaling is partly responsible for neuronal dysfunction. Sima knockdown also restores function in a Drosophila model of the mitochondrial disease Leigh syndrome and in a Drosophila model of familial Parkinson’s disease. Thus, mitochondrial retrograde signaling regulates neuronal activity and can be manipulated to enhance neuronal function, despite mitochondrial impairment.
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Almannai, Mohammed, Ayman W. El-Hattab, and Fernando Scaglia. "Mitochondrial DNA replication: clinical syndromes." Essays in Biochemistry 62, no. 3 (June 27, 2018): 297–308. http://dx.doi.org/10.1042/ebc20170101.
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Each nucleated cell contains several hundreds of mitochondria, which are unique organelles in being under dual genome control. The mitochondria contain their own DNA, the mtDNA, but most of mitochondrial proteins are encoded by nuclear genes, including all the proteins required for replication, transcription, and repair of mtDNA. MtDNA replication is a continuous process that requires coordinated action of several enzymes that are part of the mtDNA replisome. It also requires constant supply of deoxyribonucleotide triphosphates(dNTPs) and interaction with other mitochondria for mixing and unifying the mitochondrial compartment. MtDNA maintenance defects are a growing list of disorders caused by defects in nuclear genes involved in different aspects of mtDNA replication. As a result of defects in these genes, mtDNA depletion and/or multiple mtDNA deletions develop in affected tissues resulting in variable manifestations that range from adult-onset mild disease to lethal presentation early in life.
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Kroon, A. M., and C. Van den Bogert. "Biogenesis of mitochondria and genetics of mitochondrial defects." Journal of Inherited Metabolic Disease 10, S1 (March 1987): 54–61. http://dx.doi.org/10.1007/bf01812847.
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Chen, Qun, Jeremy Thompson, Ying Hu, and Edward J. Lesnefsky. "Reversing mitochondrial defects in aged hearts: role of mitochondrial calpain activation." American Journal of Physiology-Cell Physiology 322, no. 2 (February 1, 2022): C296—C310. http://dx.doi.org/10.1152/ajpcell.00279.2021.
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Aging chronically increases endoplasmic reticulum (ER) stress that contributes to mitochondrial dysfunction. Activation of calpain 1 (CPN1) impairs mitochondrial function during acute ER stress. We proposed that aging-induced ER stress led to mitochondrial dysfunction by activating CPN1. We posit that attenuation of the ER stress or direct inhibition of CPN1 in aged hearts can decrease cardiac injury during ischemia-reperfusion by improving mitochondrial function. Male young (3 mo) and aged mice (24 mo) were used in the present study, and 4-phenylbutyrate (4-PBA) was used to decrease the ER stress in aged mice. Subsarcolemmal (SSM) and interfibrillar mitochondria (IFM) were isolated. Chronic 4-PBA treatment for 2 wk decreased CPN1 activation as shown by the decreased cleavage of spectrin in cytosol and apoptosis inducing factor (AIF) and the α1 subunit of pyruvate dehydrogenase (PDH) in mitochondria. Treatment improved oxidative phosphorylation in 24-mo-old SSM and IFM at baseline compared with vehicle. When 4-PBA-treated 24-mo-old hearts were subjected to ischemia-reperfusion, infarct size was decreased. These results support that attenuation of the ER stress decreased cardiac injury in aged hearts by improving mitochondrial function before ischemia. To challenge the role of CPN1 as an effector of the ER stress, aged mice were treated with MDL-28170 (MDL, an inhibitor of calpain 1). MDL treatment improved mitochondrial function in aged SSM and IFM. MDL-treated 24-mo-old hearts sustained less cardiac injury following ischemia-reperfusion. These results support that age-induced ER stress augments cardiac injury during ischemia-reperfusion by impairing mitochondrial function through activation of CPN1.
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Campbell, Teresa, Jesse Slone, and Taosheng Huang. "Mitochondrial Genome Variants as a Cause of Mitochondrial Cardiomyopathy." Cells 11, no. 18 (September 11, 2022): 2835. http://dx.doi.org/10.3390/cells11182835.
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Mitochondria are small double-membraned organelles responsible for the generation of energy used in the body in the form of ATP. Mitochondria are unique in that they contain their own circular mitochondrial genome termed mtDNA. mtDNA codes for 37 genes, and together with the nuclear genome (nDNA), dictate mitochondrial structure and function. Not surprisingly, pathogenic variants in the mtDNA or nDNA can result in mitochondrial disease. Mitochondrial disease primarily impacts tissues with high energy demands, including the heart. Mitochondrial cardiomyopathy is characterized by the abnormal structure or function of the myocardium secondary to genetic defects in either the nDNA or mtDNA. Mitochondrial cardiomyopathy can be isolated or part of a syndromic mitochondrial disease. Common manifestations of mitochondrial cardiomyopathy are a phenocopy of hypertrophic cardiomyopathy, dilated cardiomyopathy, and cardiac conduction defects. The underlying pathophysiology of mitochondrial cardiomyopathy is complex and likely involves multiple abnormal processes in the cell, stemming from deficient oxidative phosphorylation and ATP depletion. Possible pathophysiology includes the activation of alternative metabolic pathways, the accumulation of reactive oxygen species, dysfunctional mitochondrial dynamics, abnormal calcium homeostasis, and mitochondrial iron overload. Here, we highlight the clinical assessment of mtDNA-related mitochondrial cardiomyopathy and offer a novel hypothesis of a possible integrated, multivariable pathophysiology of disease.
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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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Jackson, Thomas Daniel, Catherine Sarah Palmer, and Diana Stojanovski. "Mitochondrial diseases caused by dysfunctional mitochondrial protein import." Biochemical Society Transactions 46, no. 5 (October 4, 2018): 1225–38. http://dx.doi.org/10.1042/bst20180239.
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Mitochondria are essential organelles which perform complex and varied functions within eukaryotic cells. Maintenance of mitochondrial health and functionality is thus a key cellular priority and relies on the organelle's extensive proteome. The mitochondrial proteome is largely encoded by nuclear genes, and mitochondrial proteins must be sorted to the correct mitochondrial sub-compartment post-translationally. This essential process is carried out by multimeric and dynamic translocation and sorting machineries, which can be found in all four mitochondrial compartments. Interestingly, advances in the diagnosis of genetic disease have revealed that mutations in various components of the human import machinery can cause mitochondrial disease, a heterogenous and often severe collection of disorders associated with energy generation defects and a multisystem presentation often affecting the cardiovascular and nervous systems. Here, we review our current understanding of mitochondrial protein import systems in human cells and the molecular basis of mitochondrial diseases caused by defects in these pathways.
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Rogowska, Agata T., Olga Puchta, Anna M. Czarnecka, Aneta Kaniak, Piotr P. Stepien, and Pawel Golik. "Balance between Transcription and RNA Degradation Is Vital forSaccharomyces cerevisiaeMitochondria: Reduced Transcription Rescues the Phenotype of Deficient RNA Degradation." Molecular Biology of the Cell 17, no. 3 (March 2006): 1184–93. http://dx.doi.org/10.1091/mbc.e05-08-0796.
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The Saccharomyces cerevisiae SUV3 gene encodes the helicase component of the mitochondrial degradosome (mtEXO), the principal 3′-to-5′ exoribonuclease of yeast mitochondria responsible for RNA turnover and surveillance. Inactivation of SUV3 (suv3Δ) causes multiple defects related to overaccumulation of aberrant transcripts and precursors, leading to a disruption of mitochondrial gene expression and loss of respiratory function. We isolated spontaneous suppressors that partially restore mitochondrial function in suv3Δ strains devoid of mitochondrial introns and found that they correspond to partial loss-of-function mutations in genes encoding the two subunits of the mitochondrial RNA polymerase (Rpo41p and Mtf1p) that severely reduce the transcription rate in mitochondria. These results show that reducing the transcription rate rescues defects in RNA turnover and demonstrates directly the vital importance of maintaining the balance between RNA synthesis and degradation.
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HARDING, A. E., I. J. HOLT, J. M. COOPER, A. H. V. SCHAPIRA, M. SWEENEY, J. B. CLARK, and J. A. MORGAN-HUGHES. "Mitochondrial myopathies: genetic defects." Biochemical Society Transactions 18, no. 4 (August 1, 1990): 519–22. http://dx.doi.org/10.1042/bst0180519.
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MORGAN-HUGHES, JOHN A., J. MARK COOPER, IAN J. HOLT, ANITA E. HARDING, ANTHONY H. V. SCHAPIRA, and JOHN B. CLARK. "Mitochondrial myopathies: clinical defects." Biochemical Society Transactions 18, no. 4 (August 1, 1990): 523–26. http://dx.doi.org/10.1042/bst0180523.
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Zeviani, Massimo, and Carlo Antozzi. "Defects of Mitochondrial DNA." Brain Pathology 2, no. 2 (April 1992): 121–32. http://dx.doi.org/10.1111/j.1750-3639.1992.tb00680.x.
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Van Brunt, Jennifer. "Mitochondrial Defects and Disease." Nature Biotechnology 9, no. 4 (April 1991): 329. http://dx.doi.org/10.1038/nbt0491-329.
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El-Hattab, Ayman W., William J. Craigen, and Fernando Scaglia. "Mitochondrial DNA maintenance defects." Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease 1863, no. 6 (June 2017): 1539–55. http://dx.doi.org/10.1016/j.bbadis.2017.02.017.
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Thomas, Sunil, Albert Huang, Yueh-Ming Loo, Courtney Wilkins, Aimee McMillan, and Michael Gale. "Mitochondrial antiviral signaling molecule-mediated mitochondrial calcium regulates CD8 T cell function during acute virus infection (VIR6P.1163)." Journal of Immunology 194, no. 1_Supplement (May 1, 2015): 149.3. http://dx.doi.org/10.4049/jimmunol.194.supp.149.3.
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Abstract MAVS is a crucial adaptor molecule through which RIG-I-like receptors (RLR)s signal to mediate downstream innate antiviral and inflammatory responses. However a role for MAVS in directly programming adaptive immunity has not been defined. Here we identified a cell-intrinsic role for MAVS in programming CD8 T cells following virus infection. We utilized a mouse model of acute Lymphocytic choriomeningitis virus (LCMV) infection to define the actions of adoptively transferred WT or MAVS deficient CD8 T cells. Lack of MAVS lead to defects in CD8 T cell expansion as well as function as measured by cytokine and cytotoxic T cell effector molecule production but these parameters were not deficient in double knockout mice lacking the RLRs MDA5 and RIG-I. We identified defects in total cytoplasmic calcium, mitochondrial calcium as well as mitochondrial membrane potential in MAVS-/- CD8 T cells in vivo. We found that the inflammatory conditions of LCMV -induced cell proliferation place a metabolic load on CD8 T cells and their mitochondria such that the absence of MAVS lead to defects in mitochondrial calcium independently of the RLRs. Importantly, the MAVS defect associated with defective nuclear factor of activated T cells c1 (NFATc1) activation and consequently decreased IL-2 production. Our study assigns a cell-intrinsic role for MAVS in regulating adaptive immunity following viral infection by means of regulating mitochondrial calcium and thereby affecting T cell fitness.
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Richter, Uwe, Kah Ying Ng, Fumi Suomi, Paula Marttinen, Taina Turunen, Christopher Jackson, Anu Suomalainen, et al. "Mitochondrial stress response triggered by defects in protein synthesis quality control." Life Science Alliance 2, no. 1 (January 25, 2019): e201800219. http://dx.doi.org/10.26508/lsa.201800219.
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Mitochondria have a compartmentalized gene expression system dedicated to the synthesis of membrane proteins essential for oxidative phosphorylation. Responsive quality control mechanisms are needed to ensure that aberrant protein synthesis does not disrupt mitochondrial function. Pathogenic mutations that impede the function of the mitochondrial matrix quality control protease complex composed of AFG3L2 and paraplegin cause a multifaceted clinical syndrome. At the cell and molecular level, defects to this quality control complex are defined by impairment to mitochondrial form and function. Here, we establish the etiology of these phenotypes. We show how disruptions to the quality control of mitochondrial protein synthesis trigger a sequential stress response characterized first by OMA1 activation followed by loss of mitochondrial ribosomes and by remodelling of mitochondrial inner membrane ultrastructure. Inhibiting mitochondrial protein synthesis with chloramphenicol completely blocks this stress response. Together, our data establish a mechanism linking major cell biological phenotypes of AFG3L2 pathogenesis and show how modulation of mitochondrial protein synthesis can exert a beneficial effect on organelle homeostasis.
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ROSSIGNOL, Rodrigue, Benjamin FAUSTIN, Christophe ROCHER, Monique MALGAT, Jean-Pierre MAZAT, and Thierry LETELLIER. "Mitochondrial threshold effects." Biochemical Journal 370, no. 3 (March 15, 2003): 751–62. http://dx.doi.org/10.1042/bj20021594.
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The study of mitochondrial diseases has revealed dramatic variability in the phenotypic presentation of mitochondrial genetic defects. To attempt to understand this variability, different authors have studied energy metabolism in transmitochondrial cell lines carrying different proportions of various pathogenic mutations in their mitochondrial DNA. The same kinds of experiments have been performed on isolated mitochondria and on tissue biopsies taken from patients with mitochondrial diseases. The results have shown that, in most cases, phenotypic manifestation of the genetic defect occurs only when a threshold level is exceeded, and this phenomenon has been named the ‘phenotypic threshold effect'. Subsequently, several authors showed that it was possible to inhibit considerably the activity of a respiratory chain complex, up to a critical value, without affecting the rate of mitochondrial respiration or ATP synthesis. This phenomenon was called the ‘biochemical threshold effect'. More recently, quantitative analysis of the effects of various mutations in mitochondrial DNA on the rate of mitochondrial protein synthesis has revealed the existence of a ‘translational threshold effect'. In this review these different mitochondrial threshold effects are discussed, along with their molecular bases and the roles that they play in the presentation of mitochondrial diseases.
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Desideri, Enrico, and L. Miguel Martins. "Mitochondrial Stress Signalling: HTRA2 and Parkinson's Disease." International Journal of Cell Biology 2012 (2012): 1–6. http://dx.doi.org/10.1155/2012/607929.
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Mitochondria are cellular energy generators whose activity requires a continuous supply of oxygen. Recent genetic analysis has suggested that defects in mitochondrial quality control may be key factors in the development of Parkinson’s disease (PD). Mitochondria have a crucial role in supplying energy to the brain, and their deterioration can affect the function and viability of neurons, contributing to neurodegeneration. These organelles can sow the seeds of their own demise because they generate damaging oxygen-free radicals as a byproduct of their intrinsic physiological functions. Mitochondria have therefore evolved specific molecular quality control mechanisms to compensate for the action of damaging agents such as oxygen-free radicals. PTEN-induced putative kinase 1 (PINK1) and high-temperature-regulated A2 (HTRA2), a mitochondrial protease, have recently been proposed to be key modulators of mitochondrial molecular quality control. Here, we review some of the most recent advances in our understanding of mitochondria stress-control pathways, focusing on how signalling by the p38 stress kinase pathway may regulate mitochondrial stress by modulating the activity of HTRA2 via PINK1 and cyclin-dependent kinase 5 (CDK5). We also propose how defects in this pathway may contribute to PD.
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Elizaveta, Bon. "Mitochondrial Movement: A Review." Clinical Research Notes 3, no. 3 (April 30, 2022): 01–06. http://dx.doi.org/10.31579/2690-8816/059.
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The balance between fusion and division determines most of the functions of mitochondria, controls their bioenergetic function, mitochondrial turnover, and also protects mitochondrial DNA. The division promotes equal segregation of mitochondria into daughter cells during cell division itself and enhances the distribution of mitochondria along the cytoskeletal pathways. In addition, division can help isolate damaged mitochondrial segments and thus promote autophagy. Fusion provides protein complementation, and equal distribution of metabolites. The movement of mitochondria in the dendrites, axons and perikaryons of neurons is an important aspect of the vital activity of nerve cells. Disorders of mitochondrial fusion, division, and mobility can lead to defects in the functioning of the nervous system, which makes it important to study these processes for improvig methods of prevention, diagnosis, and correction of neurological diseases.
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Dai, Dawei, Lifang Jin, Zhenzhen Huo, Shumei Yan, Zeyang Ma, Weiwei Qi, and Rentao Song. "Maize pentatricopeptide repeat protein DEK53 is required for mitochondrial RNA editing at multiple sites and seed development." Journal of Experimental Botany 71, no. 20 (July 25, 2020): 6246–61. http://dx.doi.org/10.1093/jxb/eraa348.
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Abstract Pentatricopeptide repeat (PPR) proteins were identified as site-specific recognition factors for RNA editing in plant mitochondria and plastids. In this study, we characterized maize (Zea mays) kernel mutant defective kernel 53 (dek53), which has an embryo lethal and collapsed endosperm phenotype. Dek53 encodes an E-subgroup PPR protein, which possesses a short PLS repeat region of only seven repeats. Subcellular localization analysis indicated that DEK53 is localized in the mitochondrion. Strand- and transcript-specific RNA-seq analysis showed that the dek53 mutation affected C-to-U RNA editing at more than 60 mitochondrial C targets. Biochemical analysis of mitochondrial protein complexes revealed a significant reduction in the assembly of mitochondrial complex III in dek53. Transmission electron microscopic examination showed severe morphological defects of mitochondria in dek53 endosperm cells. In addition, yeast two-hybrid and luciferase complementation imaging assays indicated that DEK53 can interact with the mitochondrion-targeted non-PPR RNA editing factor ZmMORF1, suggesting that DEK53 might be a functional component of the organellar RNA editosome.
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Faulkner, Matthew F., and Jeannine M. Durdik. "Age-associated defects in Tcell metabolism (46.10)." Journal of Immunology 182, no. 1_Supplement (April 1, 2009): 46.10. http://dx.doi.org/10.4049/jimmunol.182.supp.46.10.
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Abstract Aging at the cellular and molecular level causes a decline in immune function. We are characterizing the responses of naïve T-cells to activation. Activated T-cells of aged mice initiate proliferation as well as their young counterparts, but have increased apoptotic rates. However, the mechanisms behind this post- activation death are not completely understood. We will show alterations in metabolic activities in T-cells of aged mice through differences in the expression of glucose transporter (Glut 1), glucose uptake and lactate production. Additionally, we will correlate these findings with autophagocytic vesicle formation by analyzing microtubule-associated protein -1 light chain 3 (LC3) as well as comparing relative amounts of actively respiring mitochondria using Mitotracker Red CM-H2XRos, a membrane potential dependant dye, and total mitochondrial mass by staining with the mitochondrial-selective fluorescence label Mitotracker Green. Levels of reactive oxygen species will be then quantified by staining with ROS specific dye DCF-DA and correlated to the ratio of mitochondrial mass to membrane potential.
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Kuznetsov, Andrey V., Stefan Schneeberger, Rüdiger Seiler, Gerald Brandacher, Walter Mark, Wolfgang Steurer, Valdur Saks, Yves Usson, Raimund Margreiter, and Erich Gnaiger. "Mitochondrial defects and heterogeneous cytochromecrelease after cardiac cold ischemia and reperfusion." American Journal of Physiology-Heart and Circulatory Physiology 286, no. 5 (May 2004): H1633—H1641. http://dx.doi.org/10.1152/ajpheart.00701.2003.
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Mitochondria play a critical role in myocardial cold ischemia-reperfusion (CIR) and induction of apoptosis. The nature and extent of mitochondrial defects and cytochrome c (Cyt c) release were determined by high-resolution respirometry in permeabilized myocardial fibers. CIR in a rat heart transplant model resulted in variable contractile performance, correlating with the decline of ADP-stimulated respiration. Respiration with succinate or N,N,N′, N′-tetramethyl- p-phenylenediamine dihydrochloride (substrates for complexes II and IV) was partially restored by added Cyt c, indicating Cyt c release. In contrast, NADH-linked respiration (glutamate+malate) was not stimulated by Cyt c, owing to a specific defect of complex I. CIR but not cold ischemia alone resulted in the loss of NADH-linked respiratory capacity, uncoupling of oxidative phosphorylation and Cyt c release. Mitochondria depleted of Cyt c by controlled hypoosmotic shock provided a kinetic model of homogenous Cyt c depletion. Comparison to Cyt c control of respiration in CIR-injured myocardial fibers indicated heterogeneity of Cyt c release. The complex I defect and uncoupling correlated with heterogeneous Cyt c release, the extent of which increased with loss of cardiac performance. These results demonstrate a complex pattern of multiple mitochondrial damage as determinants of CIR injury of the heart.
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Varghese, Merina, Wei Zhao, Jun Wang, Alice Cheng, Xianjuan Qian, Amna Chaudhry, Lap Ho, and Giulio Pasinetti. "Mitochondrial bioenergetics is defective in presymptomatic Tg2576 AD Mice." Translational Neuroscience 2, no. 1 (January 1, 2011): 1–5. http://dx.doi.org/10.2478/s13380-011-0011-8.
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AbstractAlzheimer’s disease (AD) is an age-related dementia, with the pathological hallmarks of neuritic plaques and neurofibrillary tangles, brain atrophy and loss of synaptic terminals. Dysfunctional mitochondrial bioenergetics is implicated as a contributing factor to the cognitive decline observed in AD. We hypothesized that, in the presence of the AD neurotoxic peptide beta-amyloid, mitochondrial respiration is impaired early in synaptic terminals, which are vital to cognitive performance, preferentially in cognitive centers of the brain. We compared oxygen consumption in synaptosomal and perikaryal mitochondria prepared from the cerebral cortex and cerebellum of wild type (WT) and AD transgenic Tg2576 mice. Compared to WT mice, Tg2576 mice showed decreased mitochondrial respiration in the cerebral cortex specifically in synaptosomal fraction, while the perikaryal mitochondria were unaffected. Neither mitochondrial fraction was affected in the cerebellum of Tg2576 mice as compared to WT. The occurrence of a bioenergetic defect in synaptic terminals of mice overexpressing mutant beta-amyloid, in particular in an area of the brain important to cognition, points to an early role of mitochondrial defects in the onset of cognitive deficits in AD.
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Wang, Qiang, Ann M. Ratchford, Maggie M. Y. Chi, Erica Schoeller, Antonina Frolova, Tim Schedl, and Kelle H. Moley. "Maternal Diabetes Causes Mitochondrial Dysfunction and Meiotic Defects in Murine Oocytes." Molecular Endocrinology 23, no. 10 (October 1, 2009): 1603–12. http://dx.doi.org/10.1210/me.2009-0033.
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Abstract The adverse effects of maternal diabetes on embryo development and pregnancy outcomes have recently been shown to occur as early as the one-cell zygote stage. The hypothesis of this study was that maternally inherited mitochondria in oocytes from diabetic mice are abnormal and thus responsible in part for this latency of developmental compromise. In ovulated oocytes from diabetic mice, transmission electron microscopy revealed an alteration in mitochondrial ultrastructure, and the quantitative analysis of mitochondrial DNA copy number demonstrated an increase. The levels of ATP and tricarboxylic acid cycle metabolites in diabetic oocytes were markedly reduced compared with controls, suggesting a mitochondrial metabolic dysfunction. Abnormal distribution of mitochondria within maturing oocytes also was seen in diabetic mice. Furthermore, oocytes from diabetic mice displayed a higher frequency of spindle defects and chromosome misalignment in meiosis, resulting in increased aneuploidy rates in ovulated oocytes. Collectively, our results suggest that maternal diabetes results in oocyte defects that are transmitted to the fetus by two routes: first, meiotic spindle and chromatin defects result in nondisjunction leading to embryonic aneuploidy; second, structural and functional abnormalities of oocyte mitochondria, through maternal transmission, provide the embryo with a dysfunctional complement of mitochondria that may be propagated during embryogenesis.
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Wang, Qiang, Ann M. Ratchford, Maggie M. Y. Chi, Erica Schoeller, Antonina Frolova, Tim Schedl, and Kelle H. Moley. "Maternal Diabetes Causes Mitochondrial Dysfunction and Meiotic Defects in Murine Oocytes." Journal of Clinical Endocrinology & Metabolism 94, no. 9 (September 1, 2009): 3618. http://dx.doi.org/10.1210/jcem.94.9.9995.
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The adverse effects of maternal diabetes on embryo development and pregnancy outcomes have recently been shown to occur as early as the one-cell zygote stage. The hypothesis of this study was that maternally inherited mitochondria in oocytes from diabetic mice are abnormal and thus responsible in part for this latency of developmental compromise. In ovulated oocytes from diabetic mice, transmission electron microscopy revealed an alteration in mitochondrial ultrastructure, and the quantitative analysis of mitochondrial DNA copy number demonstrated an increase. The levels of ATP and tricarboxylic acid cycle metabolites in diabetic oocytes were markedly reduced compared with controls, suggesting a mitochondrial metabolic dysfunction. Abnormal distribution of mitochondria within maturing oocytes also was seen in diabetic mice. Furthermore, oocytes from diabetic mice displayed a higher frequency of spindle defects and chromosome misalignment in meiosis, resulting in increased aneuploidy rates in ovulated oocytes. Collectively, our results suggest that maternal diabetes results in oocyte defects that are transmitted to the fetus by two routes: first, meiotic spindle and chromatin defects result in nondisjunction leading to embryonic aneuploidy; second, structural and functional abnormalities of oocyte mitochondria, through maternal transmission, provide the embryo with a dysfunctional complement of mitochondria that may be propagated during embryogenesis.
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Kiseljaković, Emina, Radivoj Jadrić, Sabaheta Hasić, Lorenka Ljuboja, Jovo Radovanović, Husein Kulenović, and Mira Winterhalter-Jadrić. "Mitochondrial medicine - a key to solve pathophysiology of 21 century diseases." Bosnian Journal of Basic Medical Sciences 2, no. 1-2 (February 20, 2008): 46–48. http://dx.doi.org/10.17305/bjbms.2002.3580.
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Over the past 13 years mitochondrial defects have been involved in wide variety of degenerative diseases - Parkinson disease, Alzheimer dementia, arteriosclerosis, ageing and cancer. Mitochondria are believed to control apoptosis or programmed cell death. Disturbance in mitochondrial metabolism has also been implicated in many common diseases such as congestive hart failure, diabetes and migraine. Scientific investigations have showed complexities in mitochondrial genetics, but at the same time, pathophysiology of mitochondrial diseases is still enigma. Mitochondria and their DNAs are opening the era of "mitochondrial medicine". What we today call "a mitochondrial medicine" is only a part of the whole panorama of diseases based on disordered mitochondrial function.
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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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Cheema, Nashwa J., Jessie M. Cameron, and David A. Hood. "Effect of rapamycin on mitochondria and lysosomes in fibroblasts from patients with mtDNA mutations." American Journal of Physiology-Cell Physiology 321, no. 1 (July 1, 2021): C176—C186. http://dx.doi.org/10.1152/ajpcell.00471.2020.
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Maintaining mitochondrial function and dynamics is crucial for cellular health. In muscle, defects in mitochondria result in severe myopathies where accumulation of damaged mitochondria causes deterioration and dysfunction. Importantly, understanding the role of mitochondria in disease is a necessity to determine future therapeutics. One of the most common myopathies is mitochondrial encephalopathy lactic acidosis stroke-like episodes (MELAS), which has no current treatment. Recently, patients with MELAS treated with rapamycin exhibited improved clinical outcomes. However, the cellular mechanisms of rapamycin effects in patients with MELAS are currently unknown. In this study, we used cultured skin fibroblasts as a window into the mitochondrial dysfunction evident in MELAS cells, as well as to study the mechanisms of rapamycin action, compared with control, healthy individuals. We observed that mitochondria from patients were fragmented, had a threefold decline in the average speed of motility, a twofold reduced mitochondrial membrane potential, and a 1.5- to 2-fold decline in basal respiration. Despite the reduction in mitochondrial function, mitochondrial import protein Tim23 was elevated in patient cell lines. MELAS fibroblasts exhibited increased MnSOD levels and lysosomal function when compared with healthy controls. Treatment of MELAS fibroblasts with rapamycin for 24 h resulted in increased mitochondrial respiration compared with control cells, a higher lysosome content, and a greater localization of mitochondria to lysosomes. Our studies suggest that rapamycin has the potential to improve cellular health even in the presence of mtDNA defects, primarily via an increase in lysosomal content.
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Leonard, JV, and AHV Schapira. "Mitochondrial respiratory chain disorders I: mitochondrial DNA defects." Lancet 355, no. 9200 (January 2000): 299–304. http://dx.doi.org/10.1016/s0140-6736(99)05225-3.
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Smith, M. G., V. R. Simon, H. O'Sullivan, and L. A. Pon. "Organelle-cytoskeletal interactions: actin mutations inhibit meiosis-dependent mitochondrial rearrangement in the budding yeast Saccharomyces cerevisiae." Molecular Biology of the Cell 6, no. 10 (October 1995): 1381–96. http://dx.doi.org/10.1091/mbc.6.10.1381.
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During early stages of meiosis I, yeast mitochondria fuse to form a single continuous thread. Thereafter, portions of the mitochondrial thread are equally distributed to daughter cells. Using time-lapse fluorescence microscopy and a membrane potential sensing dye, mitochondria are resolved as small particles at the cell periphery in pre-meiotic, living yeast. These organelles display low levels of movement. During meiosis I, we observed a threefold increase in mitochondrial motility. Mitochondrial movements were linear, occurred at a maximum velocity of 25 +/- 6.7 nm/s, and resulted in organelle collision and fusion to form elongated tubular structures. Mitochondria do not co-localize with microtubules. Destabilization of microtubules by nocodazole treatment has no significant effect on the rate and extent of thread formation. In contrast, yeast bearing temperature-sensitive mutations in the actin-encoding ACT1 gene (act1-3 and act1-133) exhibit abnormal mitochondrial aggregation, fragmentation, and enlargement as well as loss of mitochondrial motility. In act1-3 cells, mitochondrial defects and actin delocalization occur only at restrictive temperatures. The act1-133 mutation, which perturbs the myosin-binding site of actin without significantly affecting actin cytoskeletal structure in meiotic yeast, results in mitochondrial morphology and motility defects at restrictive and permissive temperatures. These studies support a role for the actin cytoskeleton in the control of mitochondrial position and movements in meiotic yeast.
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Ruan, Linhao, Yuhao Wang, Xi Zhang, Alexis Tomaszewski, Joshua T. McNamara, and Rong Li. "Mitochondria-Associated Proteostasis." Annual Review of Biophysics 49, no. 1 (May 6, 2020): 41–67. http://dx.doi.org/10.1146/annurev-biophys-121219-081604.
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Mitochondria are essential organelles in eukaryotes. Most mitochondrial proteins are encoded by the nuclear genome and translated in the cytosol. Nuclear-encoded mitochondrial proteins need to be imported, processed, folded, and assembled into their functional states. To maintain protein homeostasis (proteostasis), mitochondria are equipped with a distinct set of quality control machineries. Deficiencies in such systems lead to mitochondrial dysfunction, which is a hallmark of aging and many human diseases, such as neurodegenerative diseases, cardiovascular diseases, and cancer. In this review, we discuss the unique challenges and solutions of proteostasis in mitochondria. The import machinery coordinates with mitochondrial proteases and chaperones to maintain the mitochondrial proteome. Moreover, mitochondrial proteostasis depends on cytosolic protein quality control mechanisms during crises. In turn, mitochondria facilitate cytosolic proteostasis. Increasing evidence suggests that enhancing mitochondrial proteostasis may hold therapeutic potential to protect against protein aggregation–associated cellular defects.
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Lin, Dar-Shong, Yu-Wen Huang, Che-Sheng Ho, Pi-Lien Hung, Mei-Hsin Hsu, Tuan-Jen Wang, Tsu-Yen Wu, et al. "Oxidative Insults and Mitochondrial DNA Mutation Promote Enhanced Autophagy and Mitophagy Compromising Cell Viability in Pluripotent Cell Model of Mitochondrial Disease." Cells 8, no. 1 (January 17, 2019): 65. http://dx.doi.org/10.3390/cells8010065.
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Dysfunction of mitochondria causes defects in oxidative phosphorylation system (OXPHOS) and increased production of reactive oxygen species (ROS) triggering the activation of the cell death pathway that underlies the pathogenesis of aging and various diseases. The process of autophagy to degrade damaged cytoplasmic components as well as dysfunctional mitochondria is essential for ensuring cell survival. We analyzed the role of autophagy inpatient-specific induced pluripotent stem (iPS) cells generated from fibroblasts of patients with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) with well-characterized mitochondrial DNA mutations and distinct OXPHOS defects. MELAS iPS cells recapitulated the pathogenesis of MELAS syndrome, and showed an increase of autophagy in comparison with its isogenic normal counterpart, whereas mitophagy is very scarce at the basal condition. Our results indicated that the existence of pathogenic mtDNA alone in mitochondrial disease was not sufficient to elicit the degradation of dysfunctional mitochondria. Nonetheless, oxidative insults induced bulk macroautophagy with the accumulation of autophagosomes and autolysosomes upon marked elevation of ROS, overload of intracellular calcium, and robust depolarization of mitochondrial membrane potential, while mitochondria respiratory function was impaired and widespread mitophagy compromised cell viability. Collectively, our studies provide insights into the dysfunction of autophagy and activation of mitophagy contributing to the pathological mechanism of mitochondrial disease.