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David C. Chan - One of the best experts on this subject based on the ideXlab platform.
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Mitochondrial Fusion is required for spermatogonial differentiation and meiosis
eLife, 2019Co-Authors: Grigor Varuzhanyan, Rebecca Rojansky, Michael J. Sweredoski, Robert Graham, Sonja Hess, Mark S. Ladinsky, David C. ChanAbstract:Differentiating cells tailor their metabolism to fulfill their specialized functions. We examined whether Mitochondrial Fusion is important for metabolic tailoring during spermatogenesis. Acutely after depletion of mitofusins Mfn1 and Mfn2, spermatogenesis arrests due to failure to accomplish a metabolic shift during meiosis. This metabolic shift includes increased Mitochondrial content, Mitochondrial elongation, and upregulation of oxidative phosphorylation (OXPHOS). With long-term mitofusin loss, all differentiating germ cell types are depleted, but proliferation of stem-like undifferentiated spermatogonia remains unaffected. Thus, compared with undifferentiated spermatogonia, differentiating spermatogonia and meiotic spermatocytes have cell physiologies that require high levels of Mitochondrial Fusion. Proteomics in fibroblasts reveals that mitofusin-null cells downregulate respiratory chain complexes and Mitochondrial ribosomal subunits. Similarly, mitofusin depletion in immortalized spermatocytes or germ cells in vivo results in reduced OXPHOS subunits and activity. We reveal that by promoting OXPHOS, mitofusins enable spermatogonial differentiation and a metabolic shift during meiosis.
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titration of Mitochondrial Fusion rescues mff deficient cardiomyopathy
Journal of Cell Biology, 2015Co-Authors: Hsiuchen Chen, Michael J Mccaffery, Clary B Clish, Mohit Jain, Vamsi K Mootha, David C. ChanAbstract:Defects in Mitochondrial Fusion or fission are associated with many pathologies, raising the hope that pharmacological manipulation of Mitochondrial dynamics may have therapeutic benefit. This approach assumes that organ physiology can be restored by rebalancing Mitochondrial dynamics, but this concept remains to be validated. We addressed this issue by analyzing mice deficient in Mff, a protein important for Mitochondrial fission. Mff mutant mice die at 13 wk as a result of severe dilated cardiomyopathy leading to heart failure. Mutant tissue showed reduced Mitochondrial density and respiratory chain activity along with increased mitophagy. Remarkably, concomitant deletion of the Mitochondrial Fusion gene Mfn1 completely rescued heart dysfunction, life span, and respiratory chain function. Our results show for the first time that retuning the balance of Mitochondrial Fusion and fission can restore tissue integrity and Mitochondrial physiology at the whole-organ level. Examination of liver, testis, and cerebellum suggest, however, that the precise balance point of Fusion and fission is cell type specific.
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Physiological functions of Mitochondrial Fusion.
Annals of the New York Academy of Sciences, 2010Co-Authors: Hsiuchen Chen, David C. ChanAbstract:In recent years, the dynamic nature of mitochondria has been discovered to be critical for their function. Here we discuss the molecular basis of Mitochondrial Fusion, its protective role in neurodegeneration, and its importance in cellular function. The mitofusins Mfn1 and Mfn2, GTPases localized to the outer membrane, mediate outer-membrane Fusion. OPA1, a GTPase associated with the inner membrane, mediates subsequent inner-membrane Fusion. Mutations in Mfn2 or OPA1 cause neurodegenerative diseases. Mouse models with defects in Mitochondrial Fusion genes have provided important avenues for understanding how Fusion maintains Mitochondrial physiology and neuronal function. Mitochondrial Fusion enables content mixing within a Mitochondrial population, thereby preventing permanent loss of essential components. Cells with reduced Mitochondrial Fusion, as a consequence, show a subpopulation of mitochondria that lack mtDNA nucleoids. Such mtDNA defects lead to respiration-deficient mitochondria, and their accumulation in neurons leads to impaired outgrowth of cellular processes and ultimately neurodegeneration.
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Mitochondrial Fusion is required for mtdna stability in skeletal muscle and tolerance of mtdna mutations
Cell, 2010Co-Authors: Hsiuchen Chen, Michael J Mccaffery, Marc Vermulst, Yun E Wang, Anne Chomyn, Tomas A Prolla, David C. ChanAbstract:Mitochondria are highly mobile and dynamic organelles that continually fuse and divide. These processes allow mitochondria to exchange contents, including Mitochondrial DNA (mtDNA). Here we examine the functions of Mitochondrial Fusion in differentiated skeletal muscle through conditional deletion of the mitofusins Mfn1 and Mfn2, Mitochondrial GTPases essential for Fusion. Loss of the mitofusins causes severe Mitochondrial dysfunction, compensatory Mitochondrial proliferation, and muscle atrophy. Mutant mice have severe mtDNA depletion in muscle that precedes physiological abnormalities. Moreover, the Mitochondrial genomes of the mutant muscle rapidly accumulate point mutations and deletions. In a related experiment, we find that disruption of Mitochondrial Fusion strongly increases Mitochondrial dysfunction and lethality in a mouse model with high levels of mtDNA mutations. With its dual function in safeguarding mtDNA integrity and preserving mtDNA function in the face of mutations, Mitochondrial Fusion is likely to be a protective factor in human disorders associated with mtDNA mutations.
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Mitochondrial Fusion protects against neurodegeneration in the cerebellum
Cell, 2007Co-Authors: Hsiuchen Chen, Michael J Mccaffery, David C. ChanAbstract:Mutations in the Mitochondrial Fusion gene Mfn2 cause the human neurodegenerative disease Charcot-Marie-Tooth type 2A. However, the cellular basis underlying this relationship is poorly understood. By removing Mfn2 from the cerebellum, we established a model for neurodegeneration caused by loss of Mitochondrial Fusion. During development and after maturity, Purkinje cells require Mfn2 but not Mfn1 for dendritic outgrowth, spine formation, and cell survival. In vivo, cell culture, and electron microscopy studies indicate that mutant Purkinje cells have aberrant Mitochondrial distribution, ultrastructure, and electron transport chain activity. In fibroblasts lacking Mitochondrial Fusion, the majority of mitochondria lack Mitochondrial DNA nucleoids. This deficiency provides a molecular mechanism for the dependence of respiratory activity on Mitochondrial Fusion. Our results show that exchange of Mitochondrial contents is important for Mitochondrial function as well as organelle distribution in neurons and have important implications for understanding the mechanisms of neurodegeneration due to perturbations in Mitochondrial Fusion.
Hsiuchen Chen - One of the best experts on this subject based on the ideXlab platform.
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titration of Mitochondrial Fusion rescues mff deficient cardiomyopathy
Journal of Cell Biology, 2015Co-Authors: Hsiuchen Chen, Michael J Mccaffery, Clary B Clish, Mohit Jain, Vamsi K Mootha, David C. ChanAbstract:Defects in Mitochondrial Fusion or fission are associated with many pathologies, raising the hope that pharmacological manipulation of Mitochondrial dynamics may have therapeutic benefit. This approach assumes that organ physiology can be restored by rebalancing Mitochondrial dynamics, but this concept remains to be validated. We addressed this issue by analyzing mice deficient in Mff, a protein important for Mitochondrial fission. Mff mutant mice die at 13 wk as a result of severe dilated cardiomyopathy leading to heart failure. Mutant tissue showed reduced Mitochondrial density and respiratory chain activity along with increased mitophagy. Remarkably, concomitant deletion of the Mitochondrial Fusion gene Mfn1 completely rescued heart dysfunction, life span, and respiratory chain function. Our results show for the first time that retuning the balance of Mitochondrial Fusion and fission can restore tissue integrity and Mitochondrial physiology at the whole-organ level. Examination of liver, testis, and cerebellum suggest, however, that the precise balance point of Fusion and fission is cell type specific.
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Physiological functions of Mitochondrial Fusion.
Annals of the New York Academy of Sciences, 2010Co-Authors: Hsiuchen Chen, David C. ChanAbstract:In recent years, the dynamic nature of mitochondria has been discovered to be critical for their function. Here we discuss the molecular basis of Mitochondrial Fusion, its protective role in neurodegeneration, and its importance in cellular function. The mitofusins Mfn1 and Mfn2, GTPases localized to the outer membrane, mediate outer-membrane Fusion. OPA1, a GTPase associated with the inner membrane, mediates subsequent inner-membrane Fusion. Mutations in Mfn2 or OPA1 cause neurodegenerative diseases. Mouse models with defects in Mitochondrial Fusion genes have provided important avenues for understanding how Fusion maintains Mitochondrial physiology and neuronal function. Mitochondrial Fusion enables content mixing within a Mitochondrial population, thereby preventing permanent loss of essential components. Cells with reduced Mitochondrial Fusion, as a consequence, show a subpopulation of mitochondria that lack mtDNA nucleoids. Such mtDNA defects lead to respiration-deficient mitochondria, and their accumulation in neurons leads to impaired outgrowth of cellular processes and ultimately neurodegeneration.
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Mitochondrial Fusion is required for mtdna stability in skeletal muscle and tolerance of mtdna mutations
Cell, 2010Co-Authors: Hsiuchen Chen, Michael J Mccaffery, Marc Vermulst, Yun E Wang, Anne Chomyn, Tomas A Prolla, David C. ChanAbstract:Mitochondria are highly mobile and dynamic organelles that continually fuse and divide. These processes allow mitochondria to exchange contents, including Mitochondrial DNA (mtDNA). Here we examine the functions of Mitochondrial Fusion in differentiated skeletal muscle through conditional deletion of the mitofusins Mfn1 and Mfn2, Mitochondrial GTPases essential for Fusion. Loss of the mitofusins causes severe Mitochondrial dysfunction, compensatory Mitochondrial proliferation, and muscle atrophy. Mutant mice have severe mtDNA depletion in muscle that precedes physiological abnormalities. Moreover, the Mitochondrial genomes of the mutant muscle rapidly accumulate point mutations and deletions. In a related experiment, we find that disruption of Mitochondrial Fusion strongly increases Mitochondrial dysfunction and lethality in a mouse model with high levels of mtDNA mutations. With its dual function in safeguarding mtDNA integrity and preserving mtDNA function in the face of mutations, Mitochondrial Fusion is likely to be a protective factor in human disorders associated with mtDNA mutations.
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Mitochondrial Fusion protects against neurodegeneration in the cerebellum
Cell, 2007Co-Authors: Hsiuchen Chen, Michael J Mccaffery, David C. ChanAbstract:Mutations in the Mitochondrial Fusion gene Mfn2 cause the human neurodegenerative disease Charcot-Marie-Tooth type 2A. However, the cellular basis underlying this relationship is poorly understood. By removing Mfn2 from the cerebellum, we established a model for neurodegeneration caused by loss of Mitochondrial Fusion. During development and after maturity, Purkinje cells require Mfn2 but not Mfn1 for dendritic outgrowth, spine formation, and cell survival. In vivo, cell culture, and electron microscopy studies indicate that mutant Purkinje cells have aberrant Mitochondrial distribution, ultrastructure, and electron transport chain activity. In fibroblasts lacking Mitochondrial Fusion, the majority of mitochondria lack Mitochondrial DNA nucleoids. This deficiency provides a molecular mechanism for the dependence of respiratory activity on Mitochondrial Fusion. Our results show that exchange of Mitochondrial contents is important for Mitochondrial function as well as organelle distribution in neurons and have important implications for understanding the mechanisms of neurodegeneration due to perturbations in Mitochondrial Fusion.
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emerging functions of mammalian Mitochondrial Fusion and fission
Human Molecular Genetics, 2005Co-Authors: Hsiuchen Chen, David C. ChanAbstract:Mitochondria provide a myriad of services to the cell, including energy production, calcium buffering and regulation of apoptosis. How these diverse functions are coordinated among the hundreds of mitochondria in a given cell is largely unknown, but is probably dependent on the dynamic nature of mitochondria. In this review, we explore the latest developments in Mitochondrial dynamics in mammals. These studies indicate that mitofusins and OPA1 are essential for Mitochondrial Fusion, whereas Fis1 and Drp1 are essential for Mitochondrial fission. The overall morphology of the Mitochondrial population depends on the relative activities of these two sets of proteins. In addition to the regulation of Mitochondrial shape, these molecules also play important roles in cell and tissue physiology. Perturbation of Mitochondrial Fusion results in defects in Mitochondrial membrane potential and respiration, poor cell growth and increased susceptibility to cell death. These cellular observations may explain why Mitochondrial Fusion is essential for embryonic development. Two inherited neuropathies, Charcot–Marie–Tooth type 2A and autosomal dominant optic atrophy, are caused by mutations in mitofusin 2 and OPA1, suggesting that proper regulation of Mitochondrial dynamics is particularly vital to neurons. Mitochondrial fission accompanies several types of apoptotic cell death and appears important for progression of the apoptotic pathway. These studies provide insight into how mitochondria communicate with one another to coordinate Mitochondrial function and morphology.
Jodi Nunnari - One of the best experts on this subject based on the ideXlab platform.
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the soluble form of bax regulates Mitochondrial Fusion via mfn2 homotypic complexes
Molecular Cell, 2011Co-Authors: Suzanne Hoppins, Michael J Mccaffery, Frank Edlich, Megan M Cleland, Soojay Banerjee, Richard J Youle, Jodi NunnariAbstract:In mammals, Fusion of the Mitochondrial outer membrane is controlled by two DRPs, MFN1 and MFN2, that function in place of a single outer membrane DRP, Fzo1 in yeast. We addressed the significance of two mammalian outer membrane Fusion DRPs using an in vitro mammalian Mitochondrial Fusion assay. We demonstrate that heterotypic MFN1-MFN2 trans complexes possess greater efficacy in Fusion as compared to homotypic MFN1 or MFN2 complexes. In addition, we show that the soluble form of the proapoptotic Bcl2 protein, Bax, positively regulates Mitochondrial Fusion exclusively through homotypic MFN2 trans complexes. Together, these data demonstrate functional and regulatory distinctions between MFN1 and MFN2 and provide insight into their unique physiological roles.
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The molecular mechanism of Mitochondrial Fusion.
Biochimica et biophysica acta, 2008Co-Authors: Suzanne Hoppins, Jodi NunnariAbstract:This review is focused on Mitochondrial membrane Fusion, which is a highly conserved process from yeast to human cells. We present observations from both yeast and mammalian cells that have provided insights into the mechanism of Mitochondrial Fusion and speculate on how the key players, which are dynamin-related GTPases do the work of membrane tethering and Fusion.
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Mitochondrial Fusion in vitro.
Methods in molecular biology (Clifton N.J.), 2007Co-Authors: Shelly Meeusen, Jodi NunnariAbstract:The field of Mitochondrial dynamics has received a great deal of attention as a result of a number of studies linking Mitochondrial fission and Fusion machinery to apoptosis. Specifically, elevated levels of Mitochondrial fission or compromised Mitochondrial Fusion can sensitize cells to apoptotic stimuli. Conversely, stimulation of Mitochondrial Fusion can render cells resistant to apoptotic stimuli. In addition, the machinery involved in fission and Fusion has been spatially linked to Bax, a pro-apoptotic protein. However, the mechanistic implications of interactions between the machinery of Mitochondrial fission and Fusion and apoptotic effectors are largely unknown. Our understanding of the pathways of Mitochondrial fission and Fusion have come from genetic studies coupled with direct observation of both fission and Fusion components and Mitochondrial organelle morphology and behavior in vivo in Saccharomyces cerevisiae. These approaches have identified the key players in both Mitochondrial fission and Fusion and have generated good models for their roles in Mitochondrial dynamics. However, the lack of in vitro systems for studying these processes has impeded a deeper investigation of the mechanism. We have recapitulated the process of Mitochondrial Fusion in vitro (5). Using this in vitro Fusion assay, we have separated outer Mitochondrial membrane Fusion from inner and identified the mechanistic requirements for each step.
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In vitro assays for Mitochondrial Fusion and division.
Methods in cell biology, 2007Co-Authors: Elena Ingerman, Shelly Meeusen, Rachel M. Devay, Jodi NunnariAbstract:Publisher Summary This chapter outlines two methods that have proved instrumental in recapitulating events in vitro assay that occur during Mitochondrial division and Fusion and led to more mechanistic models of these processes. First, the chapter outlines the methodology behind an assay developed to recapitulate the process of Mitochondrial Fusion in vitro . Using this in vitro Fusion assay, the chapter separates outer Mitochondrial membrane Fusion from inner Mitochondrial membrane Fusion. Second, it focuses on the methodology of a coupled, continuous GTPase assay that has allowed accurately studying the kinetic properties of the dynamin-related GTPase—Dnm1, which is the master regulator of Mitochondrial division. This assay will be useful for future mechanistic studies of Mitochondrial division and the study of Mitochondrial Fusion that requires the activity of the dynamin-related GTPase, Fzo1/Mfn1/2 and Mgm1/OPA1. The importance of understanding the fundamental mechanism of Mitochondrial Fusion is underscored by the fact that defects in Fusion have recently been linked to the onset of neurodegenerative diseases. The mechanism of Mitochondrial Fusion is unique. No paradigm exists for Fusion of a double-membrane system. The majority of the known core Mitochondrial Fusion components belong uniquely to the dynamin-related GTPase family, whose members are large GTPase that regulate membrane dynamics through self-assembly.
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Mitochondrial Fusion Intermediates Revealed in Vitro
Science (New York N.Y.), 2004Co-Authors: Shelly Meeusen, J. Michael Mccaffery, Jodi NunnariAbstract:The events that occur during the Fusion of double-membraned mitochondria are unknown. As an essential step toward determining the mechanism of Mitochondrial Fusion, we have captured this event in vitro. Mitochondrial outer and inner membrane Fusion events were separable and mechanistically distinct, but both required guanosine 5'-triphosphate hydrolysis. Homotypic trans interactions of the ancient outer transmembrane guanosine triphosphatase, Fzo1, were required to promote the Fusion of Mitochondrial outer membranes, whereas electrical potential was also required for Fusion of inner membranes. Our conclusions provide fundamental insights into the molecular events driving Mitochondrial Fusion and advance our understanding of the evolution of Mitochondrial Fusion in eukaryotic cells.
Hiroyoshi Takano - One of the best experts on this subject based on the ideXlab platform.
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Mitochondrial Fusion and inheritance of the Mitochondrial genome
Journal of Plant Research, 2010Co-Authors: Hiroyoshi Takano, Kenta Onoue, Shigeyuki KawanoAbstract:Although maternal or uniparental inheritance of Mitochondrial genomes is a general rule, biparental inheritance is sometimes observed in protists and fungi, including yeasts. In yeast, recombination occurs between the Mitochondrial genomes inherited from both parents. Mitochondrial Fusion observed in yeast zygotes is thought to set up a space for DNA recombination. In the last decade, a universal Mitochondrial Fusion mechanism has been uncovered, using yeast as a model. On the other hand, an alternative Mitochondrial Fusion mechanism has been identified in the true slime mold Physarum polycephalum . A specific Mitochondrial plasmid, mF, has been detected as the genetic material that causes Mitochondrial Fusion in P. polycephalum . Without mF, Fusion of the mitochondria is not observed throughout the life cycle, suggesting that Physarum has no constitutive Mitochondrial Fusion mechanism. Conversely, mitochondria fuse in zygotes and during sporulation with mF. The complete mF sequence suggests that one gene, ORF640, encodes a fusogen for Physarum mitochondria. Although in general, mitochondria are inherited uniparentally, biparental inheritance occurs with specific sexual crossing in P. polycephalum . An analysis of the transmission of Mitochondrial genomes has shown that recombinations between two parental Mitochondrial genomes require Mitochondrial Fusion, mediated by mF. Physarum is a unique organism for studying Mitochondrial Fusion.
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Rearrangements of Mitochondrial DNA and the Mitochondrial Fusion-promoting plasmid (mF) are associated with defective Mitochondrial Fusion in Physarum polycephalum
Current genetics, 1996Co-Authors: Hiroyoshi Takano, Shigeyuki Kawano, Kimie Mori, Tsuneyoshi KuroiwaAbstract:A specific linear Mitochondrial plasmid (mF) is genetically associated with the Fusion of mitochondria in the true slime mould,Physarum polycephalum. In matings between mF+ and mF− strains, which respectively carry and do not carry the mF plasmid, Mitochondrial Fusion occurs in the zygote. Mitochondrial Fusion induces recombination between specific sites in the Mitochondrial DNA (mtDNA) and in the mF plasmid. To detect a region which is associated with the Mitochondrial Fusion in the mF plasmid, we isolated, by fluorescence microscopy, strains which showed defective Mitochondrial Fusion (Δmif−) from those which showed normal Mitochondrial Fusion (mif+). Analysis of the Mitochondrial genomes of Δmif− strains showed only mtDNA which recombined with the mF plasmid in mitochondria. Comparison of this recombinant mtDNA in one Δmif− strain (NG 15) with that of amif+ strain showed that a 2.2-kbp region, which included the integration site of the mF plasmid, was deleted in the Δmif− strain by recombination between the main mtDNA and the mF plasmid. In other strains, in addition to this deletion, a 6-kbp region which included both termini was deleted by recombination at six repeats of AAT sequences in the mF plasmid. Moreover, transcripts of the mF plasmid were not detected in NG15 by slot hybridization.
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a genetic system controlling Mitochondrial Fusion in the slime mould physarum polycephalum
Genetics, 1993Co-Authors: S Kawano, Hiroyoshi Takano, Kimie Mori, Jun Imai, T KurioiwaAbstract:We have identified two distinct Mitochondrial phenotypes, namely, Mif(+) (Mitochondrial Fusion) and Mif(-) (Mitochondrial Fusion-deficient), and have studied the genetic system that controls Mitochondrial Fusion in the slime mould, Physarum polycephalum. A Mitochondrial plasmid of approximately 16 kbp was identified in all Mif(+) plasmodial strains. This plasmid is apparently responsible for promoting Mitochondrial Fusion, and it is inserted into the Mitochondrial DNA (mtDNA) in successive sexual crossing with Mif(-) strains. This recombinant mtDNA and the unchanged free plasmid spread through the Mitochondrial population via the promotion of Mitochondrial Fusion. The Mif(+) strains with the plasmid were further classified as being two types: high frequency and low frequency Mitochondrial Fusion. Restriction analysis of the mtDNA suggested that the high frequency Mitochondrial Fusion type was more often heteroplasmic; within each plasmodium, mtDNAs of both parental types were usually present, in addition to the presence of the plasmid. Genetic analysis with the progeny obtained from crossing myxamoebae derived from three different isolates suggested that these progeny carried different alleles at a nuclear locus that controlled the frequency of Mitochondrial Fusion. These alleles (Mitochondrial mating-type alleles, mitA1, 2 and 3) appear to function like the mating type of the myxamoebae; Mitochondrial Fusion occurs at high frequency with the combination of unlike alleles, but at low frequency with the combination of like alleles.
Michael J Mccaffery - One of the best experts on this subject based on the ideXlab platform.
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titration of Mitochondrial Fusion rescues mff deficient cardiomyopathy
Journal of Cell Biology, 2015Co-Authors: Hsiuchen Chen, Michael J Mccaffery, Clary B Clish, Mohit Jain, Vamsi K Mootha, David C. ChanAbstract:Defects in Mitochondrial Fusion or fission are associated with many pathologies, raising the hope that pharmacological manipulation of Mitochondrial dynamics may have therapeutic benefit. This approach assumes that organ physiology can be restored by rebalancing Mitochondrial dynamics, but this concept remains to be validated. We addressed this issue by analyzing mice deficient in Mff, a protein important for Mitochondrial fission. Mff mutant mice die at 13 wk as a result of severe dilated cardiomyopathy leading to heart failure. Mutant tissue showed reduced Mitochondrial density and respiratory chain activity along with increased mitophagy. Remarkably, concomitant deletion of the Mitochondrial Fusion gene Mfn1 completely rescued heart dysfunction, life span, and respiratory chain function. Our results show for the first time that retuning the balance of Mitochondrial Fusion and fission can restore tissue integrity and Mitochondrial physiology at the whole-organ level. Examination of liver, testis, and cerebellum suggest, however, that the precise balance point of Fusion and fission is cell type specific.
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the soluble form of bax regulates Mitochondrial Fusion via mfn2 homotypic complexes
Molecular Cell, 2011Co-Authors: Suzanne Hoppins, Michael J Mccaffery, Frank Edlich, Megan M Cleland, Soojay Banerjee, Richard J Youle, Jodi NunnariAbstract:In mammals, Fusion of the Mitochondrial outer membrane is controlled by two DRPs, MFN1 and MFN2, that function in place of a single outer membrane DRP, Fzo1 in yeast. We addressed the significance of two mammalian outer membrane Fusion DRPs using an in vitro mammalian Mitochondrial Fusion assay. We demonstrate that heterotypic MFN1-MFN2 trans complexes possess greater efficacy in Fusion as compared to homotypic MFN1 or MFN2 complexes. In addition, we show that the soluble form of the proapoptotic Bcl2 protein, Bax, positively regulates Mitochondrial Fusion exclusively through homotypic MFN2 trans complexes. Together, these data demonstrate functional and regulatory distinctions between MFN1 and MFN2 and provide insight into their unique physiological roles.
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Mitochondrial Fusion is required for mtdna stability in skeletal muscle and tolerance of mtdna mutations
Cell, 2010Co-Authors: Hsiuchen Chen, Michael J Mccaffery, Marc Vermulst, Yun E Wang, Anne Chomyn, Tomas A Prolla, David C. ChanAbstract:Mitochondria are highly mobile and dynamic organelles that continually fuse and divide. These processes allow mitochondria to exchange contents, including Mitochondrial DNA (mtDNA). Here we examine the functions of Mitochondrial Fusion in differentiated skeletal muscle through conditional deletion of the mitofusins Mfn1 and Mfn2, Mitochondrial GTPases essential for Fusion. Loss of the mitofusins causes severe Mitochondrial dysfunction, compensatory Mitochondrial proliferation, and muscle atrophy. Mutant mice have severe mtDNA depletion in muscle that precedes physiological abnormalities. Moreover, the Mitochondrial genomes of the mutant muscle rapidly accumulate point mutations and deletions. In a related experiment, we find that disruption of Mitochondrial Fusion strongly increases Mitochondrial dysfunction and lethality in a mouse model with high levels of mtDNA mutations. With its dual function in safeguarding mtDNA integrity and preserving mtDNA function in the face of mutations, Mitochondrial Fusion is likely to be a protective factor in human disorders associated with mtDNA mutations.
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Mitochondrial Fusion protects against neurodegeneration in the cerebellum
Cell, 2007Co-Authors: Hsiuchen Chen, Michael J Mccaffery, David C. ChanAbstract:Mutations in the Mitochondrial Fusion gene Mfn2 cause the human neurodegenerative disease Charcot-Marie-Tooth type 2A. However, the cellular basis underlying this relationship is poorly understood. By removing Mfn2 from the cerebellum, we established a model for neurodegeneration caused by loss of Mitochondrial Fusion. During development and after maturity, Purkinje cells require Mfn2 but not Mfn1 for dendritic outgrowth, spine formation, and cell survival. In vivo, cell culture, and electron microscopy studies indicate that mutant Purkinje cells have aberrant Mitochondrial distribution, ultrastructure, and electron transport chain activity. In fibroblasts lacking Mitochondrial Fusion, the majority of mitochondria lack Mitochondrial DNA nucleoids. This deficiency provides a molecular mechanism for the dependence of respiratory activity on Mitochondrial Fusion. Our results show that exchange of Mitochondrial contents is important for Mitochondrial function as well as organelle distribution in neurons and have important implications for understanding the mechanisms of neurodegeneration due to perturbations in Mitochondrial Fusion.