Mitochondrial Fusion Is Required for mtDNA Stability in Skeletal Muscle and Tolerance of mtDNA Mutations

Division of Biology, California Institute of Technology, Pasadena, CA 91125, USA.
Cell (Impact Factor: 32.24). 04/2010; 141(2):280-9. DOI: 10.1016/j.cell.2010.02.026
Source: PubMed


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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    • "Indeed, they showed that increasing the expression of the mitochondrial fission machinery (Drp1 and FIS1 over-expression) triggers skeletal muscle atrophy, while inhibiting mitochondrial fission partly prevented the muscle atrophy triggered by FOXO3 over-expression (Romanello et al. 2010). By studying mice lacking mitofusin 1 and 2 function in skeletal muscle, Chen et al. showed that mitochondrial fusion is required to maintain the integrity of mitochondrial DNA, for normal mitochondrial function, and for normal muscle growth and development (Chen et al. 2010). Two recent articles published in The Journal of Physiology by Cannavino and colleagues (Cannavino et al. 2014, 2015) further increased our understanding of the role played by mitochondrial dynamics in muscle physiology and in the regulation of muscle mass. "

    The Journal of Physiology 07/2015; 593(14-14):2993-2994. DOI:10.1113/JP270736 · 5.04 Impact Factor
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    • "mitochondrialDNAanddelayingapoptosis(Chenetal.,2010; Ramboldetal.,2011).Infact,mitochondrialelongationmight beusefultoprotectmitochondriafrommitophagy.Inaccordance,duringtheinitialperiodofstarvationcytoplasmiccomponentsaredegraded ,whereasmitochondriabecomesubstrate muchlater(Kristensenetal.,2008),becausemitochondriaspared fromdegradationmaycontributetomaximizecellularenergy productiontosustaincellduringnutrientdeprivation(Ramboldetal .,2011).Accordingly,mitochondrialfusionhasbeen associatedwithincreaseinATPproductionduringstressand starvation(Gomesetal.,2011)producingbeneficialeffectsfor cellsunderconditionsoflownutrientsupply.Interestingly,it hasbeendemonstratedthatmitochondriaprovidemembraneto autophagosomesduringstarvation(Haileyetal.,2010)anditcan bealsosuggestedthatsparingmitochondriamaybeusefulto permitthemtoserveasanautophagosomemembranesourcein nutrientdepletionconditions. "
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    ABSTRACT: Diet induced obesity is associated with impaired mitochondrial function and dynamic behavior. Mitochondria are highly dynamic organelles and the balance in fusion/fission is strictly associated with their bioenergetics. Fusion processes are associated with the optimization of mitochondrial function, whereas fission processes are associated with the removal of damaged mitochondria. In diet-induced obesity, impaired mitochondrial function and increased fission processes were found in liver and skeletal muscle. Diverse dietary fat sources differently affect mitochondrial dynamics and bioenergetics. In contrast to saturated fatty acids, omega 3 polyunsaturated fatty acids induce fusion processes and improve mitochondrial function. Moreover, the pro-longevity effect of caloric restriction has been correlated with changes in mitochondrial dynamics leading to decreased cell oxidative injury. Noteworthy, emerging findings revealed an important role for mitochondrial dynamics within neuronal populations involved in central regulation of body energy balance. In conclusion, mitochondrial dynamic processes with their strict interconnection with mitochondrial bioenergetics are involved in energy balance and diet impact on metabolic tissues.
    Frontiers in Physiology 04/2015; 6. DOI:10.3389/fphys.2015.00109 · 3.53 Impact Factor
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    • "Thus, balancing fission and fusion is crucial to mix mtDNA genomes and favors trans-complementation, promoting the mitophagic elimination of mitochondria with excessive mutant mtDNA, but also modulating the possible clonal expansion of mutant mtDNA under specific pathological conditions. The role of fusion in mtDNA maintenance has been elegantly established in a mouse model of impaired fusion with conditional deletion of the mitofusins MFN1 and MFN2 in skeletal muscle (Chen et al., 2010). Both mtDNA depletion and accumulation of mtDNA mutation resulted from impaired fusion, remarking the need of mitochondrial fusion for mtDNA maintenance. "
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    ABSTRACT: Mitochondria are cytoplasmic organelles containing their own multi-copy genome. They are organized in a highly dynamic network, resulting from balance between fission and fusion, which maintains homeostasis of mitochondrial mass through mitochondrial biogenesis and mitophagy. Mitochondrial DNA (mtDNA) mutates much faster than nuclear DNA. In particular, mtDNA point mutations and deletions may occur somatically and accumulate with ageing, coexisting with the wild type, a condition known as heteroplasmy. Under specific circumstances, clonal expansion of mutant mtDNA may occur within single cells, causing a wide range of severe human diseases when mutant overcomes wild-type. Furthermore, mtDNA deletions accumulate and clonally expand as a consequence of deleterious mutations in nuclear genes involved in mtDNA replication and maintenance, as well as in mitochondrial fusion genes (Mitofusin-2 and OPA1), possibly implicating mtDNA nucleoids segregation. We here discuss how the intricacies of mitochondrial homeostasis impinge on the intracellular propagation of mutant mtDNA.
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