Mitochondrial fusion is required for mtDNA stability in skeletal muscle and tolerance of mtDNA mutations.
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.
Chen
Hsiuchen
H
Division of Biology, California Institute of Technology, Pasadena, CA 91125, USA.
Vermulst
Marc
M
Wang
Yun E
YE
Chomyn
Anne
A
Prolla
Tomas A
TA
McCaffery
J Michael
JM
Chan
David C
DC
D000818:Animals; D000074002:DNA Polymerase gamma; D004272:DNA, Mitochondrial / Q000235:genetics*; D004259:DNA-Directed DNA Polymerase / Q000378:metabolism; D004622:Embryo, Mammalian / Q000378:metabolism; D005260:Female; D020558:GTP Phosphohydrolases / Q000378:metabolism; D005804:Genes, Lethal; D008297:Male; D051379:Mice; D008931:Mitochondria, Muscle / Q000235:genetics / Q000502:physiology*; D017240:Mitochondrial Myopathies / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000235:genetics; D018482:Muscle, Skeletal / Q000166:cytology* / Q000502:physiology*; D009154:Mutation
D004272:DNA, Mitochondrial; D024101:Mitochondrial Proteins; D000074002:DNA Polymerase gamma; D004259:DNA-Directed DNA Polymerase; D020558:GTP Phosphohydrolases; C488750:Mfn1 protein, mouse; C488751:Mfn2 protein, mouse
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