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. ; © 2010 Elsevier Inc. Received 23 July 2009; revised 13 December 2009; accepted 9 February 2010. Published: April 15, 2010. Available online 15 April 2010. We thank Drs. S. Burden and P. Soriano for generously providing the MLC-Cre and Meox2-Cre mouse strains. We are grateful to Igor Antoshechkin, director of the Caltech Genomics Facility, for help with analysis of Solexa sequence data. This work was supported by grants to D.C.C. (R01 grant GM062967 and an Ellison Medical Foundation Senior Scholar Award) and J.M.M. (NCRR grant 1 S10 RR023454-01). ; Accepted Version - nihms200583.pdf