Does Mitochondrial Fusion Protect Against Mitochondrial DNA Mutations During Aging?

2006 senior Scholar Award in aging

A major model of aging postulates that DNA mutations accumulate within mitochondria as we age. Mitochondrial DNA (mtDNA) is particularly vulnerable, because mitochondria are a major source of reactive oxygen species, small molecules that can damage DNA. This damage causes mtDNA mutations, whose accumulation leads to inefficient mitochondrial function and thereby increased generation of reactive oxygen species. This "vicious cycle" is thought to cause the progressive decline in mitochondrial function found in aged tissues. If this model is correct, mitochondrial dynamics may be a major factor in the aging process.

Mitochondria are dynamic organelles that constantly fuse and divide. Because mitochondrial fusion promotes the mixing of individual mitochondria and their DNA, it should buffer the effects of mtDNA mutations and stabilize their inheritance during cell division. In cells that lack mitochondrial fusion, the mitochondria are forced to be autonomous organelles. Such cells and their progeny would be more prone to the detrimental effects of mitochondrial DNA mutations. We have generated mice with mutations in genes required for mitochondrial fusion. With these mice, we can test whether loss of mitochondrial fusion leads to more rapid accumulation of mtDNA mutations.

David C. Chan M.D., Ph.D.
California Institute of Technology