Mitochondrial-nuclear epistasis: implications for human aging and longevity.
There is substantial evidence that mitochondria are involved in the aging process. Mitochondrial function requires the coordinated expression of hundreds of nuclear genes and a few dozen mitochondrial genes, many of which have been associated with either extended or shortened life span. Impaired mitochondrial function resulting from mtDNA and nuclear DNA variation is likely to contribute to an imbalance in cellular energy homeostasis, increased vulnerability to oxidative stress, and an increased rate of cellular senescence and aging. The complex genetic architecture of mitochondria suggests that there may be an equally complex set of gene interactions (epistases) involving genetic variation in the nuclear and mitochondrial genomes. Results from Drosophila suggest that the effects of mtDNA haplotypes on longevity vary among different nuclear allelic backgrounds, which could account for the inconsistent associations that have been observed between mitochondrial DNA (mtDNA) haplogroups and survival in humans. A diversity of pathways may influence the way mitochondria and nuclear-mitochondrial interactions modulate longevity, including: oxidative phosphorylation; mitochondrial uncoupling; antioxidant defenses; mitochondrial fission and fusion; and sirtuin regulation of mitochondrial genes. We hypothesize that aging and longevity, as complex traits having a significant genetic component, are likely to be controlled by nuclear gene variants interacting with both inherited and somatic mtDNA variability.
Tranah
Gregory J
GJ
California Pacific Medical Center Research Institute, San Francisco Coordinating Center, UCSF, 94107-1728, USA. gtranah@sfcc-cpmc.net
D000375:Aging / Q000235:genetics* / Q000502:physiology; D002467:Cell Nucleus / Q000378:metabolism; D004272:DNA, Mitochondrial / Q000235:genetics* / Q000378:metabolism; D004843:Epistasis, Genetic; D050259:Genes, Mitochondrial / Q000235:genetics*; D014644:Genetic Variation; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D008136:Longevity / Q000235:genetics*; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D009154:Mutation / Q000235:genetics; D010085:Oxidative Phosphorylation; D018384:Oxidative Stress; D011110:Polymorphism, Genetic
D004272:DNA, Mitochondrial