Cancer is a disease of aging. Progressive decline in the mitochondrial function plays a significant role in the aging process. Recent studies have demonstrated that a decline in mitochondrial function is due to the accumulation of mutations in mitochondrial DNA (mtDNA) during the aging process. Strikingly, mitochondrial dysfunction is also one of the most common and profound phenotypes of cancer cells. Another hallmark of cancer cells is the rapid accumulation of mutations in the nuclear genome that drive tumor development. Based on these observations, we hypothesize that mitochondria may function as coordinators of aging and cancer.
To understand the mechanisms underlying aging and cancer due to mitochondrial dysfunction we tested whether mitconhondrial dysfunction impacts on the genetic stability of the nuclear genome. Using Saccharomyces cerevisiae as a model organism, we analyzed the consequences of disrupting mitochondrial function on genetic stability of the nuclear genome. In wild type yeast exposed to mitochondrial respiratory chain inhibitors or mutant yeast lacking the entire mitochondrial genome (rho0) or yeast with a mitochondrial mutation (rho-), we tested the instability of the nuclear genome by measuring the frequency of canavanine resistant colonies. The CAN1 gene of S. cerevisiae encodes a transmembrane amino acid transporter that renders the cell sensitive to lethal arginine analogue, canavanine. Any inactivating mutation in this gene results in a canavanine resistant phenotype (CANR). We calculated the frequency of canavanine resistant colonies as a measure of spontaneous nuclear mutational events in rho0 and rho- strains. We found that, compared to the wild type cells, nuclear mutational events were significantly higher in both rho0 and rho- strains. Likewise, inhibition of electron transport by antimycin and other agents in wild type cells resulted in increase frequency of mutation in nuclear genome. Our studies have also revealed that REV1, REV3 or REV7 gene products, implicated in error-prone translesion DNA synthesis, mediate the genetic instability of the nuclear genome arising as a result of mitochondrial dysfunction. Our results described here in yeast model provide a direct link between mitochondrial dysfunction and genetic instability, which has important implications in human cancer and aging.