Replication Stress Induces Age-Related Disorders via Impaired Mitochondrial Homeostasis

Aging is defined as the gradual decline of cellular, tissue and organismal homeostasis resulting in cellular senescence, organismal dysfunction and, ultimately, death. Mitochondrial function plays an important role in aging as well as onset of multiple human age-related diseases such as cognitive decline, neurological abnormalities, and cancer. Using various model systems, we have shown that mitochondrial dysfunction results in complex genomic instability, which involves nucleotide metabolism as well as multiple major DNA repair and DNA lesion synthesis/bypass pathways. DNA lesions that escape repair will arrest the replication fork, which can lead to replication stress, DNA breaks, and genome instability. To ensure the continuation of replication at damaged DNA templates, translesion synthesis (TLS) polymerases can transiently displace the replicative polymerases and replicate across the lesion. Since TLS polymerases frequently introduce the incorrect nucleotide opposite the lesion, TLS is a mutagenic process. Rev1 is a TLS polymerase that coordinate the recruitment of other TLS polymerases at the damage site and regulate the TLS. Rev1-deficient mice display mild progeroid symptoms suggesting a role for TLS in preventing premature aging. We investigated the molecular mechanisms underlying progeria in these mice and found that the absence of a functional Rev1 protein causes multifactorial mitochondrial dysfunction including abnormal mitochondrial morphology. This phenotype is particularly evident during cellular stress. The mitochondrial abnormalities appear to be caused by NAD+ depletion triggered by activation of the DNA damage sensor PARP-1.