Mitochondrial DNA Repair Processes In Oxidative Stress And Aging

National Institute On Aging

Investigators

Linked publications, trials & patents

Abstract

We generated a database dedicated to scoring diseases for mitochondrial involvement (www.mitodb.com). Based on the signs and symptoms seen in Cockayne Syndrome (CS) and other DNA repair deficient disorders like Ataxia Telangiectasia (AT) and Xeroderma Pigmentosum group A (XPA), we have classified these disorders as likely having a mitochondrial component. Xeroderma pigmentosum group A (XPA) is a classic DNA repair-deficient disorder with patients displaying sun sensitivity and cancer susceptibility. XPA patients also exhibit neurodegeneration, leading to cerebellar atrophy, neuropathy, and hearing loss, through a mechanism that has remained elusive. Thus, we proposed that there may be a nuclear DNA damage to mitochondrial crosstalk that was contributing to the neurodegeneration observed in these disorders. As a result of our work, a mitochondrial stress response phenomenon has been described and which may be common to cells undergoing chronic DNA damage with hyperactivation of PARP1. Specifically, the mitochondrial abnormalities appear to be caused by decreased activation of the NAD+-SIRT1-PGC-1α axis triggered by hyperactivation of the DNA damage sensor PARP-1. This leads to mitochondrial membrane hyper-polarization, PINK1 cleavage, and defective mitophagy. These findings underscore the importance of mitophagy in promoting a healthy pool of mitochondria and further in preventing neurodegeneration and premature aging. Ongoing research seeks to identify small molecules which can offset some of the mitochondrial dysfunction in DNA repair deficient syndromes. Additionally, we are exploring NAD+ supplementation, SIRT1 activators and other potential targets that may be of benefit to patients with DNA repair deficiencies but also to those wishing to stave off the effects of normal aging.