Unit on Oxidative DNA Damage Processing and Mitochondrial Functions
Vilhelm A Bohr, MD, Ph.D., Chief
DNA damage drives neurodegeneration, cancer, and aging. Mitochondrial dysfunction is recognized as an important contributing factor for aging and age-related degeneration. We and others are investigating the relationship between nuclear DNA damage and mitochondrial dysfunction. We find that certain DNA repair disorders with neurodegeneration like Cockayne Syndrome, Xeroderma Pigmentosum group A (XPA) and Ataxia Telangiectasia (A-T) have a mitochondrial phenotype characterized by increased mitochondrial membrane potential, increased reactive oxygen species generation and decreased mitophagy, the degradation pathway for abnormal mitochondria. This mitochondrial stress response appears to be initiated by persistent activation of PARP1 leading to diminished cellular NAD+ levels. The mitochondrial abnormalities also correlate with impaired mitophagy, the selective degradation of damaged/dysfunction mitochondria. We showed that these mitochondrial phenotypes can be partially rescued by PARP1 inhibitors or NAD+ precursors in various experimental systems and species, suggesting an evolutionarily conserved mechanism. We are pursuing pharmacological modulation of the nuclear-mitochondrial signaling network which we believe will be a promising novel approach for the prevention and treatment of age-associated diseases. Our current research shows that impaired removal of defective mitochondria is a pivotal event Alzheimer's Disease (AD) pathogenesis. Enhancement of mitophagy through NAD+ supplementation abolishes AD-related tau hyperphosphorylation in human neuronal cells and reverses memory impairment in transgenic tau nematodes and mice, suggesting that mitophagy represents a potential therapeutic intervention.
- DNA Damage Response
- DNA repair
- Double Strand Break Repair
- Base Excision Repair
- Alzheimer’s Disease
- Mitochondrial Metabolism
- Premature Aging Syndromes
- Werner’s Syndrome
- Cockayne Syndrome
- Ataxia Telangiectasia
Findings and Publications
Dan X, Babbar M, Moore A, Wechter N, Tian J, Mohanty JG, Croteau DL, Bohr VA. DNA damage invokes mitophagy through a pathway involving Spata18. Nucleic Acids Res. 2020 Jul 9;48(12):6611-6623. doi: 10.1093/nar/gkaa393. PMID: 32453416; PMCID: PMC7337932.
Demarest TG, Varma VR, Estrada D, Babbar M, Basu S, Mahajan UV, Moaddel R, Croteau DL, Thambisetty M, Mattson MP, Bohr VA. Biological sex and DNA repair deficiency drive Alzheimer's disease via systemic metabolic remodeling and brain mitochondrial dysfunction. Acta Neuropathol. 2020 Jul;140(1):25-47. doi: 10.1007/s00401-020-02152-8. Epub 2020 Apr 24. PMID: 32333098.
Fang EF, Hou Y, Palikaras K, Adriaanse BA, Kerr JS, Yang B, Lautrup S, Hasan-Olive MM, Caponio D, Dan X, Rocktäschel P, Croteau DL, Akbari M, Greig NH, Fladby T, Nilsen H, Cader MZ, Mattson MP, Tavernarakis N, Bohr VA. Mitophagy inhibits amyloid-β and tau pathology and reverses cognitive deficits in models of Alzheimer's disease. Nat Neurosci. 2019 Mar;22(3):401-412. doi: 10.1038/s41593-018-0332-9. Epub 2019 Feb 11. PMID: 30742114; PMCID: PMC6693625.
Sykora P, Kanno S, Akbari M, Kulikowicz T, Baptiste BA, Leandro GS, Lu H,Tian J, May A, Becker KA, Croteau DL, Wilson DM 3rd, Sobol RW, Yasui A, Bohr VA. DNA Polymerase Beta Participates in Mitochondrial DNA Repair. Mol Cell Biol. 2017 Jul 28;37(16):e00237-17. doi: 10.1128/MCB.00237-17. PMID: 28559431; PMCID: PMC5533889.