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. Current research shows that inhibition of PARP1, activation of SIRT1 or restoration of NAD+ using NAD+ precursors like nicotinamide riboside or nicotinamide mononucleotide, can normalize mitochondrial phenotypes.
- 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
Fang EF, et al Nuclear DNA damage signalling to mitochondria in ageing. Nat Rev Mol Cell Biol. 2016 May;17(5):308-21. doi: 10.1038/nrm.2016.14. PubMed PMID: 26956196; PubMed Central PMCID: PMC5161407.
Fang EF, et al. NAD(+) Replenishment Improves Lifespan and Healthspan in Ataxia Telangiectasia Models via Mitophagy and DNA Repair. Cell Metab. 2016 Oct 11;24(4):566-581. doi: 10.1016/j.cmet.2016.09.004. PubMed PMID: 27732836.
Fang EF, et al. Defective mitophagy in XPA via PARP-1 hyperactivation and NAD(+)/SIRT1 reduction. Cell. 2014 May 8;157(4):882-96. doi:
10.1016/j.cell.2014.03.026. PubMed PMID: 24813611; PubMed Central PMCID:PMC4625837.
Scheibye-Knudsen M, et al. Cockayne syndrome group A and B proteins converge on transcription-linked resolution of non-B DNA. Proc Natl Acad Sci U S A. 2016 Nov 1;113(44):12502-12507. PubMed PMID: 27791127; PubMed Central PMCID: PMC5098674.
Scheibye-Knudsen M, et al. A high-fat diet and NAD(+) activate Sirt1 to rescue premature aging in cockayne syndrome. Cell Metab. 2014 Nov 4;20(5):840-55. doi:10.1016/j.cmet.2014.10.005. PubMed PMID: 25440059; PubMed Central PMCID:PMC4261735.