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 inhibition of the NAD+-SIRT1-PGC-alpha axis. PARPs, the target proteins they PARylate, and the cofactor NAD+ play critical roles in the nucleus to mitochondria signaling cascade, which is linked to mitochondrial dysfunction. 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, all have the ability to normalize mitochondrial phenotypes.
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| Mitchell, Sarah J; Bernier, Michel; Aon, Miguel A et al. (2018) Nicotinamide Improves Aspects of Healthspan, but Not Lifespan, in Mice. Cell Metab 27:667-676.e4 |
| Hou, Yujun; Song, Hyundong; Croteau, Deborah L et al. (2017) Genome instability in Alzheimer disease. Mech Ageing Dev 161:83-94 |
| Karikkineth, Ajoy C; Scheibye-Knudsen, Morten; Fivenson, Elayne et al. (2017) Cockayne syndrome: Clinical features, model systems and pathways. Ageing Res Rev 33:3-17 |
| Sykora, P; Kanno, S; Akbari, M et al. (2017) DNA polymerase beta participates in mitochondrial DNA repair. Mol Cell Biol : |
| Hegde, Muralidhar L; Bohr, Vilhelm A; Mitra, Sankar (2017) DNA damage responses in central nervous system and age-associated neurodegeneration. Mech Ageing Dev 161:1-3 |
| Fang, Evandro F; Waltz, Tyler B; Kassahun, Henok et al. (2017) Tomatidine enhances lifespan and healthspan in C. elegans through mitophagy induction via the SKN-1/Nrf2 pathway. Sci Rep 7:46208 |
| Fivenson, Elayne M; Lautrup, Sofie; Sun, Nuo et al. (2017) Mitophagy in neurodegeneration and aging. Neurochem Int 109:202-209 |
| Kerr, Jesse S; Adriaanse, Bryan A; Greig, Nigel H et al. (2017) Mitophagy and Alzheimer's Disease: Cellular and Molecular Mechanisms. Trends Neurosci 40:151-166 |
| Fang, Evandro F; Lautrup, Sofie; Hou, Yujun et al. (2017) NAD+ in Aging: Molecular Mechanisms and Translational Implications. Trends Mol Med 23:899-916 |
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