The base excision repair pathway is initiated by the action of a class of enzymes known as DNA glycosylases, which recognize and release the damaged base, and thus give specificity to the DNA repair process. Mammalian cells carry two major DNA glycosylases for the repair of oxidized bases, oxoguanine DNA glycosylase (OGG1) and Endonuclease III homologue (NTH1). We found that OGG1 plays a crucial role in the repair of oxidized lesions in mitochondria and is probably the only DNA glycosylase for 8-oxoG removal in these organelles. All BER enzymes are encoded in the nucleus and transported to mitochondria;however there is very limited information on the regulation of mitochondrial BER. In mammalian mitochondria the mtDNA is found in a large protein-DNA complex known as the nucleoid. One of the most abundant protein components of mammalian nucleoids is the transcription factor TFAM, which has been postulated to have a structural function in compacting mtDNA into the nucleoid structure. Previously, we found that TFAM could inhibit BER proteins and mitochondrial pol gamma. We proposed that TFAM may be functioning like nuclear histones and therefore proposed that a TFAM remodeling protein must exit in mitochondria to allow for mtDNA metabolism. In separate studies, we documented that RECQL4 and CSB were present in mitochondria, thus we evaluated if each protein could relieve TFAM inhibition. We observed CSB, but not RECQL4, could display TFAM and alleviate its inhibition. We are continuing to search for and interrogate protein-interaction with TFAM in an attempt to more fully characterize mtDNA repair and metabolism We generated a database dedicated to scoring diseases for mitochondrial involvement. Based on the signs and symptoms seen in 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. We describe a mitochondrial stress response phenomenon which may be common to cells undergoing chronic DNA damage and hyperactivation of PARP1. Specifically, we discovered defective mitophagy in XPA due to PARP1 hyperactivation and NAD+ (and thus, SIRT1) depletion. This leads to mitochondrial membrane hyper-polarization, PINK1 cleavage and defective mitophagy. This study underscores the importance of mitophagy in promoting a healthy pool of mitochondria and in preventing neurodegeneration and premature aging.
| Baptiste, Beverly A; Katchur, Steven R; Fivenson, Elayne M et al. (2018) Enhanced mitochondrial DNA repair of the common disease-associated variant, Ser326Cys, of hOGG1 through small molecule intervention. Free Radic Biol Med 124:149-162 |
| 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 |
| 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 |
| Fang, Evandro F; Bohr, Vilhelm A (2017) NAD(+): The convergence of DNA repair and mitophagy. Autophagy 13:442-443 |
| Fakouri, Nima Borhan; Durhuus, Jon Ambæk; Regnell, Christine Elisabeth et al. (2017) Rev1 contributes to proper mitochondrial function via the PARP-NAD+-SIRT1-PGC1? axis. Sci Rep 7:12480 |
| Croteau, Deborah L; Fang, Evandro Fei; Nilsen, Hilde et al. (2017) NAD(+) in DNA repair and mitochondrial maintenance. Cell Cycle 16:491-492 |
| Misiak, Magdalena; Vergara Greeno, Rebeca; Baptiste, Beverly A et al. (2017) DNA polymerase ? decrement triggers death of olfactory bulb cells and impairs olfaction in a mouse model of Alzheimer's disease. Aging Cell 16:162-172 |
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