One theory of the mechanism of aging of post-mitotic tissues proposes that an accumulation of oxidative damage to cell components leads to a decline in cell function and ultimately, death. The major source of oxidative stress, in the form of oxygen radicals, is mitochondrial respiration and one particularly provocative form of this theory of aging suggests that oxidative damage to mitochondrial DNA (mt-DNA) gives rise to deletions and other mutations, which accumulate during the many cycles of mitochondrial division that occur during the lifetime of a myocyte or neurone, eventually giving rise to a failure in mitochondrial energy transduction. This project examines both aspects of this suggested mechanism, viz mitochondrial production of oxygen radicals (ROS) and the accrual of oxidative damage to mitochondria. This year we have characterized the production of H2O2 by isolated rat heart mitochondria. We have shown that it is relatively active with succinate as oxidizable substrate, much less so with pyruvate, glutamate and other NAD-linked substrates. Rates of H2O2 formation correlate closely with the degree of energization of the mitochondrial inner membrane, measured as the membrane potential 2, and with the fractional reduction of mitochondrial NAD. Contrary to literature findings, the main generator of H2O2 is Complex I (NADH-coenzyme Q-oxidoreductase). Supplementation with Mn2+ strongly potentiates H2O2 formation, possibly via activation of mitochondrial superoxide dismutase (SOD). Comparison of cardiac mitochondria from young adults (6 month old) and senescent (24 month-old) rats indicated no change in the activity of H2O2 generation.
| Scheibye-Knudsen, Morten; Croteau, Deborah L; Bohr, Vilhelm A (2013) Mitochondrial deficiency in Cockayne syndrome. Mech Ageing Dev 134:275-83 |
| Ramamoorthy, Mahesh; Sykora, Peter; Scheibye-Knudsen, Morten et al. (2012) Sporadic Alzheimer disease fibroblasts display an oxidative stress phenotype. Free Radic Biol Med 53:1371-80 |
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| Gredilla, Ricardo; Garm, Christian; Holm, Rikke et al. (2010) Differential age-related changes in mitochondrial DNA repair activities in mouse brain regions. Neurobiol Aging 31:993-1002 |
| Canugovi, Chandrika; Maynard, Scott; Bayne, Anne-Cécile V et al. (2010) The mitochondrial transcription factor A functions in mitochondrial base excision repair. DNA Repair (Amst) 9:1080-9 |
| Maynard, Scott; Schurman, Shepherd H; Harboe, Charlotte et al. (2009) Base excision repair of oxidative DNA damage and association with cancer and aging. Carcinogenesis 30:2-10 |
| de Souza-Pinto, Nadja C; Maynard, Scott; Hashiguchi, Kazunari et al. (2009) The recombination protein RAD52 cooperates with the excision repair protein OGG1 for the repair of oxidative lesions in mammalian cells. Mol Cell Biol 29:4441-54 |
| de Souza-Pinto, Nadja C; Wilson 3rd, David M; Stevnsner, Tinna V et al. (2008) Mitochondrial DNA, base excision repair and neurodegeneration. DNA Repair (Amst) 7:1098-109 |
| Bohr, V A; Ottersen, O P; Tonjum, T (2007) Genome instability and DNA repair in brain, ageing and neurological disease. Neuroscience 145:1183-6 |
| Weissman, L; de Souza-Pinto, N C; Stevnsner, T et al. (2007) DNA repair, mitochondria, and neurodegeneration. Neuroscience 145:1318-29 |
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