Authors: Schlotterer A; Hamann A; Kukudov G; Ibrahim Y; Heckmann B; Bozorgmehr F; Pfeiffer M; Hutter H; Stern D; Du X; Brownlee M; Bierhaus A; Nawroth P; Morcos M
Abstract: Deletions in mitochondrial DNA (mtDNA) accumulate during aging. Expression of the Caenorhabditis elegans apurinic/apyrimidinic endonuclease 1 (APE1) ortholog exo-3, involved in DNA repair, is reduced by 45% (P < 0.05) during aging of C. elegans. Suppression of exo-3 by treatment with RNAi resulted in a threefold increase in mtDNA deletions (P < 0.05), twofold enhanced generation of reactive oxygen species (ROS) (P < 0.01), distortion of the structural integrity of the nervous system, reduction of head motility by 43% (P < 0.01) and whole animal motility by 38% (P < 0.05). Suppression of exo-3 significantly reduced life span: mean life span decreased from 18.5 +/- 0.4 to 15.4 +/- 0.1 days (P < 0.001) and maximum life span from 25.9 +/- 0.4 to 23.2 +/- 0.1 days (P = 0.001). Additional treatment of exo-3-suppressed animals with a mitochondrial uncoupler decreased ROS levels, reduced neuronal damage, and increased motility and life span. Additional suppression of the C. elegans p53 ortholog cep-1 in exo-3 RNAi-treated animals similarly decreased ROS levels, preserved neuronal integrity, and increased motility and life span. In wild-type animals, suppression of cep-1, involved in downregulation of exo-3, increased expression of exo-3 without a significant effect on ROS levels, preserved neuronal integrity, and increased motility and life span. Suppression of the C. elegans thioredoxin orthologs trx-1 and trx-2, involved in the redox chaperone activity of exo-3, overrides the protective effect of cep-1 RNAi treatment on neuronal integrity, neuronal function, mean and maximum life span. These results show that APE1/EXO-3, p53/CEP-1, and thioredoxin affect each other and that these interactions determine aging as well as neuronal structure and function.Keywords: *Aging; Animals; Caenorhabditis elegans/genetics/*metabolism; Caenorhabditis elegans Proteins/genetics/*metabolism; DNA, Mitochondrial/genetics; DNA-(Apurinic or Apyrimidinic Site) Lyase/genetics/metabolism; Gene Deletion; RNA Interference; Reactive Oxygen Species/metabolism; Thioredoxins/genetics/*metabolism; Tumor Suppressor Protein p53/genetics/*metabolism
Journal: Aging cell
Date: March 30, 2010
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Schlotterer A, Hamann A, Kukudov G, Ibrahim Y, Heckmann B, Bozorgmehr F, Pfeiffer M, Hutter H, Stern D, Du X, Brownlee M, Bierhaus A, Nawroth P, Morcos M (2010) Apurinic/apyrimidinic endonuclease 1, p53, and thioredoxin are linked in control of aging in C. elegans. Aging cell 9: 420-32.