Apurinic/apyrimidinic endonuclease 1, p53, and thioredoxin are linked in control of aging in C. elegans

Andreas Schlotterer, Andreas Hamann, Georgi Kukudov, Youssef Ibrahim, Britta Heckmann, Farastuk Bozorgmehr, Michael Pfeiffer, Harald Hutter, David Stern, Xueliang Du, Michael Brownlee, Angelika Bierhaus, Peter Nawroth, Michael Morcos

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)420-432
Number of pages13
JournalAging cell
Volume9
Issue number3
DOIs
StatePublished - Jun 1 2010

Keywords

  • Aging
  • C. elegans
  • DNA repair
  • Mitochondrial DNA
  • Reactive oxygen species
  • p53

ASJC Scopus subject areas

  • Aging
  • Cell Biology

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