Open AccessApurinic/apyrimidinic endonuclease 1, p53, and thioredoxin are linked in control of aging in C. elegans
Author(s) -
Schlotterer Andreas,
Hamann Andreas,
Kukudov Georgi,
Ibrahim Youssef,
Heckmann Britta,
Bozorgmehr Farastuk,
Pfeiffer Michael,
Hutter Harald,
Stern David,
Du Xueliang,
Brownlee Michael,
Bierhaus Angelika,
Nawroth Peter,
Morcos Michael
Publication year - 2010
Publication title -
aging cell
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.103
H-Index - 140
eISSN - 1474-9726
pISSN - 1474-9718
DOI - 10.1111/j.1474-9726.2010.00572.x
Subject(s) - ap site , biology , endonuclease , thioredoxin , dna (apurinic or apyrimidinic site) lyase , genetics , computational biology , microbiology and biotechnology , dna , gene
Summary 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.