A Caenorhabditis elegans mutant lacking functional nicotinamide nucleotide transhydrogenase displays increased sensitivity to oxidative stress.
Proton-translocating mitochondrial nicotinamide nucleotide transhydrogenase (NNT) was investigated regarding its physiological role in Caenorhabditis elegans. NNT catalyzes the reduction of NADP(+) by NADH driven by the electrochemical proton gradient, Deltap, and is thus a potentially important source of mitochondrial NADPH. Mitochondrial detoxification of reactive oxygen species (ROS) by glutathione-dependent peroxidases depends on NADPH for regeneration of reduced glutathione. Transhydrogenase may therefore be directly involved in the defense against oxidative stress. nnt-1 deletion mutants of C. elegans, nnt-1(sv34), were isolated and shown to grow essentially as wild type under normal laboratory conditions, but with a strongly lowered GSH/GSSG ratio. Under conditions of oxidative stress, caused by the superoxide-generating agent methyl viologen, growth of worms lacking nnt-1 activity was severely impaired. A similar result was obtained by using RNAi. Reintroducing nnt-1 in the nnt-1(sv34) knockout mutant led to a partial rescue of growth under oxidative stress conditions. These results provide evidence for the first time that nnt-1 is important in the defense against mitochondrial oxidative stress.
Arkblad
Eva L
EL
Umeå Center for Molecular Pathogenesis, Umeå University, SE-901 87 Umeå, Sweden.
Tuck
Simon
S
Pestov
Nikolay B
NB
Dmitriev
Ruslan I
RI
Kostina
Maria B
MB
Stenvall
Jörgen
J
Tranberg
Mattias
M
Rydström
Jan
J
D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics*; D029742:Caenorhabditis elegans Proteins / Q000502:physiology; D049109:Cell Proliferation; D004563:Electrochemistry; D017353:Gene Deletion; D005978:Glutathione; D049452:Green Fluorescent Proteins / Q000378:metabolism; D015151:Immunoblotting; D008928:Mitochondria / Q000378:metabolism; D008956:Models, Chemical; D008957:Models, Genetic; D009154:Mutation; D009249:NADP / Q000737:chemistry; D009250:NADP Transhydrogenases / Q000235:genetics* / Q000502:physiology; D018384:Oxidative Stress; D010269:Paraquat / Q000494:pharmacology; D010641:Phenotype; D010957:Plasmids / Q000378:metabolism; D011522:Protons; D034622:RNA Interference; D012330:RNA, Double-Stranded / Q000737:chemistry; D013997:Time Factors
D029742:Caenorhabditis elegans Proteins; D011522:Protons; D012330:RNA, Double-Stranded; D049452:Green Fluorescent Proteins; D009249:NADP; D009250:NADP Transhydrogenases; D005978:Glutathione; D010269:Paraquat