title: Succinate dehydrogenase upregulation destabilize complex I and limits the lifespan of gas-1 mutant.
abstract: Many Caenorhabditis elegans mutants with dysfunctional mitochondrial electron transport chain are surprisingly long lived. Both short-lived (gas-1(fc21)) and long-lived (nuo-6(qm200)) mutants of mitochondrial complex I have been identified. However, it is not clear what are the pathways determining the difference in longevity. We show that even in a short-lived gas-1(fc21) mutant, many longevity assurance pathways, shown to be important for lifespan prolongation in long-lived mutants, are active. Beside similar dependence on alternative metabolic pathways, short-lived gas-1(fc21) mutants and long-lived nuo-6(qm200) mutants also activate hypoxia-inducible factor -1α (HIF-1α) stress pathway and mitochondrial unfolded protein response (UPR(mt)). The major difference that we detected between mutants of different longevity, is in the massive loss of complex I accompanied by upregulation of complex II levels, only in short-lived, gas-1(fc21) mutant. We show that high levels of complex II negatively regulate longevity in gas-1(fc21) mutant by decreasing the stability of complex I. Furthermore, our results demonstrate that increase in complex I stability, improves mitochondrial function and decreases mitochondrial stress, putting it inside a "window" of mitochondrial dysfunction that allows lifespan prolongation.
authors.affiliation: Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, Cologne University, Cologne, Germany.
authors.forename: Claire
authors.initials: C
authors.lastname: Pujol
authors.forename: Ivana
authors.initials: I
authors.lastname: Bratic-Hench
authors.forename: Marija
authors.initials: M
authors.lastname: Sumakovic
authors.forename: Jürgen
authors.initials: J
authors.lastname: Hench
authors.forename: Arnaud
authors.initials: A
authors.lastname: Mourier
authors.forename: Linda
authors.initials: L
authors.lastname: Baumann
authors.forename: Victor
authors.initials: V
authors.lastname: Pavlenko
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Trifunovic
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans / Q000166:cytology / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D029742:Caenorhabditis elegans Proteins / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D004795:Enzyme Stability; D008136:Longevity / Q000235:genetics*; D008928:Mitochondria / Q000201:enzymology / Q000378:metabolism; D009154:Mutation; D009245:NADH Dehydrogenase / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D013385:Succinate Dehydrogenase / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D029742:Caenorhabditis elegans Proteins; D017382:Reactive Oxygen Species; D013385:Succinate Dehydrogenase; D009245:NADH Dehydrogenase; C468009:GAS-1 protein, C elegans
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