Mitonuclear protein imbalance as a conserved longevity mechanism.

Authors: Houtkooper RH; Mouchiroud L; Ryu D; Moullan N; Katsyuba E; Knott G; Williams RW; Auwerx J

Abstract: Longevity is regulated by a network of closely linked metabolic systems. We used a combination of mouse population genetics and RNA interference in Caenorhabditis elegans to identify mitochondrial ribosomal protein S5 (Mrps5) and other mitochondrial ribosomal proteins as metabolic and longevity regulators. MRP knockdown triggers mitonuclear protein imbalance, reducing mitochondrial respiration and activating the mitochondrial unfolded protein response. Specific antibiotics targeting mitochondrial translation and ethidium bromide (which impairs mitochondrial DNA transcription) pharmacologically mimic mrp knockdown and extend worm lifespan by inducing mitonuclear protein imbalance, a stoichiometric imbalance between nuclear and mitochondrially encoded proteins. This mechanism was also conserved in mammalian cells. In addition, resveratrol and rapamycin, longevity compounds acting on different molecular targets, similarly induced mitonuclear protein imbalance, the mitochondrial unfolded protein response and lifespan extension in C. elegans. Collectively these data demonstrate that MRPs represent an evolutionarily conserved protein family that ties the mitochondrial ribosome and mitonuclear protein imbalance to the mitochondrial unfolded protein response, an overarching longevity pathway across many species.

Journal: Nature
Volume: 497
Issue: 7450
Pages: 451-7
Date: May 24, 2013
PMID: 23698443
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Houtkooper RH, Mouchiroud L, Ryu D, Moullan N, Katsyuba E, Knott G, Williams RW, Auwerx J (2013) Mitonuclear protein imbalance as a conserved longevity mechanism. Nature 497: 451-7.

Study Lifespan Factors:
  • mrps-5
  • nkcc-1 Na-K-Cl Cotransporter homolog
  • ttll-9 Tubulin Tyrosine Ligase Like
  • mrpl-1
  • mrpl-2
  • mrpl-37

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