title: Mitonuclear protein imbalance as a conserved longevity mechanism.
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.
authors.affiliation: Laboratory for Integrative and Systems Physiology, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland.
authors.forename: Riekelt H
authors.initials: RH
authors.lastname: Houtkooper
authors.forename: Laurent
authors.initials: L
authors.lastname: Mouchiroud
authors.forename: Dongryeol
authors.initials: D
authors.lastname: Ryu
authors.forename: Norman
authors.initials: N
authors.lastname: Moullan
authors.forename: Elena
authors.initials: E
authors.lastname: Katsyuba
authors.forename: Graham
authors.initials: G
authors.lastname: Knott
authors.forename: Robert W
authors.initials: RW
authors.lastname: Williams
authors.forename: Johan
authors.initials: J
authors.lastname: Auwerx
mesh_terms: D000375:Aging / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D017173:Caenorhabditis elegans / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism; D004318:Doxycycline / Q000494:pharmacology; D019143:Evolution, Molecular; D005260:Female; D008136:Longevity / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008928:Mitochondria / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D040641:Quantitative Trait Loci; D034622:RNA Interference; D015203:Reproducibility of Results; D012269:Ribosomal Proteins / Q000235:genetics / Q000378:metabolism*; D020123:Sirolimus / Q000494:pharmacology; D056811:Unfolded Protein Response / Q000235:genetics / Q000502:physiology
chemical_list: D000900:Anti-Bacterial Agents; D029742:Caenorhabditis elegans Proteins; D024101:Mitochondrial Proteins; D012269:Ribosomal Proteins; C581639:mrps-5 protein, C elegans; C030831:ribosomal protein S5; D004318:Doxycycline; D020123:Sirolimus