Mitonuclear protein imbalance as a conserved longevity mechanism

Riekelt H. Houtkooper, Laurent Mouchiroud, Dongryeol Ryu, Norman Moullan, Elena Katsyuba, Graham Knott, Robert Williams, Johan Auwerx

Research output: Contribution to journalArticle

395 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)451-457
Number of pages7
JournalNature
Volume497
Issue number7450
DOIs
StatePublished - May 29 2013

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Mitochondrial Proteins
Unfolded Protein Response
Proteins
Caenorhabditis elegans
Ethidium
Ribosomal Proteins
Population Genetics
Sirolimus
RNA Interference
Mitochondrial DNA
Respiration
Anti-Bacterial Agents

All Science Journal Classification (ASJC) codes

  • General

Cite this

Houtkooper, R. H., Mouchiroud, L., Ryu, D., Moullan, N., Katsyuba, E., Knott, G., ... Auwerx, J. (2013). Mitonuclear protein imbalance as a conserved longevity mechanism. Nature, 497(7450), 451-457. https://doi.org/10.1038/nature12188

Mitonuclear protein imbalance as a conserved longevity mechanism. / Houtkooper, Riekelt H.; Mouchiroud, Laurent; Ryu, Dongryeol; Moullan, Norman; Katsyuba, Elena; Knott, Graham; Williams, Robert; Auwerx, Johan.

In: Nature, Vol. 497, No. 7450, 29.05.2013, p. 451-457.

Research output: Contribution to journalArticle

Houtkooper, RH, Mouchiroud, L, Ryu, D, Moullan, N, Katsyuba, E, Knott, G, Williams, R & Auwerx, J 2013, 'Mitonuclear protein imbalance as a conserved longevity mechanism', Nature, vol. 497, no. 7450, pp. 451-457. https://doi.org/10.1038/nature12188
Houtkooper RH, Mouchiroud L, Ryu D, Moullan N, Katsyuba E, Knott G et al. Mitonuclear protein imbalance as a conserved longevity mechanism. Nature. 2013 May 29;497(7450):451-457. https://doi.org/10.1038/nature12188
Houtkooper, Riekelt H. ; Mouchiroud, Laurent ; Ryu, Dongryeol ; Moullan, Norman ; Katsyuba, Elena ; Knott, Graham ; Williams, Robert ; Auwerx, Johan. / Mitonuclear protein imbalance as a conserved longevity mechanism. In: Nature. 2013 ; Vol. 497, No. 7450. pp. 451-457.
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