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Mitonuclear protein imbalance as a conserved longevity mechanism

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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.

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Figure 1: Lifespan regulation in BXD recombinant inbred mice.
Figure 2: Validation of Mrps5 as a candidate longevity gene.
Figure 3: mrps-5 RNAi prevents ageing-associated functional decline and alters mitochondrial function.
Figure 4: mrp genes confer longevity effects through UPRmt.
Figure 5: Specific antibiotics extend lifespan by phenocopying mrps-5 knockdown.
Figure 6: Conserved function of mitonuclear protein imbalance and UPRmt in longevity.

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Acknowledgements

We thank P. Gönczy and the Caenorhabditis Genetics Center for sharing or providing reagents. R.H.H. is supported by fellowships from NWO-Rubicon and AMC, and L.M. by an FRM fellowship. J.A. is the Nestlé Chair in Energy Metabolism and supported by EPFL, ERC (2008-AdG-23138), Velux Stiftung and SNSF. R.W.W. and GeneNetwork are supported by the National Institutes of Health (NIH) (P20-DA 21131, UO1AA13499 and U01AA14425), and the UT Center for Integrative and Translational Genomics. R.W.W. and J.A. are supported by NIH grant R01AG043930.

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Authors

Contributions

D.R., N.M. and E.K. contributed equally to this work. R.H.H., L.M. and J.A. conceived and designed the project. R.H.H. and R.W.W. performed QTL mapping and sequence analyses. R.H.H., L.M., E.K., D.R., N.M., G.K. performed experiments. R.H.H. and J.A. wrote the manuscript with contributions from all other authors.

Corresponding author

Correspondence to Johan Auwerx.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Information

This file contains Supplementary Tables 1-4 and Supplementary Figures 1-10. (PDF 4703 kb)

Movement of wild type worms at day 13 of adulthood

Time lapse video of 13-day old N2 worms treated with HT115 control bacteria. (MOV 22 kb)

Movement of mrps-5 RNAi worms at day 13 of adulthood

Time lapse video of 13-day old N2 worms treated with mrps-5 RNAi bacteria. These worms move more than HT115 controls (see Supplementary Video 1). (MOV 19 kb)

Movement of wild type worms at day 20 of adulthood

Time lapse video of 20-day old N2 worms treated with HT115 control bacteria. (MOV 13 kb)

Movement of mrps-5 RNAi worms at day 20 of adulthood

Time lapse video of 20-day old N2 worms treated with mrps-5 RNAi bacteria. These worms move more than HT115 controls (see Supplementary Video 3). (MOV 15 kb)

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Houtkooper, R., Mouchiroud, L., Ryu, D. et al. Mitonuclear protein imbalance as a conserved longevity mechanism. Nature 497, 451–457 (2013). https://doi.org/10.1038/nature12188

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