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Prohibitin couples diapause signalling to mitochondrial metabolism during ageing in C. elegans

Abstract

Marked alterations in cellular energy metabolism are a universal hallmark of the ageing process1. The biogenesis and function of mitochondria, the energy-generating organelles in eukaryotic cells, are primary longevity determinants. Genetic or pharmacological manipulations of mitochondrial activity profoundly affect the lifespan of diverse organisms2. However, the molecular mechanisms regulating mitochondrial biogenesis and energy metabolism during ageing are poorly understood. Prohibitins are ubiquitous, evolutionarily conserved proteins, which form a ring-like, high-molecular-mass complex at the inner membrane of mitochondria3. Here, we show that the mitochondrial prohibitin complex promotes longevity by modulating mitochondrial function and fat metabolism in the nematode Caenorhabditis elegans. We found that prohibitin deficiency shortens the lifespan of otherwise wild-type animals. Notably, knockdown of prohibitin promotes longevity in diapause mutants or under conditions of dietary restriction. In addition, prohibitin deficiency extends the lifespan of animals with compromised mitochondrial function or fat metabolism. Depletion of prohibitin influences ATP levels, animal fat content and mitochondrial proliferation in a genetic-background- and age-specific manner. Together, these findings reveal a novel mechanism regulating mitochondrial biogenesis and function, with opposing effects on energy metabolism, fat utilization and ageing in C. elegans. Prohibitin may have a similar key role in modulating energy metabolism during ageing in mammals.

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Figure 1: Prohibitin deficiency markedly extends the lifespan of dauer-defective C. elegans mutants while shortening the lifespan of otherwise wild-type animals.
Figure 2: Prohibitin deficiency further extends the lifespan of mitochondrial and dietary-restricted C. elegans mutants.
Figure 3: Effects of prohibitin depletion on energy metabolism.
Figure 4: Prohibitin depletion and intestinal fat-storing cell mitochondrial content.

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Acknowledgements

We thank A. Pasparaki for technical support with experiments. Some nematode strains used in this work were provided by the C. elegans Gene Knockout Project at OMRF (http://www.mutantfactory.ouhsc.edu/), which is part of the International C. elegans Gene Knockout Consortium, the Caenorhabditis Genetics Center, which is funded by the NIH National Center for Research Resources (NCRR), and S. Mitani (National Bioresource Project) in Japan. We thank A. Fire for plasmid vectors and J. Berden for antibodies. This work was funded by grants from EMBO, the European Research Council (ERC), the Marie Curie Fellowships Programme and the European Commission Coordination Action ENINET (contract number LSHM-CT-2005-19063).

Author Contributions M.A.-S. and N.T. designed and performed experiments, analysed data and wrote the manuscript.

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Correspondence to Marta Artal-Sanz or Nektarios Tavernarakis.

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Artal-Sanz, M., Tavernarakis, N. Prohibitin couples diapause signalling to mitochondrial metabolism during ageing in C. elegans. Nature 461, 793–797 (2009). https://doi.org/10.1038/nature08466

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