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

Nature volume 461, pages 793–797 (2009)Cite this article

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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References

  1. Roberts, S. B. & Rosenberg, I. Nutrition and aging: changes in the regulation of energy metabolism with aging. Physiol. Rev. 86, 651–667 (2006)

    Article  CAS  Google Scholar 

  2. Balaban, R. S., Nemoto, S. & Finkel, T. Mitochondria, oxidants, and aging. Cell 120, 483–495 (2005)

    Article  CAS  Google Scholar 

  3. Back, J. W. et al. A structure for the yeast prohibitin complex: structure prediction and evidence from chemical crosslinking and mass spectrometry. Protein Sci. 11, 2471–2478 (2002)

    Article  CAS  Google Scholar 

  4. Nijtmans, L. G. et al. Prohibitins act as a membrane-bound chaperone for the stabilization of mitochondrial proteins. EMBO J. 19, 2444–2451 (2000)

    Article  CAS  Google Scholar 

  5. Mishra, S., Murphy, L. C., Nyomba, B. L. & Murphy, L. J. Prohibitin: a potential target for new therapeutics. Trends Mol. Med. 11, 192–197 (2005)

    Article  CAS  Google Scholar 

  6. Artal-Sanz, M. et al. The mitochondrial prohibitin complex is essential for embryonic viability and germline function in Caenorhabditis elegans . J. Biol. Chem. 278, 32091–32099 (2003)

    Article  Google Scholar 

  7. Kimura, K. D., Tissenbaum, H. A., Liu, Y. & Ruvkun, G. daf-2, an insulin receptor-like gene that regulates longevity and diapause in Caenorhabditis elegans . Science 277, 942–946 (1997)

    Article  CAS  Google Scholar 

  8. Kenyon, C. The plasticity of aging: insights from long-lived mutants. Cell 120, 449–460 (2005)

    Article  CAS  Google Scholar 

  9. Shaw, W. M. et al. The C. elegans TGF-β dauer pathway regulates longevity via insulin signaling. Curr. Biol. 17, 1635–1645 (2007)

    Article  CAS  Google Scholar 

  10. Estevez, M. et al. The daf-4 gene encodes a bone morphogenetic protein receptor controlling C. elegans dauer larva development. Nature 365, 644–649 (1993)

    Article  ADS  CAS  Google Scholar 

  11. Ren, P. et al. Control of C. elegans larval development by neuronal expression of a TGF-β homolog. Science 274, 1389–1391 (1996)

    Article  ADS  CAS  Google Scholar 

  12. Li, W., Kennedy, S. G. & Ruvkun, G. daf-28 encodes a C. elegans insulin superfamily member that is regulated by environmental cues and acts in the DAF-2 signaling pathway. Genes Dev. 17, 844–858 (2003)

    Article  CAS  Google Scholar 

  13. Van Gilst, M. R., Hadjivassiliou, H., Jolly, A. & Yamamoto, K. R. Nuclear hormone receptor NHR-49 controls fat consumption and fatty acid composition in C. elegans . PLoS Biol. 3, e53 (2005)

    Article  Google Scholar 

  14. Francis, R., Barton, M. K., Kimble, J. & Schedl, T. gld-1, a tumor suppressor gene required for oocyte development in Caenorhabditis elegans . Genetics 139, 579–606 (1995)

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Coates, P. J., Jamieson, D. J., Smart, K., Prescott, A. R. & Hall, P. A. The prohibitin family of mitochondrial proteins regulate replicative lifespan. Curr. Biol. 7, 607–610 (1997)

    Article  CAS  Google Scholar 

  16. Coates, P. J. et al. Mammalian prohibitin proteins respond to mitochondrial stress and decrease during cellular senescence. Exp. Cell Res. 265, 262–273 (2001)

    Article  ADS  CAS  Google Scholar 

  17. Gershman, B. et al. High-resolution dynamics of the transcriptional response to nutrition in Drosophila: a key role for dFOXO. Physiol. Genom. 29, 24–34 (2007)

    Article  CAS  Google Scholar 

  18. Nakae, J. et al. Forkhead transcription factor FoxO1 in adipose tissues regulates energy storage and expenditure. Diabetes 57, 563–576 (2008)

    Article  CAS  Google Scholar 

  19. Rea, S. & Johnson, T. E. A metabolic model for life span determination in Caenorhabditis elegans . Dev. Cell 5, 197–203 (2003)

    Article  CAS  Google Scholar 

  20. Schulz, T. J. et al. Glucose restriction extends Caenorhabditis elegans life span by inducing mitochondrial respiration and increasing oxidative stress. Cell Metab. 6, 280–293 (2007)

    Article  CAS  Google Scholar 

  21. Apfeld, J., O'Connor, G., McDonagh, T., DiStefano, P. S. & Curtis, R. The AMP-activated protein kinase AAK-2 links energy levels and insulin-like signals to lifespan in C. elegans . Genes Dev. 18, 3004–3009 (2004)

    Article  CAS  Google Scholar 

  22. Jones, R. G. et al. AMP-activated protein kinase induces a p53-dependent metabolic checkpoint. Mol. Cell 18, 283–293 (2005)

    Article  CAS  Google Scholar 

  23. Oh, S. W. et al. JNK regulates lifespan in Caenorhabditis elegans by modulating nuclear translocation of forkhead transcription factor/DAF-16. Proc. Natl Acad. Sci. USA 102, 4494–4499 (2005)

    Article  ADS  CAS  Google Scholar 

  24. Paradis, S. & Ruvkun, G. Caenorhabditis elegans Akt/PKB transduces insulin receptor-like signals from AGE-1 PI3 kinase to the DAF-16 transcription factor. Genes Dev. 12, 2488–2498 (1998)

    Article  CAS  Google Scholar 

  25. Merkwirth, C. et al. Prohibitins control cell proliferation and apoptosis by regulating OPA1-dependent cristae morphogenesis in mitochondria. Genes Dev. 22, 476–488 (2008)

    Article  CAS  Google Scholar 

  26. Olichon, A. et al. Loss of OPA1 perturbates the mitochondrial inner membrane structure and integrity, leading to cytochrome c release and apoptosis. J. Biol. Chem. 278, 7743–7746 (2003)

    Article  CAS  Google Scholar 

  27. Schleicher, M. et al. Prohibitin-1 maintains the angiogenic capacity of endothelial cells by regulating mitochondrial function and senescence. J. Cell Biol. 180, 101–112 (2008)

    Article  CAS  Google Scholar 

  28. Tatsuta, T., Model, K. & Langer, T. Formation of membrane-bound ring complexes by prohibitins in mitochondria. Mol. Biol. Cell 16, 248–259 (2005)

    Article  CAS  Google Scholar 

  29. Ashrafi, K. et al. Genome-wide RNAi analysis of Caenorhabditis elegans fat regulatory genes. Nature 421, 268–272 (2003)

    Article  ADS  CAS  Google Scholar 

  30. Soukas, A. A., Kane, E. A., Carr, C. E., Melo, J. A. & Ruvkun, G. Rictor/TORC2 regulates fat metabolism, feeding, growth, and life span in Caenorhabditis elegans . Genes Dev. 23, 496–511 (2009)

    Article  CAS  Google Scholar 

  31. Kampkötter, A. et al. Effects of the flavonoids kaempferol and fisetin on thermotolerance, oxidative stress and FoxO transcription factor DAF-16 in the model organism Caenorhabditis elegans . Arch. Toxicol. 81, 849–858 (2007)

    Article  Google Scholar 

  32. Cristina, D., Cary, M., Lunceford, A., Clarke, C. & Kenyon, C. A regulated response to impaired respiration slows behavioral rates and increases lifespan in Caenorhabditis elegans . PLoS Genet. 5, e1000450 (2009)

    Article  Google Scholar 

  33. Braeckman, B. P., Houthoofd, K., De Vreese, A. & Vanfleteren, J. R. Assaying metabolic activity in ageing Caenorhabditis elegans . Mech. Ageing Dev. 123, 105–119 (2002)

    Article  CAS  Google Scholar 

  34. Gášková, D., DeCorby, A. & Lemire, B. D. DiS-C3(3) monitoring of in vivo mitochondrial membrane potential in C. elegans . Biochem. Biophys. Res. Commun. 354, 814–819 (2007)

    Article  Google Scholar 

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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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  1. Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology, Heraklion 71110, Crete, Greece ,

    Marta Artal-Sanz & Nektarios Tavernarakis

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  1. Marta Artal-Sanz
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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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