Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Glucose metabolism inhibits apoptosis in neurons and cancer cells by redox inactivation of cytochrome c

Abstract

Neurons and cancer cells use glucose extensively, yet the precise advantage of this adaptation remains unclear. These two seemingly disparate cell types also show an increased regulation of the apoptotic pathway, which allows for their long-term survival1. Here we show that both neurons and cancer cells strictly inhibit cytochrome c-mediated apoptosis by a mechanism dependent on glucose metabolism. We report that the pro-apoptotic activity of cytochrome c is influenced by its redox state and that increases in reactive oxygen species (ROS) following an apoptotic insult lead to the oxidation and activation of cytochrome c. In healthy neurons and cancer cells, however, cytochrome c is reduced and held inactive by intracellular glutathione (GSH), generated as a result of glucose metabolism by the pentose phosphate pathway. These results uncover a striking similarity in apoptosis regulation between neurons and cancer cells and provide insight into an adaptive advantage offered by the Warburg effect for cancer cell evasion of apoptosis and for long-term neuronal survival.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Endogenous cytochrome c release is incapable of inducing apoptosis in NGF-maintained sympathetic neurons.
Figure 2: Oxidation of cytochrome c increases its apoptotic activity.
Figure 3: Role of the pentose phosphate shunt in cytochrome c-mediated apoptosis.
Figure 4: Glucose metabolism protects cancer cells from cytochrome c-mediated apoptosis.

Similar content being viewed by others

References

  1. Wright, K.M. & Deshmukh, M. Restricting apoptosis for postmitotic cell survival and its relevance to cancer. Cell Cycle 5, 1616–1620 (2006).

    Article  CAS  Google Scholar 

  2. Yuan, J. & Yankner, B.A. Apoptosis in the nervous system. Nature 407, 802–809 (2000).

    Article  CAS  Google Scholar 

  3. Green, D.R. & Evan, G.I. A matter of life and death. Cancer Cell 1, 19–30 (2002).

    Article  CAS  Google Scholar 

  4. Wang, X. The expanding role of mitochondria in apoptosis. Genes Dev. 15, 2922–2933 (2001).

    CAS  PubMed  Google Scholar 

  5. Schubert, D. Glucose metabolism and Alzheimer's disease. Ageing Res. Rev. 4, 240–257 (2005).

    Article  CAS  Google Scholar 

  6. Warburg, O. On the origin of cancer cells. Science 123, 309–314 (1956).

    Article  CAS  Google Scholar 

  7. Esposti, M.D. The roles of Bid. Apoptosis 7, 433–440 (2002).

    Article  CAS  Google Scholar 

  8. Potts, P.R., Singh, S., Knezek, M., Thompson, C.B. & Deshmukh, M. Critical function of endogenous XIAP in regulating caspase activation during sympathetic neuronal apoptosis. J. Cell Biol. 163, 789–799 (2003).

    Article  CAS  Google Scholar 

  9. Deshmukh, M., Kuida, K. & Johnson, E.M. Jr., Caspase inhibition extends the commitment to neuronal death beyond cytochrome c release to the point of mitochondrial depolarization. J. Cell Biol. 150, 131–143 (2000).

    Article  CAS  Google Scholar 

  10. Neame, S.J., Rubin, L.L. & Philpott, K.L. Blocking cytochrome c activity within intact neurons inhibits apoptosis. J. Cell Biol. 142, 1583–1593 (1998).

    Article  CAS  Google Scholar 

  11. Vaughn, A.E. & Deshmukh, M. Essential postmitochondrial function of p53 uncovered in DNA damage-induced apoptosis in neurons. Cell Death Differ. 14, 973–981 (2007).

    Article  CAS  Google Scholar 

  12. Yang, J. et al. Prevention of apoptosis by Bcl-2: release of cytochrome c from mitochondria blocked. Science 275, 1129–1132 (1997).

    Article  CAS  Google Scholar 

  13. Hancock, J.T., Desikan, R. & Neill, S.J. Does the redox status of cytochrome C act as a fail-safe mechanism in the regulation of programmed cell death? Free Radic. Biol. Med. 31, 697–703 (2001).

    Article  CAS  Google Scholar 

  14. Pan, Z., Voehringer, D.W. & Meyn, R.E. Analysis of redox regulation of cytochrome c-induced apoptosis in a cell-free system. Cell Death Differ. 6, 683–688 (1999).

    Article  CAS  Google Scholar 

  15. Suto, D., Sato, K., Ohba, Y., Yoshimura, T. & Fujii, J. Suppression of the pro-apoptotic function of cytochrome c by singlet oxygen via a haem redox state-independent mechanism. Biochem. J. 392, 399–406 (2005).

    Article  CAS  Google Scholar 

  16. Hampton, M.B., Zhivotovsky, B., Slater, A.F., Burgess, D.H. & Orrenius, S. Importance of the redox state of cytochrome c during caspase activation in cytosolic extracts. Biochem. J. 329, 95–99 (1998).

    Article  CAS  Google Scholar 

  17. Kluck, R.M. et al. Cytochrome c activation of CPP32-like proteolysis plays a critical role in a Xenopus cell-free apoptosis system. EMBO J. 16, 4639–4649 (1997).

    Article  CAS  Google Scholar 

  18. Borutaite, V. & Brown, G.C. Mitochondrial regulation of caspase activation by cytochrome oxidase and tetramethylphenylenediamine via cytosolic cytochrome c redox state. J. Biol. Chem. 282, 31124–31130 (2007).

    Article  CAS  Google Scholar 

  19. Li, M., Wang, A.J. & Xu, J.X. Redox state of cytochrome c regulates cellular ROS and caspase cascade in permeablized cell model. Protein Pept. Lett. 15, 200–205 (2008).

    Article  CAS  Google Scholar 

  20. Doyle, D.F. et al. Changing the transition state for protein (Un) folding. Biochemistry 35, 7403–7411 (1996).

    Article  CAS  Google Scholar 

  21. Cai, J. & Jones, D.P. Mitochondrial redox signaling during apoptosis. J. Bioenerg. Biomembr. 31, 327–334 (1999).

    Article  CAS  Google Scholar 

  22. Kirkland, R.A. & Franklin, J.L. Evidence for redox regulation of cytochrome C release during programmed neuronal death: antioxidant effects of protein synthesis and caspase inhibition. J. Neurosci. 21, 1949–1963 (2001).

    Article  CAS  Google Scholar 

  23. Greenlund, L.J., Deckwerth, T.L. & Johnson, E.M. Jr. Superoxide dismutase delays neuronal apoptosis: a role for reactive oxygen species in programmed neuronal death. Neuron 14, 303–315 (1995).

    Article  CAS  Google Scholar 

  24. Kaplowitz, N., Aw, T.Y. & Ookhtens, M. The regulation of hepatic glutathione. Annu Rev. Pharmacol. Toxicol. 25, 715–744 (1985).

    Article  CAS  Google Scholar 

  25. Verhagen, A.M. & Vaux, D.L. Cell death regulation by the mammalian IAP antagonist Diablo/Smac. Apoptosis 7, 163–166 (2002).

    Article  CAS  Google Scholar 

  26. Bensaad, K. et al. TIGAR, a p53-inducible regulator of glycolysis and apoptosis. Cell 126, 107–120 (2006).

    Article  CAS  Google Scholar 

  27. Kuo, W., Lin, J. & Tang, T.K. Human glucose-6-phosphate dehydrogenase (G6PD) gene transforms NIH 3T3 cells and induces tumors in nude mice. Int. J. Cancer 85, 857–864 (2000).

    Article  CAS  Google Scholar 

  28. Nutt, L.K. et al. Metabolic regulation of oocyte cell death through the CaMKII-mediated phosphorylation of caspase-2. Cell 123, 89–103 (2005).

    Article  CAS  Google Scholar 

  29. Deckwerth, T.L. & Johnson, E.M. Jr. Temporal analysis of events associated with programmed cell death (apoptosis) of sympathetic neurons deprived of nerve growth factor. J Cell Biol. 123, 1207–1222 (1993).

    Article  CAS  Google Scholar 

  30. Carney, J.M., Smith, C.D., Carney, A.M. & Butterfield, D.A. Aging- and oxygen-induced modifications in brain biochemistry and behavior. Ann. NY Acad. Sci. 738, 44–53 (1994).

    Article  CAS  Google Scholar 

  31. Rego, A.C. & Oliveira, C.R. Mitochondrial dysfunction and reactive oxygen species in excitotoxicity and apoptosis: implications for the pathogenesis of neurodegenerative diseases. Neurochem. Res. 28, 1563–1574 (2003).

    Article  CAS  Google Scholar 

  32. Tietze, F. Enzymic method for quantitative determination of nanogram amounts of total and oxidized glutathione: applications to mammalian blood and other tissues. Anal. Biochem. 27, 502–522 (1969).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank Jeffery Rathmell, Gary Pielak, Eugene Johnson and members of the Deshmukh Lab for helpful discussions and critical review of this manuscript. This work was supported by NIH grants NS42197 and GM078366 (to M.D.), NS055486 (to A.E.V.) and by the UNC Cancer Research Fund.

Author information

Authors and Affiliations

Authors

Contributions

A.E.V. performed all experiments; A.E.V. and M.D. planned the project and analysed the data.

Corresponding author

Correspondence to Mohanish Deshmukh.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

Supplementary Information (PDF 755 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Vaughn, A., Deshmukh, M. Glucose metabolism inhibits apoptosis in neurons and cancer cells by redox inactivation of cytochrome c. Nat Cell Biol 10, 1477–1483 (2008). https://doi.org/10.1038/ncb1807

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ncb1807

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing