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


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.

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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.


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

    CAS  Article  Google Scholar 

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

    CAS  Article  Google Scholar 

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

    CAS  Article  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).

    CAS  Article  Google Scholar 

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

    CAS  Article  Google Scholar 

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

    CAS  Article  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).

    CAS  Article  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).

    CAS  Article  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).

    CAS  Article  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).

    CAS  Article  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).

    CAS  Article  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).

    CAS  Article  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).

    CAS  Article  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).

    CAS  Article  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).

    CAS  Article  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).

    CAS  Article  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).

    CAS  Article  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).

    CAS  Article  Google Scholar 

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

    CAS  Article  Google Scholar 

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

    CAS  Article  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).

    CAS  Article  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).

    CAS  Article  Google Scholar 

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

    CAS  Article  Google Scholar 

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

    CAS  Article  Google Scholar 

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

    CAS  Article  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).

    CAS  Article  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).

    CAS  Article  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).

    CAS  Article  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).

    CAS  Article  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).

    CAS  Article  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).

    CAS  Article  Google Scholar 

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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.

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

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Correspondence to Mohanish Deshmukh.

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The authors declare no competing financial interests.

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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).

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