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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.

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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.

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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.

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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). https://doi.org/10.1038/ncb1807

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