GAPDH and autophagy preserve survival after apoptotic cytochrome c release in the absence of caspase activation

Colell A. et al., Cell 129, 983–997 (2007)

Abstract

Apoptosis is a genetic program of cell death required for normal embryonic development and tissue homeostasis.  When the mitochondrial pathway of apoptosis is engaged, mitochondrial outer-membrane permeabilization (MOMP) results in the release of cytochrome c from the mitochondria into the cytosol, thus triggering caspase activation and subsequent apoptosis.  Previous study indicated that addition of caspase inhibitors fails to rescue cells from death when cytochrome c is released following MOMP.¹  Similarly, caspase-independent cell death (CICD) hat can be inhibited by Bcl-2 occurs in the cells lacking Apaf-1 or caspase-9.¹  How cells resist CICD after MOMP remains largely unknown.  Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is one of the key enzymes involved in glycolysis.  It catalyzes the reversible oxidative phosphorylation of glyceraldehyde-3-phosphate and serves to break down glucose for energy.  GAPDH is constitutively and stably expressed at high levels in most tissues and cells, and considered to be a “housekeeping” gene.  In this paper, the authors demonstrated that enforced expression of GAPDH protected cells from CICD by extending the maintenance of mitochondrial transmembrane potential (DYm) following MOMP in the presence of pancaspase inhibitors.  Increased intracellular ATP levels through glycolysis by GAPDH were associated with this protective effect when cells were maintained in high glucose media.  Nuclear GAPDH has been recently implicated in transcriptional regulation.²  The authors performed microarray analysis to identify candidate genes induced by GAPDH.  Interestingly, they identified Atg12, an important component participating in the process ofautophagy.  The cells expressing a GAPDHD2 mutant lacking nuclear localization sequence retained high ATP levels but underwent CICD when these cells were treated with proapoptotic agents in the presence of pancaspase inhibitors.  Ectopic overexpression of Atg12 prevented CICD in the cells expressing GAPDHD2, suggesting that GAPDH-induced Atg12 expression and autophagy contributed to the protection from CICD.  Together, GAPDH mediates an elevation in glycolysis and increased Atg12 expression that cooperate to protect cells from CICD.

References

1.      Xiang J., Chao D. T. and Korsmeyer S. J. BAX-induced cell death may not require interleukin 1 beta-converting enzyme-like proteases. Proc. Natl. Acad. Sci. USA 93, 14559–14563 (1996).

2.      Mazzola J. L. and Sirover M. A. Subcellular localization of human glyceraldehyde-3-phosphate dehydrogenase is independent of its glycolytic function. Biochim. Biophys. Acta 1622, 50–56 (2003).