Filling a GAP(DH) in caspase-independent cell death

Abstract

Mitochondrial outer-membrane permeabilization can lead to cell death even without activation of caspases. In this issue of Cell, Colell et al. (2007) identify the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase as a potent inhibitor of caspase-independent cell death that may allow metabolically active cells to survive mitochondrial insult.

Figure 1. GAPDH as a Regulator of caspase-Independent cell Death

GAPDH was identified in a genetic screen in which cells were infected with a retroviral cDNA library and treated with caspase inhibitors and staurosporine (STS), which leads to mitochondrial outer-membrane permeabilization. Surviving cell clones were cultured with staurosporine alone to identify those that specifically resisted caspase-independent cell death but were susceptible to apoptosis. The proposed mechanism for GAPDH-mediated resistance to caspase-independent cell death occurs through dual cytoplasmic and nuclear functions. In the cytoplasm, GAPDH promotes glucose metabolism to sustain cellular ATP levels. In the nucleus, GAPDH leads to induction of ATG12 expression, which enhances degradation of damaged mitochondria through autophagy.