GAPDH and autophagy preserve survival after apoptotic cytochrome c release in the absence of caspase activation.
In cells undergoing apoptosis, mitochondrial outer-membrane permeabilization (MOMP) is followed by caspase activation promoted by released cytochrome c. Although caspases mediate the apoptotic phenotype, caspase inhibition is generally not sufficient for survival following MOMP; instead cells undergo a "caspase-independent cell death" (CICD). Thus, MOMP may represent a point of commitment to cell death. Here, we identify glyceraldehyde-3-phosphate dehydrogenase (GAPDH) as a critical regulator of CICD. GAPDH-expressing cells preserved their clonogenic potential following MOMP, provided that caspase activation was blocked. GAPDH-mediated protection of cells from CICD involved an elevation in glycolysis and a nuclear function that correlated with and was replaced by an increase in Atg12 expression. Consistent with this, protection from CICD reflected an increase in and a dependence upon autophagy, associated with a transient decrease in mitochondrial mass. Therefore, GAPDH mediates an elevation in glycolysis and enhanced autophagy that cooperate to protect cells from CICD.
Colell
Anna
A
Department of Cell Death and Proliferation, Institut d'Investigacions Biomediques de Barcelona (IIBB-CSIC), IDIBAPS, 08036 Barcelona, Spain.
Ricci
Jean-Ehrland
JE
Tait
Stephen
S
Milasta
Sandra
S
Maurer
Ulrich
U
Bouchier-Hayes
Lisa
L
Fitzgerald
Patrick
P
Guio-Carrion
Ana
A
Waterhouse
Nigel J
NJ
Li
Cindy Wei
CW
Mari
Bernard
B
Barbry
Pascal
P
Newmeyer
Donald D
DD
Beere
Helen M
HM
Green
Douglas R
DR
D017209:Apoptosis; D001343:Autophagy; D020169:Caspases / Q000378:metabolism; D002470:Cell Survival / Q000502:physiology*; D045304:Cytochromes c / Q000378:metabolism; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000235:genetics / Q000502:physiology*; D006367:HeLa Cells; D006801:Humans; D019169:Jurkat Cells; D008928:Mitochondria / Q000378:metabolism; D051336:Mitochondrial Membranes / Q000378:metabolism; D034622:RNA Interference
D045304:Cytochromes c; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases; D020169:Caspases