Apoptosome-deficient cells lose cytochrome c through proteasomal degradation but survive by autophagy-dependent glycolysis.
Cytochrome c release from mitochondria promotes apoptosome formation and caspase activation. The question as to whether mitochondrial permeabilization kills cells via a caspase-independent pathway when caspase activation is prevented is still open. Here we report that proneural cells of embryonic origin, when induced to die but rescued by apoptosome inactivation are deprived of cytosolic cytochrome c through proteasomal degradation. We also show that, in this context, those cells keep generating ATP by glycolysis for a long period of time and that they keep their mitochondria in a depolarized state that can be reverted. Moreover, under these conditions, such apoptosome-deficient cells activate a Beclin 1-dependent autophagy pathway to sustain glycolytic-dependent ATP production. Our findings contribute to elucidating what the point-of-no-return in apoptosis is. They also help in clarifying the issue of survival of apoptosome-deficient proneural cells under stress conditions. Unraveling this issue could be highly relevant for pharmacological intervention and for therapies based on neural stem cell transfer in the treatment of neurological disorders.
Laboratory of Molecular Neuroembryology, IRCCS Fondazione Santa Lucia, 00143, Rome, Italy.
Elisabetta
E
Ferraro
Angela
A
Pulicati
Maria Teresa
MT
Cencioni
Mauro
M
Cozzolino
Francesca
F
Navoni
Simona
S
di Martino
Roberta
R
Nardacci
Maria Teresa
MT
Carrì
Francesco
F
Cecconi
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D053478:Apoptosomes / Q000378:metabolism*; D001343:Autophagy; D000071186:Beclin-1; D020169:Caspases / Q000378:metabolism; D002470:Cell Survival; D045304:Cytochromes c / Q000378:metabolism*; D004789:Enzyme Activation; D005786:Gene Expression Regulation; D006019:Glycolysis; D051379:Mice; D008954:Models, Biological; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism
D051017:Apoptosis Regulatory Proteins; D053478:Apoptosomes; D000071186:Beclin-1; C115010:Becn1 protein, mouse; D011506:Proteins; D000255:Adenosine Triphosphate; D045304:Cytochromes c; D020169:Caspases; D046988:Proteasome Endopeptidase Complex