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Vol. 19, Issue 8, 3576-3588, August 2008

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Apoptosome-deficient Cells Lose Cytochrome c through Proteasomal Degradation but Survive by Autophagy-dependent Glycolysis

Elisabetta Ferraro^*, Angela Pulicati^*,, Maria Teresa Cencioni, Mauro Cozzolino, Francesca Navoni^*, Simona di Martino^*, Roberta Nardacci^||, Maria Teresa Carrì^,¶, and Francesco Cecconi^*,

*Laboratory of Molecular Neuroembryology, Laboratory of Neurochemistry, and Laboratory of Neuroimmunology, IRCCS Fondazione Santa Lucia, 00143, Rome, Italy; Dulbecco Telethon Institute at the ^¶Department of Biology, University of Rome "Tor Vergata," 00133 Rome, Italy; and ^||National Institute for Infectious Diseases IRCCS "L. Spallanzani," 00149 Rome, Italy

Submitted September 4, 2007; Revised May 22, 2008; Accepted June 2, 2008
Monitoring Editor: Donald D. Newmeyer

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.

Address correspondence to: Francesco Cecconi (francesco.cecconi{at}uniroma2.it)

Abbreviations used: m, mitochondrial transmembrane potential; ANT, adenine nucleotide translocator; C9DN, caspase-9 dominant negative; DCF, 2',7'-dichlorodihydrofluorescein; ETNA^–/–, embryonic telencephalic naïve Apaf1^–/–; FCCP, carbonyl cyanide p-(trifluoromethoxy) phenylhydrazone; MEFs, mouse embryonic fibroblasts; MOMP, mitochondrial outer membrane permeabilization; Mpyr, methylpyruvate; MTS, 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt; ROS, reactive oxygen species; TMPD, N,N,N',N'-tetramethyl-p-phenylenediamine; TMRE, tetramethylrhodamine ethyl ester.