During apoptosis induced by various stimuli, cytochrome c is released from mitochondria into the cytosol where it participates in caspase activation. This process has been proposed to be an irreversible consequence of mitochondrial permeability transition pore opening, which leads to mitochondrial swelling and rupture of the outer mitochondrial membrane. Here we present data demonstrating that NGF-deprived sympathetic neurons protected from apoptosis by caspase inhibitors possess mitochondria which, though depleted of cytochrome c and reduced in size, remained structurally intact as viewed by electron microscopy. After re-exposure of neurons to NGF, mitochondria recovered their normal size and their cytochrome c content, by a process requiring de novo protein synthesis. Altogether, these data suggest that depletion of cytochrome c from mitochondria is a controlled process compatible with function recovery. The ability of sympathetic neurons to recover fully from trophic factor deprivation provided irreversible caspase inhibitors have been present during the insult period, has therapeutical implications for a number of acute neuropathologies.
The Release of Cytochrome c from Mitochondria during Apoptosis of NGF-deprived Sympathetic Neurons Is a Reversible Event
Address correspondence to J.-C. Martinou, Serono Pharmaceutical Research Institute, Ares Serono International S.A., 14 chemin des Aulx, CH-1228 Plan-les-Ouates, Geneva, Switzerland. Tel.: (41) 22 706 9822. Fax: (41) 22 794 6965. E-mail: [email protected]
We are very grateful to S. Catsicas (University of Lausanne, Switzerland) for having made possible the collaboration between S. Fakan (University of Lausanne) and J.-C. Martinou and for his interest in this work; to S. Arkinstall and K. Maundrell (SPRI, Geneva, Switzerland) for critical reading of the manuscript; T. Wells for encouraging support; J. Fakan, V. Mamin, and F. Voinesco (University of Lausanne) for excellent technical assistance; N. Ruchonnet and S. Tapia (University of Lausanne) for help with morphometrical and quantitative evaluation of the results; and C. Hebert (SPRI, Geneva, Switzerland) for artwork.
Work performed at the Center of Electron Microscopy (University of Lausanne, Lausanne, Switzerland) was supported by funds from Ares Serono. Part of this work was also supported by grants from the European Community (Biotech grant BIO4CT96 0774 to J.-C. Martinou).
Isabelle Martinou, Solange Desagher, Robert Eskes, Bruno Antonsson, Elisabeth André, Stanislav Fakan, Jean-Claude Martinou; The Release of Cytochrome c from Mitochondria during Apoptosis of NGF-deprived Sympathetic Neurons Is a Reversible Event . J Cell Biol 8 March 1999; 144 (5): 883–889. doi: https://doi.org/10.1083/jcb.144.5.883
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