The Release of Cytochrome c from Mitochondria during Apoptosis of NGF-deprived Sympathetic Neurons Is a Reversible Event

doi:10.1083/jcb.144.5.883

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© The Rockefeller University Press, 0021-9525/1999//883 $5.00
The Journal of Cell Biology, Volume 144, Number 5, , 1999 883-889

Regular Articles

The Release of Cytochrome c from Mitochondria during Apoptosis of NGF-deprived Sympathetic Neurons Is a Reversible Event

Isabelle Martinou^*, Solange Desagher^*, Robert Eskes^*, Bruno Antonsson^*, Elisabeth André^*, Stanislav Fakan, and Jean-Claude Martinou^*

^* Serono Pharmaceutical Research Institute, Ares Serono International S.A., CH-1228 Plan-les-Ouates, Geneva, Switzerland; and Center of Electron Microscopy, University of Lausanne, CH-1005 Lausanne, Switzerland

During apoptosis induced by various stimuli, cytochrome c isreleased from mitochondria into the cytosol where it participatesin caspase activation. This process has been proposed to bean irreversible consequence of mitochondrial permeability transitionpore opening, which leads to mitochondrial swelling and ruptureof the outer mitochondrial membrane. Here we present data demonstratingthat NGF-deprived sympathetic neurons protected from apoptosisby caspase inhibitors possess mitochondria which, though depleted of cytochrome c and reduced in size, remained structurallyintact as viewed by electron microscopy. After re-exposure ofneurons to NGF, mitochondria recovered their normal size andtheir cytochrome c content, by a process requiring de novoprotein synthesis. Altogether, these data suggest that depletionof cytochrome c from mitochondria is a controlled process compatible with function recovery. The ability of sympathetic neuronsto recover fully from trophic factor deprivation provided irreversiblecaspase inhibitors have been present during the insult period,has therapeutical implications for a number of acute neuropathologies.

Key Words: apoptosis • Bax • cytochrome c • mitochondria • caspases

Abbreviations used in this paper: ANT, adenine nucleotide translocator; BAF, Boc-aspartyl(Ome)-fluoromethylketone; HM, heavy membrane fraction enriched in mitochondria; PTP, permeability transition pore; SCG, sympathetic neurons from newborn rat cervical superior ganglia.

We are very grateful to S. Catsicas (University of Lausanne,Switzerland) for having made possible the collaboration betweenS. Fakan (University of Lausanne) and J.-C. Martinou and forhis 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 helpwith morphometrical and quantitative evaluation of the results;and C. Hebert (SPRI, Geneva, Switzerland) for artwork.

Work performed at the Center of Electron Microscopy (Universityof Lausanne, Lausanne, Switzerland) was supported by fundsfrom Ares Serono. Part of this work was also supported by grantsfrom the European Community (Biotech grant BIO4CT96 0774 toJ.-C. Martinou).

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