The Journal of Experimental Medicine
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© The Rockefeller University Press, 0022-1007/1997/7/25/ $5.00
The Journal of Experimental Medicine, Volume 186, Number 1, July 7, 1997 25-37

Articles

The Central Executioner of Apoptosis: Multiple Connections between Protease Activation and Mitochondria in Fas/APO-1/CD95- and Ceramide-induced Apoptosis

Santos A. Susin*, Naoufal Zamzami*, Maria Castedo*, Eric Daugas*, Hong-Gang Wang{ddagger}, Stephan Geley§, Florence Fassy||, John C. Reed{ddagger}, and Guido Kroemer*

From the * Centre National de la Recherche Scientifique-UPR420, B.P.8, F-94801 Villejuif, France; {ddagger} The Burnham Institute, La Jolla, California 92037; § Institute for General and Experimental Pathology of the University of Innsbruck, A-6020 Innsbruck, Austria; and || Division Santé, Domain Immunologie, ROUSSEL UCLAF, F-93235 Romainville, France

According to current understanding, cytoplasmic events including activation of protease cascades and mitochondrial permeability transition (PT) participate in the control of nuclear apoptosis. However, the relationship between protease activation and PT has remained elusive. When apoptosis is induced by cross-linking of the Fas/APO-1/CD95 receptor, activation of interleukin-1β converting enzyme (ICE; caspase 1) or ICE-like enzymes precedes the disruption of the mitochondrial inner transmembrane potential ({Delta}{Psi}m). In contrast, cytosolic CPP32/ Yama/Apopain/caspase 3 activation, plasma membrane phosphatidyl serine exposure, and nuclear apoptosis only occur in cells in which the {Delta}{Psi}m is fully disrupted. Transfection with the cowpox protease inhibitor crmA or culture in the presence of the synthetic ICE-specific inhibitor Ac-YVAD.cmk both prevent the {Delta}{Psi}m collapse and subsequent apoptosis. Cytosols from anti-Fas–treated human lymphoma cells accumulate an activity that induces PT in isolated mitochondria in vitro and that is neutralized by crmA or Ac-YVAD.cmk. Recombinant purified ICE suffices to cause isolated mitochondria to undergo PT-like large amplitude swelling and to disrupt their {Delta}{Psi}m. In addition, ICE-treated mitochondria release an apoptosis-inducing factor (AIF) that induces apoptotic changes (chromatin condensation and oligonucleosomal DNA fragmentation) in isolated nuclei in vitro. AIF is a protease (or protease activator) that can be inhibited by the broad spectrum apoptosis inhibitor Z-VAD.fmk and that causes the proteolytical activation of CPP32. Although Bcl-2 is a highly efficient inhibitor of mitochondrial alterations (large amplitude swelling + {Delta}{Psi}m collapse + release of AIF) induced by prooxidants or cytosols from ceramide-treated cells, it has no effect on the ICE-induced mitochondrial PT and AIF release. These data connect a protease activation pathway with the mitochondrial phase of apoptosis regulation. In addition, they provide a plausible explanation of why Bcl-2 fails to interfere with Fas-triggered apoptosis in most cell types, yet prevents ceramide- and prooxidant-induced apoptosis.

Address correspondence to Dr. Guido Kroemer, 19 rue Guy Môquet, B.P. 8, F-94801 Villejuif, France. FAX: 33-1-49-58-35-09.

1Abbreviations used in this paper: {Delta}{Psi}m, mitochondrial transmembrane potential; AIF, apoptosis-inducing factor; CFS, cell-free system; CMXRos, cholormethyl-X-rosamine; ICE, interleukin 1β converting enzyme; mClCCP, carbonyl cyanide m-chlorophenylhydrazone; PT, permeability transition; t-BHP, ter-butylhydroperoxide.


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