000095967 001__ 95967 000095967 005__ 20201027161503.0 000095967 0247_ $$2doi$$a10.1084/jem.189.2.381 000095967 0248_ $$2sideral$$a116948 000095967 037__ $$aART-1999-116948 000095967 041__ $$aeng 000095967 100__ $$aSusin, Santos A. 000095967 245__ $$aMitochondrial Release of Caspase-2 and -9 during the Apoptotic Process 000095967 260__ $$c1999 000095967 5060_ $$aAccess copy available to the general public$$fUnrestricted 000095967 5203_ $$aThe barrier function of mitochondrial membranes is perturbed early during the apoptotic process. Here we show that the mitochondria contain a caspase-like enzymatic activity cleaving the caspase substrate Z-VAD.afc, in addition to three biological activities previously suggested to participate in the apoptotic process: (a) cytochrome c; (b) an apoptosis-inducing factor (AIF) which causes isolated nuclei to undergo apoptosis in vitro; and (c) a DNAse activity. All of these factors, which are biochemically distinct, are released upon opening of the permeability transition (PT) pore in a coordinate, Bcl-2-inhibitable fashion. Caspase inhibitors fully neutralize the Z-VAD.afc-cleaving activity, have a limited effect on the AIF activity, and have no effect at all on the DNase activities. Purification of proteins reacting with the biotinylated caspase substrate Z-VAD, immunodetection, and immunodepletion experiments reveal the presence of procaspase-2 and -9 in mitochondria. Upon induction of PT pore opening, these procaspases are released from purified mitochondria and become activated. Similarly, upon induction of apoptosis, both procaspases redistribute from the mitochondrion to the cytosol and are processed to generate enzymatically active caspases. This redistribution is inhibited by Bcl-2. Recombinant caspase-2 and -9 suffice to provoke full-blown apoptosis upon microinjection into cells. Altogether, these data suggest that caspase-2 and -9 zymogens are essentially localized in mitochondria and that the disruption of the outer mitochondrial membrane occurring early during apoptosis may be critical for their subcellular redistribution and activation. 000095967 540__ $$9info:eu-repo/semantics/openAccess$$aby-nc-sa$$uhttp://creativecommons.org/licenses/by-nc-sa/3.0/es/ 000095967 590__ $$a15.651$$b1999 000095967 591__ $$aMEDICINE, RESEARCH & EXPERIMENTAL$$b2 / 76 = 0.026$$c1999$$dQ1$$eT1 000095967 591__ $$aIMMUNOLOGY$$b4 / 115 = 0.035$$c1999$$dQ1$$eT1 000095967 655_4 $$ainfo:eu-repo/semantics/article$$vinfo:eu-repo/semantics/publishedVersion 000095967 700__ $$aLorenzo, Hans K. 000095967 700__ $$aZamzami, Naoufal 000095967 700__ $$0(orcid)0000-0002-2315-9079$$aMarzo, Isabel 000095967 700__ $$aBrenner, Catherine 000095967 700__ $$aLarochette, Nathanael 000095967 700__ $$aPrévost, Marie-Christine 000095967 700__ $$aAlzari, Pedro M. 000095967 700__ $$aKroemer, Guido 000095967 773__ $$g189, 2 (1999), 381-394$$pJ. exp. med.$$tJOURNAL OF EXPERIMENTAL MEDICINE$$x0022-1007 000095967 8564_ $$s811868$$uhttps://zaguan.unizar.es/record/95967/files/texto_completo.pdf$$yVersión publicada 000095967 8564_ $$s533918$$uhttps://zaguan.unizar.es/record/95967/files/texto_completo.jpg?subformat=icon$$xicon$$yVersión publicada 000095967 909CO $$ooai:zaguan.unizar.es:95967$$particulos$$pdriver 000095967 951__ $$a2020-10-27-15:03:55 000095967 980__ $$aARTICLE
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