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Permeabilization of the mitochondrial outer membrane by Bax/truncated Bid (tBid) proteins as sensitized by cardiolipin hydroperoxide translocation: mechanistic implications for the intrinsic pathway of oxidative apoptosis.
Korytowski, Witold; Basova, Liana V; Pilat, Anna; Kernstock, Robert M; Girotti, Albert W.
Afiliación
  • Korytowski W; Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA.
J Biol Chem ; 286(30): 26334-43, 2011 Jul 29.
Article en En | MEDLINE | ID: mdl-21642428
Cytochrome c (cyt c) release upon oxidation of cardiolipin (CL) in the mitochondrial inner membrane (IM) under oxidative stress occurs early in the intrinsic apoptotic pathway. We postulated that CL oxidation mobilizes not only cyt c but also CL itself in the form of hydroperoxide (CLOOH) species. Relatively hydrophilic CLOOHs could assist in apoptotic signaling by translocating to the outer membrane (OM), thus promoting recruitment of the pro-apoptotic proteins truncated Bid (tBid) and Bax for generation of cyt c-traversable pores. Initial testing of these possibilities showed that CLOOH-containing liposomes were permeabilized more readily by tBid plus Ca(2+) than CL-containing counterparts. Moreover, CLOOH translocated more rapidly from IM-mimetic to OM-mimetic liposomes than CL and permitted more extensive OM permeabilization. We found that tBid bound more avidly to CLOOH-containing membranes than to CL counterparts, and binding increased with increasing CLOOH content. Permeabilization of CLOOH-containing liposomes in the presence of tBid could be triggered by monomeric Bax, consistent with tBid/Bax cooperation in pore formation. Using CL-null mitochondria from a yeast mutant, we found that tBid binding and cyt c release were dramatically enhanced by transfer acquisition of CLOOH. Additionally, we observed a pre-apoptotic IM-to-OM transfer of oxidized CL in cardiomyocytes treated with the Complex III blocker, antimycin A. These findings provide new mechanistic insights into the role of CL oxidation in the intrinsic pathway of oxidative apoptosis.
Asunto(s)

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Cardiolipinas / Apoptosis / Membranas Mitocondriales / Proteína X Asociada a bcl-2 / Proteína Proapoptótica que Interacciona Mediante Dominios BH3 / Peróxidos Lipídicos / Mitocondrias Límite: Animals / Humans Idioma: En Revista: J Biol Chem Año: 2011 Tipo del documento: Article País de afiliación: Estados Unidos

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Cardiolipinas / Apoptosis / Membranas Mitocondriales / Proteína X Asociada a bcl-2 / Proteína Proapoptótica que Interacciona Mediante Dominios BH3 / Peróxidos Lipídicos / Mitocondrias Límite: Animals / Humans Idioma: En Revista: J Biol Chem Año: 2011 Tipo del documento: Article País de afiliación: Estados Unidos