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
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
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DOI：
10.1074/jbc.m110.188516
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发表时间：
2011-07-29
影响因子：
4.8
通讯作者：
Girotti, Albert W.
中科院分区：
文献类型：
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作者：
Korytowski, Witold;Basova, Liana V.;Girotti, Albert W.
细胞色素c(Cytc)在氧化应激下氧化线粒体内膜(IM)中的心磷脂(CL)时释放的细胞色素c(Cytc)发生在固有的凋亡途径的早期。我们推测，CL氧化不仅能动员细胞色素C，还能以过氧化氢(ClOOH)形式动员CL本身。相对亲水性的CLOOHs可以通过转移到外膜(OM)来帮助细胞凋亡信号，从而促进促凋亡蛋白截短BID(TBID)和Bax的募集，从而产生细胞可穿透的孔。对这些可能性的初步测试表明，与含CL的脂质体相比，含ClOOH的脂质体更容易被TBID加钙离子渗透。此外，与CL相比，ClOOH从IM模拟脂质体转移到OM模拟脂质体的速度更快，并允许更广泛的OM渗透。我们发现，TBID与含ClOOH的膜的结合比与CL的结合更强烈，并且结合强度随着ClOOH含量的增加而增加。在TBID存在的情况下，含ClOOH的脂质体可以由单体Bax引发渗透，这与TBID/Bax在孔道形成中的合作是一致的。利用酵母突变株的CL缺失线粒体，我们发现ClOOH的转移获取显著增强了tbid结合和细胞色素c的释放。此外，我们观察到在用复合III阻滞剂抗霉素A处理的心肌细胞中，氧化的CL在凋亡前的IM-OM转移。这些发现为CL氧化在氧化凋亡的内在途径中的作用提供了新的机制见解。
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 Ca2+ 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.