Mitochondria and cell death
Mitochondria and cell death
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DOI：
10.1042/bst0280170
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发表时间：
2000-02-01
影响因子：
3.9
通讯作者：
O'Toole, A
中科院分区：
文献类型：
--
作者：
Halestrap, AP;Doran, E;O'Toole, A
线粒体通过打开线粒体通透性转换孔（MPTP）在细胞凋亡和坏死中发挥核心作用。这被认为是通过Ca 2+引发的腺嘌呤核苷酸移位酶（ANT）结合到基质亲环素-D的构象变化，我们现在已经证明了这一点直接通过重组的纯成分。MPTP的开放引起线粒体的肿胀和解偶联，这不受限制地导致坏死。在缺血/再灌注损伤的心脏，我们已经表明MPTP直接开放。心脏的恢复与随后的闭合相关，并且防止打开或增强闭合的药剂保护免受损伤。瞬时MPTP开放也可能通过最初引起外膜肿胀和破裂以释放细胞色素c（cyt c）而参与细胞凋亡，细胞色素c随后激活半胱天冬酶级联并启动细胞凋亡。随后的MPTP关闭可以维持ATP水平，确保细胞死亡保持为细胞凋亡而不是坏死，低血糖或缺血性损伤后发生的海马体细胞凋亡就是通过这种方式触发的。其他细胞凋亡刺激，如细胞因子或生长因子的去除也涉及线粒体细胞色素c的释放，但在这里有争议的MPTP是否参与。在许多情况下，在没有任何线粒体去极化的情况下观察到cyt c释放，表明MPTP不打开。最近的数据，我们自己和其他人已经揭示了一个特定的外膜细胞色素c释放途径，涉及孔蛋白，不释放其他膜间蛋白，如腺苷酸激酶。这是由Bcl-2家族的促凋亡成员（例如BAX）打开的，并由抗凋亡成员（例如Bcl-x（L））阻止。我们自己的数据表明，这一途径可能直接与接触部位内膜中的ANT相互作用。
Mitochondria play a central role in both apoptosis and necrosis through the opening of the mitochondrial permeability transition pore (MPTP). This is thought to be formed through a Ca2+-triggered conformational change of the adenine nucleotide translocase (ANT) bound to matrix cyclophilin-D and we have now demonstrated this directly by reconstitution of the pure components. Opening of the MPTP causes swelling and uncoupling of mitochondria which, unrestrained, leads to necrosis. In ischaemia/reperfusion injury of the heart we have shown MPTP opening directly. Recovery of hearts correlates with subsequent closure, and agents that prevent opening or enhance closure protect from injury. Transient MPTP opening may also be involved in apoptosis by initially causing swelling and rupture of the outer membrane to release cytochrome c (cyt c), which then activates the caspase cascade and sets apoptosis in motion. Subsequent MPTP closure allows ATP levels to be maintained, ensuring that cell death remains apoptotic rather than necrotic, Apoptosis in the hippocampus that occurs after a hypoglycaemic or ischaemic insult is triggered by this means. Other apoptotic stimuli such as cytokines or removal of growth factors also involve mitochondrial cyt c release, but here there is controversy over whether the MPTP is involved. In many cases cyt c release is seen without any mitochondrial depolarization, suggesting that the MPTP does not open. Recent data of our own and others have revealed a specific outer-membrane cyt c-release pathway involving porin that does not release other intermembrane proteins such as adenylate kinase. This is opened by pro-apototic members of the Bcl-2 family such as BAX and prevented by anti-apoptotic members such as Bcl-x(L). Our own data suggest that this pathway may interact directly with the ANT in the inner membrane at contact sites.