Complement 1q-binding protein inhibits the mitochondrial permeability transition pore and protects against oxidative stress-induced death.
Complement 1q-binding protein inhibits the mitochondrial permeability transition pore and protects against oxidative stress-induced death.
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DOI：
10.1042/bj20101431
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发表时间：
2011-01-01
期刊：
影响因子：
--
通讯作者：
Baines CP
中科院分区：
文献类型：
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作者：
McGee AM;Baines CP
线粒体通透性转换(MPT)孔的打开是线粒体介导的细胞死亡的关键事件。然而，除了CypD(亲环素D)外，MPT孔的确切分子组成仍然不确定。C1qBP(补体1Q结合蛋白)最近被认为是MPT孔道复合体的重要组成部分。为了研究C1qBP是否确实在MPT和细胞死亡中起关键作用，我们在小鼠胚胎成纤维细胞(MEF)中进行了功能获得和功能丧失实验。我们首先证实了C1qBP是一种可溶性蛋白，定位于小鼠细胞和组织中的线粒体基质。同样，用腺病毒在MEF中过表达C1qBP导致其唯一定位于线粒体。令我们惊讶的是，C1qBP蛋白水平的增加实际上抑制了过氧化氢诱导的MPT和细胞死亡。相反，用siRNA(小干扰RNA)敲除内源性C1qBP使MEF对H_2O_2诱导的MPT和细胞死亡敏感。此外，我们还发现C1qBP可以直接与CypD结合。因此，C1qBP似乎是MPT孔的内源性抑制物，很可能是通过与CypD结合，从而保护细胞免受氧化应激的影响。
Opening of the MPT (mitochondrial permeability transition) pore is a critical event in mitochondrial-mediated cell death. However, with the exception of CypD (cyclophilin D), the exact molecular composition of the MPT pore remains uncertain. C1qbp (complement 1q-binding protein) has recently been hypothesized to be an essential component of the MPT pore complex. To investigate whether C1qbp indeed plays a critical role in MPT and cell death, we conducted both gain-of-function and loss-of-function experiments in MEFs (mouse embryonic fibroblasts). We first confirmed that C1qbp is a soluble protein that localizes to the mitochondrial matrix in mouse cells and tissues. Similarly, overexpression of C1qbp in MEFs using an adenovirus resulted in its exclusive localization to mitochondria. To our surprise, increased C1qbp protein levels actually suppressed H2O2-induced MPT and cell death. Antithetically, knockdown of endogenous C1qbp with siRNA (small interfering RNA) sensitized the MEFs to H2O2-induced MPT and cell death. Moreover, we found that C1qbp could directly bind to CypD. Therefore C1qbp appears to act as an endogenous inhibitor of the MPT pore, most likely through binding to CypD, and thus protects cells against oxidative stress.