Mitochondrial ATP synthase displays features that are characteristic of themPTP. Its activity is inhibited by the concurrent binding of the two mPTP inhibitors ADP and Mg, whereas the mPTP inducer inorganic phosphate abolishes this block. A strategic component of the mPTP, cyclophilin D (CypD), interacts with the peripheral stalk of ATP 1synthase, reducing its catalytic activity. This activity is restored when cyclosporine A (a mPTP inhibitor) displaces CypD (Giorgio et al., 2009). Finally, Bcl-Xl, which inhibits the mPTP, interacts with ATP synthase and promotes its activity (Alavian et al., 2011). Moreover, it has been demonstrated that the c subunit of mitochondrial ATP synthase (the only transmembrane subunit of the ATP synthase with a gating capacity when oligomerized as c-ring (McGeoch and Palmer, 1999)) is a fundamental regulator of mPTP activity (Bonora et al., 2013, De Marchi et al., 2014). This idea was supported by a subsequent study describing currents that were sensitive to mPTP regulators and generated by isolated c subunits on artificial bilayers and in isolated mitochondria (Azarashvili et al., 2014). The proposal that the c-ring forms the core of the mPTP is now supported by a recent work by Alavian et al. that demonstrates how the c-ring can generate a non-specific current ascribable to the mPTP (Alavian et al., 2014). This fascinating study raises new questions concerning a potential mechanism that can transform an evolved enzymatic complex into a non-specific and detrimental channel. First, the precise mechanisms involved in forming this pore are unclear. Alavian et al. showed that rearrangement of the c-ring occurs during mitochondrial permeability transition. The authors suggested that through this mechanism, the c-ring diameter should increase, generating non-specific channels. It should be noted that in other species, the stoichiometry of the c-ring can vary widely, by as much as 15 monomers for one ring (Pogoryelov et al., 2007). Nevertheless, no MPT-like activity was observed in this study, suggesting that an increase in the c-ring diameter is not sufficient for inducing MPT-like activities. Other intriguing questions are what mechanism could isolate the c-ring from the complex and what molecular factors are required for these events to occur. In the study by Alavian et al., they proposed that this event requires CypD activity, but they did not propose a molecular mechanism through which this activity could be transmitted to the c subunit. Despite themany questions that remain unanswered, these findings add a new piece to the complicated puzzle of the mPTP structure.

中文翻译：

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阐明 mPTP 的分子机制和身份

线粒体 ATP 合酶显示出 PTP 特有的特征。它的活性受到两种 mPTP 抑制剂 ADP 和 Mg 的同时结合的抑制，而 mPTP 诱导剂无机磷酸盐消除了这种阻断。mPTP 的战略成分亲环蛋白 D (CypD) 与 ATP 1 合酶的外周茎相互作用，降低其催化活性。当环孢菌素 A（一种 mPTP 抑制剂）取代 CypD 时，这种活性就会恢复（Giorgio 等，2009）。最后，抑制 mPTP 的 Bcl-Xl 与 ATP 合酶相互作用并促进其活性（Alavian 等，2011）。此外，已经证明线粒体 ATP 合酶的 c 亚基（ATP 合酶的唯一跨膜亚基在寡聚化为 c 环时具有门控能力（McGeoch 和 Palmer，1999)) 是 mPTP 活性的基本调节器（Bonora 等人，2013 年，De Marchi 等人，2014 年）。这一想法得到了随后的一项研究的支持，该研究描述了对 mPTP 调节器敏感的电流，并由人工双层和分离线粒体中的分离 c 亚基产生（Azarashvili 等，2014）。C 形环构成 mPTP 核心的提议现在得到了 Alavian 等人最近的一项工作的支持。这演示了 c 形环如何产生归因于 mPTP 的非特异性电流（Alavian 等，2014）。这项引人入胜的研究提出了关于一种潜在机制的新问题，该机制可以将进化的酶复合物转化为非特异性和有害的通道。首先，形成这个孔的确切机制尚不清楚。阿拉维安等人。表明 c 环的重排发生在线粒体通透性转变期间。作者建议通过这种机制，c 形环直径应该增加，产生非特异性通道。应该注意的是，在其他物种中，c 环的化学计量可以有很大差异，一个环有多达 15 个单体（Pogoryelov 等，2007）。然而，在这项研究中没有观察到 MPT 样活动，这表明 c 环直径的增加不足以诱导 MPT 样活动。其他有趣的问题是什么机制可以将 c 环与复合物分离，以及这些事件的发生需要哪些分子因素。在 Alavian 等人的研究中，他们提出这个事件需要 CypD 活动，但他们没有提出一种分子机制，通过这种机制可以将这种活动传递给 c 亚基。尽管有许多问题仍未得到解答，但这些发现为 mPTP 结构的复杂难题增添了新的一块。