Li Bo, Chauvin Christiane, De Paulis Damien, De Oliveira Frédéric, Gharib Abdallah, Vial Guillaume, Lablanche Sandrine, Leverve Xavier, Bernardi Paolo, Ovize Michel, Fontaine Eric
University Claude Bernard Lyon 1, Lyon, France.
Biochim Biophys Acta. 2012 Sep;1817(9):1628-34. doi: 10.1016/j.bbabio.2012.05.011. Epub 2012 May 31.
Inhibition of the mitochondrial permeability transition pore (PTP) has proved to be an effective strategy for preventing oxidative stress-induced cell death, and the pore represents a viable cellular target for drugs. Here, we report that inhibition of complex I by rotenone is more effective at PTP inhibition than cyclosporin A in tissues that express low levels of the cyclosporin A mitochondrial target, cyclophilin D; and, conversely, that tissues in which rotenone does not affect the PTP are characterized by high levels of expression of cyclophilin D and sensitivity to cyclosporin A. Consistent with a regulatory role of complex I in the PTP-inhibiting effects of rotenone, the concentrations of the latter required for PTP inhibition precisely match those required to inhibit respiration; and a similar effect is seen with the antidiabetic drug metformin, which partially inhibits complex I. Remarkably (i) genetic ablation of cyclophilin D or its displacement with cyclosporin A restored PTP inhibition by rotenone in tissues that are otherwise resistant to its effects; and (ii) rotenone did not inhibit the PTP unless phosphate was present, in striking analogy with the phosphate requirement for the inhibitory effects of cyclosporin A [Basso et al. (2008) J. Biol. Chem. 283, 26307-26311]. These results indicate that inhibition of complex I by rotenone or metformin and displacement of cyclophilin D by cyclosporin A affect the PTP through a common mechanism; and that cells can modulate their PTP response to complex I inhibition by modifying the expression of cyclophilin D, a finding that has major implications for pore modulation in vivo.
事实证明，抑制线粒体通透性转换孔（PTP）是预防氧化应激诱导的细胞死亡的有效策略，并且该孔是药物可行的细胞靶点。在此，我们报告，在表达低水平环孢素A线粒体靶点亲环蛋白D的组织中，鱼藤酮对复合体I的抑制在PTP抑制方面比环孢素A更有效；相反，鱼藤酮不影响PTP的组织其特征在于亲环蛋白D的高表达水平以及对环孢素A敏感。与复合体I在鱼藤酮的PTP抑制作用中的调节作用一致，PTP抑制所需的鱼藤酮浓度与抑制呼吸所需的浓度精确匹配；抗糖尿病药物二甲双胍也有类似作用，它部分抑制复合体I。值得注意的是：（i）亲环蛋白D的基因敲除或用环孢素A替代它可恢复鱼藤酮在原本对其作用有抗性的组织中的PTP抑制作用；（ii）鱼藤酮除非有磷酸盐存在，否则不抑制PTP，这与环孢素A抑制作用对磷酸盐的需求惊人地相似[巴索等人（2008年）《生物化学杂志》283卷，26307 - 26311页]。这些结果表明，鱼藤酮或二甲双胍对复合体I的抑制以及环孢素A对亲环蛋白D的替代通过共同机制影响PTP；并且细胞可以通过改变亲环蛋白D的表达来调节其对复合体I抑制的PTP反应，这一发现对体内孔道调节具有重要意义。
