Halestrap Andrew P
The Department of Biochemistry and The Bristol Heart Institute, School of Medical Sciences, University of Bristol, University Walk, Bristol, BS8 1TD, UK.
J Bioenerg Biomembr. 2009 Apr;41(2):113-21. doi: 10.1007/s10863-009-9206-x.
The combination of calcium overload and oxidative stress opens a non-specific pore in the inner mitochondrial membrane known as the mitochondrial permeability transition pore (MPTP). This uncouples oxidative phosphorylation and compromises intracellular ATP levels eventually leading to necrotic cell death. In cardiac ischemia and reperfusion, as during treatment of a coronary thrombosis or cardiac surgery, the extent of MPTP opening determines the amount of irreversible damage (infarct size). Furthermore, cardioprotection can be achieved by inhibiting MPTP opening either directly with cyclosporin A analogues, or indirectly by reducing oxidative stress. The detailed molecular mechanism of the MPTP remains uncertain. Knockout studies have confirmed important regulatory roles for cyclophilin-D (CyP-D) and the adenine nucleotide translocase (ANT) but not the voltage dependent anion channel. Our own studies have implicated a calcium-triggered conformational change of the mitochondrial phosphate carrier that is facilitated by CyP-D and modulated by the conformation of the ANT.
钙超载与氧化应激相结合会在内线粒体膜上打开一个非特异性孔道，即线粒体通透性转换孔（MPTP）。这会使氧化磷酸化解偶联，并损害细胞内ATP水平，最终导致坏死性细胞死亡。在心脏缺血和再灌注过程中，如在冠状动脉血栓形成治疗或心脏手术期间，MPTP开放的程度决定了不可逆损伤（梗死面积）的大小。此外，通过用环孢素A类似物直接抑制MPTP开放，或通过降低氧化应激间接抑制MPTP开放，均可实现心脏保护。MPTP的详细分子机制仍不确定。基因敲除研究证实了亲环素D（CyP-D）和腺嘌呤核苷酸转位酶（ANT）具有重要的调节作用，但电压依赖性阴离子通道并非如此。我们自己的研究表明，线粒体磷酸盐载体的钙触发构象变化由CyP-D促进，并受ANT构象调节。
