Role of the c subunit of the FO ATP synthase in mitochondrial permeability transition
Role of the c subunit of the FO ATP synthase in mitochondrial permeability transition
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DOI：
10.4161/cc.23599
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发表时间：
2013-02-15
期刊：
影响因子：
4.3
通讯作者：
Pinton, Paolo
中科院分区：
文献类型：
--
作者：
Bonora, Massimo;Bononi, Angela;Pinton, Paolo
术语“线粒体渗透性转变”（MPT）是指线粒体内膜对低分子量溶质的渗透性的突然增加。由于渗透力，MPT被大量水流入线粒体基质所破坏，最终导致细胞器的结构崩溃。因此，MPT可以启动线粒体外膜透化（MOMP），促进凋亡的caspase级联反应以及caspase非依赖性细胞死亡机制的激活。MPT似乎是由所谓的“渗透性转换孔复合物”（PTPC）的开放介导的，PTPC是一种在线粒体内膜和外膜之间的连接处组装的特征不明显且多功能的超分子实体。尽管有相当多的实验努力，PTP C的精确分子组成仍然不清楚，只有其成分之一，亲环素D（CYPD），已被认为在细胞死亡的调节中起着至关重要的作用。相反，遗传实验的结果表明，PTP C的其他主要成分，如电压依赖性阴离子通道（VDAC）和腺嘌呤核苷酸移位酶（ANT），是MPT驱动的MOMP的抑制剂。在这里，我们证明了F-O ATP合酶的c亚基是必需的MPT，线粒体碎片和细胞死亡诱导的胞浆钙超载和氧化应激在糖酵解和呼吸细胞模型。我们的研究结果有力地表明，与CYPD类似，F-O ATP合酶的c亚基构成了PTP C的关键组分。
The term "mitochondrial permeability transition" (MPT) refers to an abrupt increase in the permeability of the inner mitochondrial membrane to low molecular weight solutes. Due to osmotic forces, MPT is paralleled by a massive influx of water into the mitochondrial matrix, eventually leading to the structural collapse of the organelle. Thus, MPT can initiate mitochondrial outer membrane permeabilization (MOMP), promoting the activation of the apoptotic caspase cascade as well as of caspase-independent cell death mechanisms. MPT appears to be mediated by the opening of the so-called "permeability transition pore complex" (PTPC), a poorly characterized and versatile supramolecular entity assembled at the junctions between the inner and outer mitochondrial membranes. In spite of considerable experimental efforts, the precise molecular composition of the PTP C remains obscure and only one of its constituents, cyclophilin D (CYPD), has been ascribed with a crucial role in the regulation of cell death. Conversely, the results of genetic experiments indicate that other major components of the PTP C, such as voltage-dependent anion channel (VDAC) and adenine nucleotide translocase (ANT), are dispensable for MPT-driven MOMP. Here, we demonstrate that the c subunit of the F-O ATP synthase is required for MPT, mitochondrial fragmentation and cell death as induced by cytosolic calcium overload and oxidative stress in both glycolytic and respiratory cell models. Our results strongly suggest that, similar to CYPD, the c subunit of the F-O ATP synthase constitutes a critical component of the PTP C.