Department of Medical Sciences, Section of Experimental Medicine, Laboratory for Technologies of Advanced Therapies, University of Ferrara, Ferrara, Italy.
Maria Cecilia Hospital, GVM Care & Research, Ravenna, Italy.
Nat Rev Mol Cell Biol. 2022 Apr;23(4):266-285. doi: 10.1038/s41580-021-00433-y. Epub 2021 Dec 8.
Mitochondrial permeability transition (mPT) is a phenomenon that abruptly causes the flux of low molecular weight solutes (molecular weight up to 1,500) across the generally impermeable inner mitochondrial membrane. The mPT is mediated by the so-called mitochondrial permeability transition pore (mPTP), a supramolecular entity assembled at the interface of the inner and outer mitochondrial membranes. In contrast to mitochondrial outer membrane permeabilization, which mostly activates apoptosis, mPT can trigger different cellular responses, from the physiological regulation of mitophagy to the activation of apoptosis or necrosis. Although there are several molecular candidates for the mPTP, its molecular nature remains contentious. This lack of molecular data was a significant setback that prevented mechanistic insight into the mPTP, pharmacological targeting and the generation of informative animal models. In recent years, experimental evidence has highlighted mitochondrial FF ATP synthase as a participant in mPTP formation, although a molecular model for its transition to the mPTP is still lacking. Recently, the resolution of the FF ATP synthase structure by cryogenic electron microscopy led to a model for mPTP gating. The elusive molecular nature of the mPTP is now being clarified, marking a turning point for understanding mitochondrial biology and its pathophysiological ramifications. This Review provides an up-to-date reference for the understanding of the mammalian mPTP and its cellular functions. We review current insights into the molecular mechanisms of mPT and validated observations - from studies in vivo or in artificial membranes - on mPTP activity and functions. We end with a discussion of the contribution of the mPTP to human disease. Throughout the Review, we highlight the multiple unanswered questions and, when applicable, we also provide alternative interpretations of the recent discoveries.
线粒体通透性转换（mPT）是一种现象，它会突然导致低分子量溶质（分子量高达 1500）穿过通常不可渗透的线粒体内膜。mPT 是由所谓的线粒体通透性转换孔（mPTP）介导的，mPTP 是一种在内外膜界面组装的超分子实体。与主要激活细胞凋亡的线粒体外膜通透性增加不同，mPT 可以引发不同的细胞反应，从自噬的生理调节到细胞凋亡或坏死的激活。尽管有几个分子候选物被认为与 mPTP 有关，但它的分子本质仍然存在争议。缺乏分子数据是一个重大挫折，阻碍了对 mPTP 的机制理解、药理学靶向和有信息的动物模型的产生。近年来，实验证据强调了线粒体 FF ATP 合酶作为 mPTP 形成的参与者，尽管其向 mPTP 转变的分子模型仍然缺乏。最近，低温电子显微镜解析了 FF ATP 合酶的结构，提出了 mPTP 门控的模型。mPTP 难以捉摸的分子本质现在正在被阐明，这标志着理解线粒体生物学及其病理生理后果的一个转折点。本综述为理解哺乳动物 mPTP 及其细胞功能提供了最新的参考。我们回顾了 mPT 的分子机制的最新见解以及在体内或人工膜中对 mPTP 活性和功能的验证性观察。我们以讨论 mPTP 对人类疾病的贡献结束。在整个综述中，我们强调了多个未解决的问题，并在适用的情况下，还提供了对最近发现的替代解释。
