Molecular mechanisms and consequences of mitochondrial permeability transition

Mitochondrial permeability transition - mediated by the opening of the so-called mitochondrial permeability transition pore - causes abrupt flux of low molecular weight solutes across the generally impermeable inner mitochondrial membrane. Recent studies provide new insights into the molecular nature and mechanisms of the mitochondrial permeability transition pore and the physiological consequences of its opening. 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 F1Fo 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 F1Fo 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.

Automated summary

Mitochondrial permeability transition, mediated by the opening of the mitochondrial permeability transition pore, causes flux of low molecular weight solutes across the inner mitochondrial membrane, triggering various cellular responses. Recent studies have shed light on the molecular nature and mechanisms of the mitochondrial permeability transition pore, paving the way for understanding mitochondrial biology and its pathophysiological consequences.