Bonora Massimo, Morganti Claudia, Morciano Giampaolo, Pedriali Gaia, Lebiedzinska-Arciszewska Magdalena, Aquila Giorgio, Giorgi Carlotta, Rizzo Paola, Campo Gianluca, Ferrari Roberto, Kroemer Guido, Wieckowski Mariusz R, Galluzzi Lorenzo, Pinton Paolo
Department of Morphology, Surgery and Experimental Medicine, Section of General Pathology, University of Ferrara, Ferrara, Italy.
Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, Ferrara, Italy.
EMBO Rep. 2017 Jul;18(7):1077-1089. doi: 10.15252/embr.201643602. Epub 2017 May 31.
The impact of the mitochondrial permeability transition (MPT) on cellular physiology is well characterized. In contrast, the composition and mode of action of the permeability transition pore complex (PTPC), the supramolecular entity that initiates MPT, remain to be elucidated. Specifically, the precise contribution of the mitochondrial FF ATP synthase (or subunits thereof) to MPT is a matter of debate. We demonstrate that FF ATP synthase dimers dissociate as the PTPC opens upon MPT induction. Stabilizing FF ATP synthase dimers by genetic approaches inhibits PTPC opening and MPT Specific mutations in the FF ATP synthase c subunit that alter C-ring conformation sensitize cells to MPT induction, which can be reverted by stabilizing FF ATP synthase dimers. Destabilizing FF ATP synthase dimers fails to trigger PTPC opening in the presence of mutants of the c subunit that inhibit MPT The current study does not provide direct evidence that the C-ring is the long-sought pore-forming subunit of the PTPC, but reveals that PTPC opening requires the dissociation of FF ATP synthase dimers and involves the C-ring.
线粒体通透性转换（MPT）对细胞生理学的影响已得到充分表征。相比之下，作为引发MPT的超分子实体的通透性转换孔复合物（PTPC）的组成和作用方式仍有待阐明。具体而言，线粒体F₀F₁ATP合酶（或其亚基）对MPT的确切贡献存在争议。我们证明，在MPT诱导时PTPC开放时，F₀F₁ATP合酶二聚体解离。通过遗传方法稳定F₀F₁ATP合酶二聚体可抑制PTPC开放和MPT。F₀F₁ATP合酶c亚基中改变C环构象的特定突变使细胞对MPT诱导敏感，这可通过稳定F₀F₁ATP合酶二聚体来逆转。在存在抑制MPT的c亚基突变体的情况下，使F₀F₁ATP合酶二聚体不稳定未能触发PTPC开放。当前的研究没有提供直接证据表明C环是长期寻找的PTPC的成孔亚基，但揭示了PTPC开放需要F₀F₁ATP合酶二聚体的解离并且涉及C环。
