Mitochondrial permeability transition involves dissociation of F1FO ATP synthase dimers and C‐ring conformation. (31st May 2017)

• Record Type: Journal Article
• Authors: 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
• Is Part Of: EMBO reports. Volume 18:Number 7(2017)
• Page Start: 1077
• Page End: 1089
• Publication Date: 2017-05-31
• Subjects: ATP synthasome -- ATP5G1 -- cyclosporine A -- CYPD -- regulated necrosis; Molecular biology -- Periodicals; Molecular Biology -- Periodicals; Molecular biology; Periodicals; 572.8
• DOI: 10.15252/embr.201643602
• Languages: English
• ISSNs: 1469-221X

Abstract

Abstract: 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 F1 FO ATP synthase (or subunits thereof) to MPT is a matter of debate. We demonstrate that F1 FO ATP synthase dimers dissociate as the PTPC opens upon MPT induction. Stabilizing F1 FO ATP synthase dimers by genetic approaches inhibits PTPC opening and MPT. Specific mutations in the F1 FO ATP synthase c subunit that alter C‐ring conformation sensitize cells to MPT induction, which can be reverted by stabilizing F1 FO ATP synthase dimers. Destabilizing F1 FO 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 F1 FO ATP synthase dimers and involves the C‐ring. Synopsis: F1 FO ATP synthase dimer dissociation plays a crucial role in MPT and allows PTPC opening. In the same context, c subunit‐specific mutations altering the C‐ring conformation prime cells for MPT induction. MPT is linked with dissociation of F1 FO ATP synthase dimers and their stabilization by ATPIF1 or ATP5I overexpression inhibits PTPC opening. The glycine zipper domain of the c subunit plays a central role in the MPT process as specific mutations promoting conformational changes in the C‐ring structure affect PTPC opening. A proper C‐ring conformation is required for MPT induction once F1 FO ATP synthase dimers have dissociated. Abstract : F1 FO ATP synthase dimer dissociation plays a crucial role in MPT and allows PTPC opening. In the same context, c subunit‐specific mutations altering the C‐ring conformation prime cells for MPT induction.