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Mitochondrial permeability transition involves dissociation of F 1 F O ATP synthase dimers and C‐ring conformation
Author(s) -
Bonora Massimo,
Morganti Claudia,
Morciano Giampaolo,
Pedriali Gaia,
LebiedzinskaArciszewska Magdalena,
Aquila Giorgio,
Giorgi Carlotta,
Rizzo Paola,
Campo Gianluca,
Ferrari Roberto,
Kroemer Guido,
Wieckowski Mariusz R,
Galluzzi Lorenzo,
Pinton Paolo
Publication year - 2017
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.15252/embr.201643602
Subject(s) - atp synthase , atp synthase gamma subunit , protein subunit , chemistry , stereochemistry , mitochondrial permeability transition pore , dissociation (chemistry) , biochemistry , enzyme , atp hydrolysis , atpase , gene , programmed cell death , apoptosis
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 F 1 F O ATP synthase (or subunits thereof) to MPT is a matter of debate. We demonstrate that F 1 F O ATP synthase dimers dissociate as the PTPC opens upon MPT induction. Stabilizing F 1 F O ATP synthase dimers by genetic approaches inhibits PTPC opening and MPT . Specific mutations in the F 1 F O ATP synthase c subunit that alter C‐ring conformation sensitize cells to MPT induction, which can be reverted by stabilizing F 1 F O ATP synthase dimers. Destabilizing F 1 F O 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 F 1 F O ATP synthase dimers and involves the C‐ring.