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EMBO Rep. 2017 Jul;18(7):1077-1089. doi: 10.15252/embr.201643602. Epub 2017 May 31.

Mitochondrial permeability transition involves dissociation of F1FO ATP synthase dimers and C-ring conformation.

Author information

1
Department of Morphology, Surgery and Experimental Medicine, Section of General Pathology, University of Ferrara, Ferrara, Italy.
2
Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, Ferrara, Italy.
3
Department of Biochemistry, Nencki Institute of Experimental Biology, Warsaw, Poland.
4
Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy.
5
Cardiovascular Institute, University of Ferrara, Ferrara, Italy.
6
Université Paris Descartes/Paris V, Paris, France.
7
Université Pierre et Marie Curie/Paris VI, Paris, France.
8
INSERM, U1138, Paris, France.
9
Equipe 11 labellisée par la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, Paris, France.
10
Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, Paris, France.
11
Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Campus, Villejuif, France.
12
Department of Women's and Children's Health, Karolinska University Hospital, Stockholm, Sweden.
13
Department of Biochemistry, Nencki Institute of Experimental Biology, Warsaw, Poland m.wieckowski@nencki.gov.pl deadoc@vodafone.it paolo.pinton@unife.it.
14
Université Paris Descartes/Paris V, Paris, France m.wieckowski@nencki.gov.pl deadoc@vodafone.it paolo.pinton@unife.it.
15
Department of Radiation Oncology, Weill Cornell Medical College, New York, NY, USA.
16
Department of Morphology, Surgery and Experimental Medicine, Section of General Pathology, University of Ferrara, Ferrara, Italy m.wieckowski@nencki.gov.pl deadoc@vodafone.it paolo.pinton@unife.it.

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 F1FO ATP synthase (or subunits thereof) to MPT is a matter of debate. We demonstrate that F1FO ATP synthase dimers dissociate as the PTPC opens upon MPT induction. Stabilizing F1FO ATP synthase dimers by genetic approaches inhibits PTPC opening and MPT Specific mutations in the F1FO ATP synthase c subunit that alter C-ring conformation sensitize cells to MPT induction, which can be reverted by stabilizing F1FO ATP synthase dimers. Destabilizing F1FO 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 F1FO ATP synthase dimers and involves the C-ring.

KEYWORDS:

CYPD ; ATP synthasome; ATP5G1; cyclosporine A; regulated necrosis

PMID:
28566520
PMCID:
PMC5494524
DOI:
10.15252/embr.201643602
[Indexed for MEDLINE]
Free PMC Article

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