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Proc Natl Acad Sci U S A. 2014 Jul 22;111(29):10580-5. doi: 10.1073/pnas.1401591111. Epub 2014 Jun 16.

An uncoupling channel within the c-subunit ring of the F1FO ATP synthase is the mitochondrial permeability transition pore.

Author information

1
Section of Endocrinology, Department of Internal Medicine, Yale University, New Haven, CT 06520-8020;Division of Brain Sciences, Department of Medicine, Imperial College London, London W12 0NN, United Kingdom;
2
Departments of Pediatrics (Cardiology).
3
Section of Endocrinology, Department of Internal Medicine, Yale University, New Haven, CT 06520-8020;
4
Department of Cell Biology, Yale University, New Haven, CT 06520-8002.
5
Departments of Pediatrics (Cardiology),Internal Medicine (Aab Cardiovascular Research Institute), andPharmacology and Physiology, University of Rochester Medical Center, Rochester, NY 14642; and.
6
Section of Endocrinology, Department of Internal Medicine, Yale University, New Haven, CT 06520-8020; elizabeth.jonas@yale.edu.

Abstract

Mitochondria maintain tight regulation of inner mitochondrial membrane (IMM) permeability to sustain ATP production. Stressful events cause cellular calcium (Ca(2+)) dysregulation followed by rapid loss of IMM potential known as permeability transition (PT), which produces osmotic shifts, metabolic dysfunction, and cell death. The molecular identity of the mitochondrial PT pore (mPTP) was previously unknown. We show that the purified reconstituted c-subunit ring of the FO of the F1FO ATP synthase forms a voltage-sensitive channel, the persistent opening of which leads to rapid and uncontrolled depolarization of the IMM in cells. Prolonged high matrix Ca(2+) enlarges the c-subunit ring and unhooks it from cyclophilin D/cyclosporine A binding sites in the ATP synthase F1, providing a mechanism for mPTP opening. In contrast, recombinant F1 beta-subunit applied exogenously to the purified c-subunit enhances the probability of pore closure. Depletion of the c-subunit attenuates Ca(2+)-induced IMM depolarization and inhibits Ca(2+) and reactive oxygen species-induced cell death whereas increasing the expression or single-channel conductance of the c-subunit sensitizes to death. We conclude that a highly regulated c-subunit leak channel is a candidate for the mPTP. Beyond cell death, these findings also imply that increasing the probability of c-subunit channel closure in a healthy cell will enhance IMM coupling and increase cellular metabolic efficiency.

KEYWORDS:

apoptosis; excitotoxicity; ion channel; metabolism; necrosis

PMID:
24979777
PMCID:
PMC4115574
DOI:
10.1073/pnas.1401591111
[Indexed for MEDLINE]
Free PMC Article

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