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

TitleAn uncoupling channel within the c-subunit ring of the F1FO ATP synthase is the mitochondrial permeability transition pore.
Publication TypeJournal Article
Year of Publication2014
AuthorsAlavian, KN, Beutner, G, Lazrove, E, Sacchetti, S, Park, H-A, Licznerski, P, Li, H, Nabili, P, Hockensmith, K, Graham, M, Porter, GA, Jonas, EA
JournalProc Natl Acad Sci U S A
Volume111
Issue29
Pagination10580-5
Date Published2014 Jul 22
ISSN1091-6490
KeywordsAnimals, Calcium, Cell Death, HEK293 Cells, Humans, Ion Channel Gating, Ion Channels, Liposomes, Mitochondria, Mitochondrial Membrane Transport Proteins, Mitochondrial Membranes, Mutation, Protein Conformation, Protein Subunits, Proton-Translocating ATPases, Rats, Reactive Oxygen Species
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.

DOI10.1073/pnas.1401591111
Alternate JournalProc. Natl. Acad. Sci. U.S.A.
Citation Key10.1073/pnas.1401591111
PubMed ID24979777
PubMed Central IDPMC4115574
Grant ListR01 NS064967 / NS / NINDS NIH HHS / United States
R01 NS081746 / NS / NINDS NIH HHS / United States
NS064967 / NS / NINDS NIH HHS / United States
R56 NS064967 / NS / NINDS NIH HHS / United States
R37 NS045876 / NS / NINDS NIH HHS / United States