title: An uncoupling channel within the c-subunit ring of the F1FO ATP synthase is the mitochondrial permeability transition pore.
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.
authors: 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;
authors: Kambiz N
authors: KN
authors: Alavian
authors: Departments of Pediatrics (Cardiology).
authors: Gisela
authors: G
authors: Beutner
authors: Section of Endocrinology, Department of Internal Medicine, Yale University, New Haven, CT 06520-8020;
authors: Emma
authors: E
authors: Lazrove
authors: Section of Endocrinology, Department of Internal Medicine, Yale University, New Haven, CT 06520-8020;
authors: Silvio
authors: S
authors: Sacchetti
authors: Section of Endocrinology, Department of Internal Medicine, Yale University, New Haven, CT 06520-8020;
authors: Han-A
authors: HA
authors: Park
authors: Section of Endocrinology, Department of Internal Medicine, Yale University, New Haven, CT 06520-8020;
authors: Pawel
authors: P
authors: Licznerski
authors: Section of Endocrinology, Department of Internal Medicine, Yale University, New Haven, CT 06520-8020;
authors: Hongmei
authors: H
authors: Li
authors: Section of Endocrinology, Department of Internal Medicine, Yale University, New Haven, CT 06520-8020;
authors: Panah
authors: P
authors: Nabili
authors: Departments of Pediatrics (Cardiology).
authors: Kathryn
authors: K
authors: Hockensmith
authors: Department of Cell Biology, Yale University, New Haven, CT 06520-8002.
authors: Morven
authors: M
authors: Graham
authors: Departments of Pediatrics (Cardiology),Internal Medicine (Aab Cardiovascular Research Institute), andPharmacology and Physiology, University of Rochester Medical Center, Rochester, NY 14642; and.
authors: George A
authors: http://orcid.org/0000-0003-0726-9988
authors: GA
authors: Porter
authors: Section of Endocrinology, Department of Internal Medicine, Yale University, New Haven, CT 06520-8020; elizabeth.jonas@yale.edu.
authors: Elizabeth A
authors: EA
authors: Jonas
mesh_terms: D000818:Animals; D002118:Calcium / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects; D007473:Ion Channels / Q000378:metabolism*; D008081:Liposomes / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D033681:Mitochondrial Membrane Transport Proteins / Q000737:chemistry / Q000378:metabolism*; D051336:Mitochondrial Membranes / Q000187:drug effects / Q000378:metabolism; D000083162:Mitochondrial Permeability Transition Pore; D009154:Mutation / Q000235:genetics; D011487:Protein Conformation; D021122:Protein Subunits / Q000378:metabolism*; D006180:Proton-Translocating ATPases / Q000737:chemistry / Q000378:metabolism*; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D007473:Ion Channels; D008081:Liposomes; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D021122:Protein Subunits; D017382:Reactive Oxygen Species; D006180:Proton-Translocating ATPases; D002118:Calcium
keywords: apoptosis; excitotoxicity; ion channel; metabolism; necrosis