title: Mitochondrial permeability transition pore induction is linked to formation of the complex of ATPase C-subunit, polyhydroxybutyrate and inorganic polyphosphate.
abstract: Mitochondrial permeability transition pore (mPTP) opening allows free movement of ions and small molecules leading to mitochondrial membrane depolarization and ATP depletion that triggers cell death. A multi-protein complex of the mitochondrial ATP synthase has an essential role in mPTP. However, the molecular identity of the central 'pore' part of mPTP complex is not known. A highly purified fraction of mammalian mitochondria containing C-subunit of ATPase (C-subunit), calcium, inorganic polyphosphate (polyP) and polyhydroxybutyrate (PHB) forms ion channels with properties that resemble the native mPTP. We demonstrate here that amount of this channel-forming complex dramatically increases in intact mitochondria during mPTP activation. This increase is inhibited by both Cyclosporine A, an inhibitor of mPTP and Ruthenium Red, an inhibitor of the Mitochondrial Calcium Uniporter. Similar increases in the amount of complex formation occurs in areas of mouse brain damaged by ischemia-reperfusion injury. These findings suggest that calcium-induced mPTP is associated withde novoassembly of a channel comprising C-subunit, polyP and PHB.
authors.affiliation: Department of Physiology and Biophysics, Faculty of Medicine, Dalhousie University , Halifax, NS, B3H 4R2 Canada.
authors.forename: P A
authors.initials: PA
authors.lastname: Elustondo
authors.affiliation: Departments of Psychiatry and Pharmacology, Brain Repair Centre, Faculty of Medicine Dalhousie University , Halifax, NS, B3H 4R2f Canada.
authors.forename: M
authors.initials: M
authors.lastname: Nichols
authors.affiliation: Department of Physiology and Biophysics, Faculty of Medicine, Dalhousie University , Halifax, NS, B3H 4R2 Canada.
authors.forename: A
authors.initials: A
authors.lastname: Negoda
authors.affiliation: Departments of Psychiatry and Pharmacology, Brain Repair Centre, Faculty of Medicine Dalhousie University , Halifax, NS, B3H 4R2f Canada.
authors.forename: A
authors.initials: A
authors.lastname: Thirumaran
authors.affiliation: Department of Cancer Biology and Pharmacology, University of Illinois College of Medicine , 1 Illini Drive, Peoria, IL 61605, USA.
authors.forename: E
authors.initials: E
authors.lastname: Zakharian
authors.affiliation: Departments of Psychiatry and Pharmacology, Brain Repair Centre, Faculty of Medicine Dalhousie University , Halifax, NS, B3H 4R2f Canada.
authors.forename: G S
authors.initials: GS
authors.lastname: Robertson
authors.affiliation: Department of Physiology and Biophysics, Faculty of Medicine, Dalhousie University, Halifax, NS, B3H 4R2 Canada; Department of Basic Sciences, New York University, College of Dentistry, 345 East 24th Street, New York, NY 10010, USA.
authors.forename: E V
authors.initials: EV
authors.lastname: Pavlov