title: Knockout of cyclophilin D in Ppif⁻/⁻ mice increases stability of brain mitochondria against Ca²⁺ stress.
abstract: The mitochondrial peptidyl prolyl isomerase cyclophilin D (CypD) activates permeability transition (PT). To study the role of CypD in this process we compared the functions of brain mitochondria isolated from wild type (BMWT) and CypD knockout (Ppif(-/-)) mice (BMKO) with and without CypD inhibitor Cyclosporin A (CsA) under normal and Ca(2+) stress conditions. Our data demonstrate that BMKO are characterized by higher rates of glutamate/malate-dependent oxidative phosphorylation, higher membrane potential and higher resistance to detrimental Ca(2+) effects than BMWT. Under the elevated Ca(2+) and correspondingly decreased membrane potential the dose response in BMKO shifts to higher Ca(2+) concentrations as compared to BMWT. However, significantly high Ca(2+) levels result in complete loss of membrane potential in BMKO, too. CsA diminishes the loss of membrane potential in BMWT but has no protecting effect in BMKO. The results are in line with the assumption that PT is regulated by CypD under the control of matrix Ca(2+). Due to missing of CypD the BMKO can favor PT only at high Ca(2+) concentrations. It is concluded that CypD sensitizes the brain mitochondria to PT, and its inhibition by CsA or CypD absence improves the complex I-related mitochondrial function and increases mitochondria stability against Ca(2+) stress.
authors.affiliation: Department of Neurology, Otto-von-Guericke-University, Magdeburg D-39120, Germany; Institute of Ecology and Use of Mineral Resources, Academy of Sciences of Tatarstan, Kazan 420087, Russian Federation.
authors.forename: T
authors.initials: T
authors.lastname: Gainutdinov
authors.affiliation: Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Howard Hughes Medical Institute, Cincinnati, OH 45229, USA.
authors.forename: J D
authors.initials: JD
authors.lastname: Molkentin
authors.affiliation: Department of Neurology, Otto-von-Guericke-University, Magdeburg D-39120, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Siemen
authors.affiliation: Department of Neurology, Otto-von-Guericke-University, Magdeburg D-39120, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Ziemer
authors.affiliation: Department of Neurology, Otto-von-Guericke-University, Magdeburg D-39120, Germany.
authors.forename: G
authors.initials: G
authors.lastname: Debska-Vielhaber
authors.affiliation: Department of Neurology, Otto-von-Guericke-University, Magdeburg D-39120, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Vielhaber
authors.affiliation: Leibniz Institute for Neurobiology, Brennecke Str. 6, Magdeburg D-39118, Germany.
authors.forename: Z
authors.initials: Z
authors.lastname: Gizatullina
authors.affiliation: Department of Surgery, Drexel University College of Medicine, Philadelphia, PA 19102, USA. Electronic address: zorynbay@drexelmed.edu.
authors.forename: Z
authors.initials: Z
authors.lastname: Orynbayeva
authors.affiliation: Department of Neurology, Otto-von-Guericke-University, Magdeburg D-39120, Germany; Leibniz Institute for Neurobiology, Brennecke Str. 6, Magdeburg D-39118, Germany. Electronic address: frank.gellerich@med.ovgu.de.
authors.forename: F N
authors.initials: FN
authors.lastname: Gellerich
mesh_terms: D000818:Animals; D001921:Brain / Q000502:physiology*; D002118:Calcium / Q000378:metabolism*; D019069:Cell Respiration / Q000502:physiology; D002478:Cells, Cultured; D000081406:Peptidyl-Prolyl Isomerase F; D021983:Cyclophilins / Q000235:genetics / Q000378:metabolism*; D042967:Electron Transport Complex I / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008928:Mitochondria / Q000502:physiology*; D018384:Oxidative Stress / Q000502:physiology*; D010100:Oxygen / Q000378:metabolism*
chemical_list: D000081406:Peptidyl-Prolyl Isomerase F; C000631446:PPIF protein, mouse; D021983:Cyclophilins; D042967:Electron Transport Complex I; D010100:Oxygen; D002118:Calcium
keywords: Brain mitochondria; Ca(2+) stress; Complex I respiration; Cyclophilin D; Cyclosporin A; Glutamate; Mitochondrial permeability transition