title: Mitochondrial Ca2+and regulation of the permeability transition pore.
abstract: The mitochondrial permeability transition pore was originally described in the 1970's as a Ca2+activated pore and has since been attributed to the pathogenesis of many diseases. Here we evaluate how each of the current models of the pore complex fit to what is known about how Ca2+regulates the pore, and any insight that provides into the molecular identity of the pore complex. We also discuss the central role of Ca2+in modulating the pore's open probability by directly regulating processes, such as ATP/ADP balance through the tricarboxylic acid cycle, electron transport chain, and mitochondrial membrane potential. We review how Ca2+influences second messengers such as reactive oxygen/nitrogen species production and polyphosphate formation. We discuss the evidence for how Ca2+regulates post-translational modification of cyclophilin D including phosphorylation by glycogen synthase kinase 3 beta, deacetylation by sirtuins, and oxidation/ nitrosylation of key residues. Lastly we introduce a novel view into how Ca2+activated proteolysis through calpains in the mitochondria may be a driver of sustained pore opening during pathologies such as ischemia reperfusion injury.
authors: Center for Translational Medicine, Department of Medicine, Sidney Kimmel Medical College, Thomas Jefferson University, 1020 Locust Street, Suite 543D, Philadelphia, PA, 19107, USA.
authors: Stephen
authors: S
authors: Hurst
authors: Mitocare Center for Mitochondria Research, Department of Pathology Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA, 19107, USA.
authors: Jan
authors: J
authors: Hoek
authors: Center for Translational Medicine, Department of Medicine, Sidney Kimmel Medical College, Thomas Jefferson University, 1020 Locust Street, Suite 543D, Philadelphia, PA, 19107, USA. shey-shing.sheu@jefferson.edu.
authors: Shey-Shing
authors: SS
authors: Sheu
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D000081406:Peptidyl-Prolyl Isomerase F; D021983:Cyclophilins / Q000378:metabolism; D006801:Humans; D053078:Membrane Potential, Mitochondrial; D008929:Mitochondria, Heart; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism*; D000083162:Mitochondrial Permeability Transition Pore; D059748:Proteolysis; D017382:Reactive Oxygen Species / Q000378:metabolism; D015427:Reperfusion Injury
chemical_list: D000081406:Peptidyl-Prolyl Isomerase F; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D017382:Reactive Oxygen Species; D021983:Cyclophilins; D002118:Calcium
keywords: Calcium; Calpain; Cyclophilin D; Glycogen synthase kinase 3 Beta; Mitochondrial permeability transition pore; Reactive oxygen species