title: Restoration of Ca2+-inhibited oxidative phosphorylation in cardiac mitochondria by mitochondrial Ca2+ unloading.
abstract: Mitochondria, the major source of cellular ATP, display high vulnerability to metabolic stress, in particular to excessive Ca2+ loading. Here, we show that Ca2+-inhibited mitochondrial ATP generation could be restored through stimulated Ca2+ discharge from mitochondrial matrix. This was demonstrated using a Ca2+ ionophore or through Na+/Ca2+ exchange-mediated decrease of mitochondrial Ca2+ load. Furthermore, diazoxide, a mitochondrial potassium channel opener, which maintained mitochondrial Ca2+ homeostasis, also restored Ca2+-inhibited ATP synthesis and preserved the structural integrity of Ca2+-challenged mitochondria. Thus, under conditions of excessive mitochondrial Ca2+ overload targeting mitochondrial Ca2+ transport pathways restores oxidative phosphorylation required for vital cellular processes. This study, therefore, identifies an effective strategy capable to rescue Ca2+-disrupted mitochondrial energetics.
authors.affiliation: Department of Medicine, Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Mayo Foundation, Rochester, MN 55905, USA.
authors.forename: E L
authors.initials: EL
authors.lastname: Holmuhamedov
authors.forename: C
authors.initials: C
authors.lastname: Ozcan
authors.forename: A
authors.initials: A
authors.lastname: Jahangir
authors.forename: A
authors.initials: A
authors.lastname: Terzic
mesh_terms: D000255:Adenosine Triphosphate / Q000096:biosynthesis / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D003981:Diazoxide / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D020128:Inhibitory Concentration 50; D008854:Microscopy, Electron; D008928:Mitochondria / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism*; D010766:Phosphorylation; D015221:Potassium Channels / Q000378:metabolism; D051381:Rats; D013997:Time Factors; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D015221:Potassium Channels; D014665:Vasodilator Agents; D000255:Adenosine Triphosphate; D003981:Diazoxide; D010100:Oxygen; D002118:Calcium