Restoration of CA2+-inhibited oxidative phosphorylation in cardiac mitochondria by mitochondrial Ca2+ unloading |
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Authors: | Holmuhamedov Ekhson L Ozcan Cevher Jahangir Arshad Terzic Andre |
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Institution: | (1) Division of Cardiovascular Diseases, Departments of Medicine, Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Mayo Foundation, Guggenheim 7, Rochester, MN 55905, USA |
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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. |
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Keywords: | ATP mitochondria Ca& 2+ overload diazoxide cardioprotection bioenergetics potassium channel opener |
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