title: Increased calcium vulnerability of senescent cardiac mitochondria: protective role for a mitochondrial potassium channel opener.
abstract: In senescence, endogenous mechanisms of cardioprotection are apparently attenuated resulting in increased vulnerability to ischemia-reperfusion. In particular, mitochondria, which are essential in maintaining cardiac energetic and ionic homeostasis, are susceptible to Ca2+ overload, a component of metabolic injury. However, effective means of protecting senescent mitochondria are lacking. Here, mitochondrial function and structure were assessed using ion-selective mini-electrodes, high-performance liquid chromatography and electron microscopy. Aging decreased ADP-induced oxygen consumption and prolonged the time associated with ADP to ATP conversion, which manifested as a reduced rate of oxidative phosphorylation. Aging also reduced mitochondrial Ca2+ handling, and increased Ca2+-induced mitochondrial damage. Diazoxide, a potassium channel opener, reduced Ca2+ loading and protected the functional and structural integrity of senescent mitochondria from Ca2+-induced injury. In this way, the present study identifies the potential usefulness for pharmacotherapy in protecting vulnerable senescent mitochondria from conditions of Ca2+ overload, such as ischemia-reperfusion.
authors.affiliation: Division of Cardiovascular Diseases, Departments of Medicine, Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Mayo Foundation, Guggenheim 7, Rochester, MN 55905, USA.
authors.forename: A
authors.initials: A
authors.lastname: Jahangir
authors.forename: C
authors.initials: C
authors.lastname: Ozcan
authors.forename: E L
authors.initials: EL
authors.lastname: Holmuhamedov
authors.forename: A
authors.initials: A
authors.lastname: Terzic
mesh_terms: D000375:Aging; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D003981:Diazoxide; D015640:Ion Channel Gating; D008929:Mitochondria, Heart / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism*; D010084:Oxidation-Reduction; D010766:Phosphorylation; D015221:Potassium Channels / Q000378:metabolism*; D051381:Rats; D011916:Rats, Inbred F344
chemical_list: D015221:Potassium Channels; D003981:Diazoxide; D002118:Calcium