Increased calcium vulnerability of senescent cardiac mitochondria: Protective role for a mitochondrial potassium channel opener

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.