Evidence for mitochondrial K+ channels and their role in cardioprotection

Abstract

Twenty years after the discovery of sarcolemmal ATP-sensitive K+ channels and 12 years after the discovery of mitochondrial K(ATP) (mitoK(ATP)) channels, progress has been remarkable, but many questions remain. In the case of the former, detailed structural information is available, and it is well accepted that the channel couples bioenergetics to cellular electrical excitability; however, in the heart, a clear physiological or pathophysiological role has yet to be defined. For mitoK(ATP), structural information is lacking, but there is abundant evidence linking the opening of the channel to protection against ischemia-reperfusion injury or apoptosis. This review updates recent progress in understanding the physiological role of mitoK(ATP) and highlights outstanding questions and controversies, with the intent of stimulating additional investigation on this topic.

Figure 1

Concentration-dependent effects of diazoxide. Diazoxide potently activates mitoK_ATP in isolated mitochondria and protects against ischemic contracture and LDH release with saturation near 50 µmol/L Diazoxide inhibits mitochondrial Ca²⁺ accumulation during simulated ischemia and oxidizes mitochondrial flavoproteins in isolated myocytes with similar potency (K_1/2 ≈25 µmol/L). All of the above effects are inhibited by K_ATP channel blockers. Depolarization of Δψ_m attributed to SDH inhibition under normoxic conditions in pancreatic islet cells occurs in the 0.1- to 1-mmol/L concentration range and is not inhibited by K_ATP channel blockers.

Figure 2

Mitigation of ischemic injury by preconditioning. Ischemic or pharmacological preconditioning diminishes accumulation of intracellular Na⁺ and Ca²⁺ ions during a long ischemia and blunts reperfusion-induced Ca²⁺ overload and ROS generation. These actions favor improved mitochondrial energy generation and suppress necrotic and apoptotic cell death.