The Slo(w) path to identifying the mitochondrial channels responsible for ischemic protection

Mitochondria play an important role in tissue ischemia and reperfusion (IR) injury, with energetic failure and the opening of the mitochondrial permeability transition pore being the major causes of IR-induced cell death. Thus, mitochondria are an appropriate focus for strategies to protect against IR injury. Two widely studied paradigms of IR protection, particularly in the field of cardiac IR, are ischemic preconditioning (IPC) and volatile anesthetic preconditioning (APC). While the molecular mechanisms recruited by these protective paradigms are not fully elucidated, a commonality is the involvement of mitochondrial K⁺ channel opening. In the case of IPC, research has focused on a mitochondrial ATP-sensitive K⁺ channel (mitoK_ATP), but, despite recent progress, the molecular identity of this channel remains a subject of contention. In the case of APC, early research suggested the existence of a mitochondrial large-conductance K⁺ (BK, big conductance of potassium) channel encoded by the Kcnma1 gene, although more recent work has shown that the channel that underlies APC is in fact encoded by Kcnt2 In this review, we discuss both the pharmacologic and genetic evidence for the existence and identity of mitochondrial K⁺ channels, and the role of these channels both in IR protection and in regulating normal mitochondrial function.