Identification of an ATP-Sensitive Potassium Channel in the Inner Mitochondrial Membrane

Abstract

ATP-sensitive potassium channels (KATP) are widely distributed ion channels acting as sensors of cellular metabolism. In the plasma membrane (pmKATP) they couple cell excitability with energy availability. They are also reported to be located to intracellular membranes, in particular in mitochondria, but in this context even their existence is still a matter of debate. Here, we unambiguously identify a mitochondria-localized protein complex that mediates ATP-sensitive potassium currents, referred to as mitoKATP. We show that similarly to its plasma membrane counterpart, mitoKATP is composed of a pore-forming subunit (MITOK) and an ATP-binding subunit (MITOSUR). In vitro reconstitution of MITOK together with MITOSUR recapitulates the main electrophysiological properties and pharmacological profile of mitoKATP. Overexpression of MITOK alone causes loss of mitochondrial membrane potential (▵Ψm), decrease of mitochondrial Ca2+ uptake, organelle fragmentation and disruption of cristae, in line with an increased cation permeability of the inner mitochondrial membrane. However, the concomitant overexpression of the MITOSUR subunit restores the correct channel gating and rescues organelle injury. Conversely, MITOK ablation causes mitochondrial dysfunction characterized by instability of mitochondrial membrane potential, widening of intracristal space and decreased performance of oxidative phosphorylation. Most importantly, loss of MITOK in mice suppresses cardioprotection elicited by diazoxide-induced pharmacological preconditioning. Overall, our data indicate that the hereby-identified novel components forming mitoKATP control organelle volume, thereby representing key players in shaping mitochondrial physiology with a potential impact on several pathological processes.