The mitochondrial ATP-dependent potassium channel (mitoKATP) controls skeletal muscle structure and function

Abstract

MitoK_ATP is a channel of the inner mitochondrial membrane that controls mitochondrial K⁺ influx according to ATP availability. Recently, the genes encoding the pore-forming (MITOK) and the regulatory ATP-sensitive (MITOSUR) subunits of mitoK_ATP were identified, allowing the genetic manipulation of the channel. Here, we analyzed the role of mitoK_ATP in determining skeletal muscle structure and activity. Mitok^-/- muscles were characterized by mitochondrial cristae remodeling and defective oxidative metabolism, with consequent impairment of exercise performance and altered response to damaging muscle contractions. On the other hand, constitutive mitochondrial K⁺ influx by MITOK overexpression in the skeletal muscle triggered overt mitochondrial dysfunction and energy default, increased protein polyubiquitination, aberrant autophagy flux, and induction of a stress response program. MITOK overexpressing muscles were therefore severely atrophic. Thus, the proper modulation of mitoK_ATP activity is required for the maintenance of skeletal muscle homeostasis and function.