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Recently, the genes encoding the pore-forming (MITOK) and the regulatory ATP-sensitive (MITOSUR) subunits of mitoK<jats:sub>ATP<\/jats:sub> were identified, allowing the genetic manipulation of the channel. Here, we analyzed the role of mitoK<jats:sub>ATP<\/jats:sub> in determining skeletal muscle structure and activity. <jats:italic>Mitok<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> 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<jats:sup>+<\/jats:sup> 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. 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