Susceptibility to simvastatin-induced toxicity is partly determined by mitochondrial respiration and phosphorylation state of Akt

► Statin-induced myotoxicity is a major side-effect. ► Impairment of mitochondrial respiration is one sign of sensitivity to statins. ► Phosphorylation of Akt is reduced by simvastatin treatment in sensitive cells. ► Inhibiting Akt causes mitochondrial dysfunction and non-sensitive HepG2 cells. ► Rap1 could link statins to mitochondrial dysfunction.