Statin-Induced Myopathy Is Associated with Mitochondrial Complex III Inhibition

Highlights

• Most statin lactones are more potent complex III inhibitors than their acid forms

• The Q_o site of complex III was identified as off-target of statin lactones

• Mitochondrial complex III activity is lowered in statin-induced myopathy patients

• Inhibition could be attenuated by convergent electron flow into complex III

Summary

Cholesterol-lowering statins effectively reduce the risk of major cardiovascular events. Myopathy is the most important adverse effect, but its underlying mechanism remains enigmatic. In C2C12 myoblasts, several statin lactones reduced respiratory capacity and appeared to be strong inhibitors of mitochondrial complex III (CIII) activity, up to 84% inhibition. The lactones were in general three times more potent inducers of cytotoxicity than their corresponding acid forms. The Q_o binding site of CIII was identified as off-target of the statin lactones. These findings could be confirmed in muscle tissue of patients suffering from statin-induced myopathies, in which CIII enzyme activity was reduced by 18%. Respiratory inhibition in C2C12 myoblasts could be attenuated by convergent electron flow into CIII, restoring respiration up to 89% of control. In conclusion, CIII inhibition was identified as a potential off-target mechanism associated with statin-induced myopathies.