Schirris 2015 Cell Metab
|Schirris TJ, Renkema GH, Ritschel T, Voermans NC, Bilos A, van Engelen BG, Brandt U, Koopman WJ, Beyrath JD, Rodenburg RJ, Willems PH, Smeitink JA, Russel FG (2015) Statin-induced myopathy is associated with mitochondrial complex III inhibition. Cell Metab 22:399-407.|
Abstract: 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 Qo 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.
• Keywords: C2C12 myoblasts
Labels: MiParea: Respiration, Patients, Pharmacology;toxicology Pathology: Myopathy
Organism: Human, Mouse Tissue;cell: Skeletal muscle, Other cell lines Preparation: Permeabilized cells Enzyme: Complex III, Complex V;ATP synthase
Coupling state: ROUTINE, OXPHOS, ET Pathway: N, S, Gp, CIV, NS, ROX HRR: Oxygraph-2k