Statin Side Effects Linked to Off-Target Reaction in Muscle Mitochondria

1/9/15 - In Cell Metabolism on September 1, NCMD researchers show, in mice and humans, that statins yield an off-target reaction that disrupts muscle mitochondria function, possibly causing the side-effects.
 
Cholesterol-lowering statins effectively reduce the risk of major cardiovascular events. Myopathy is the most important adverse effect, but its underlying mechanism remains enigmatic. Statins exist in the body in two chemical forms, acid and lactone. Most statins are administered in their pharmacological active acid form, which slows down the production of cholesterol in the liver. The acid form can turn into the lactone form within the body, but the lactone form has no therapeutic effect.
 
In the latest Cell Metabolism issue Tom Schirris (photo left), Jan Smeitink (photo middle) and Frans Russel (photo right), Departments of Pharmacology and Toxicology and Pediatrics, mitochondrial diseases theme, found together with other colleagues that lactones can unintentionally interfere with the cellular respiratory capacity and appeared to be strong inhibitors of mitochondrial complex III activity. The Qo binding site of complex III 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 complex III enzyme activity was reduced. Respiratory inhibition in C2C12 myoblasts could be attenuated by convergent electron flow into complex III.
 
These results lead to several opportunities to synthesize new classes of cholesterol-lowering drugs without the unwanted muscle effects, as well as the development of new avenues to counteract these effects, both of which are currently investigated by the authors. Additionally, this study warrants for further independent studies to indicate the usefulness of complex III activity as a predictive marker for statin-induced myopathies and to investigate whether inter-individual differences in the enzymatic conversion of the acid into the lactone form could be an explanation for the differences between patients in susceptibility for statin-induced muscle pain.
 
Authors_CellMetab_0915
Authors (from left to right): Tom Schirris, Prof Jan Smeitink, Prof Frans Russel.
 
Reference:
 
Tom J.J. Schirris, G. Herma Renkema, Tina Ritschel, Nicol C. Voermans, Albert Bilos, Baziel G.M. van Engelen, Ulrich Brandt, Werner J.H. Koopman, Julien D. Beyrath, Richard J. Rodenburg, Peter H.G.M. Willems, Jan A.M. Smeitink, and Frans G.M. Russel, Statin-Induced Myopathy Is Associated with Mitochondrial Complex III Inhibition, Cell Metabolism (2015)
 
Read more in the full press release.
 

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