Statin-Induced Myopathy Is Associated with Mitochondrial Complex III Inhibition

被引：175

作者：

Schirris, Tom J. J. ^{[1
,2
]}

Renkema, G. Herma ^{[2
,3
]}

Ritschel, Tina ^{[4
]}

Voermans, Nicol C. ^{[5
]}

Bilos, Albert ^{[1
]}

van Engelen, Baziel G. M. ^{[5
]}

Brandt, Ulrich ^{[3
]}

Koopman, Werner J. H. ^{[2
,6
]}

Beyrath, Julien D. ^{[1
,2
]}

Rodenburg, Richard J. ^{[2
,3
]}

Willems, Peter H. G. M. ^{[2
,6
]}

Smeitink, Jan A. M. ^{[2
,3
]}

Russel, Frans G. M. ^{[1
,2
]}

机构：

[1] Radboud Univ Nijmegen, Med Ctr, Dept Pharmacol & Toxicol, NL-6500 HB Nijmegen, Netherlands

[2] Radboud Univ Nijmegen, Med Ctr, Nijmegen Ctr Mitochondrial Disorders, Ctr Syst Biol & Bioenerget, NL-6500 HB Nijmegen, Netherlands

[3] Radboud Univ Nijmegen, Med Ctr, Nijmegen Ctr Mitochondrial Disorders, Dept Pediat, NL-6500 HB Nijmegen, Netherlands

[4] Radboud Univ Nijmegen, Med Ctr, Ctr Mol & Biomol Informat, Computat Discovery & Design Grp, NL-6500 HB Nijmegen, Netherlands

[5] Radboud Univ Nijmegen, Med Ctr, Dept Neurol, NL-6500 HB Nijmegen, Netherlands

[6] Radboud Univ Nijmegen, Med Ctr, Dept Biochem, NL-6500 HB Nijmegen, Netherlands

来源：

CELL METABOLISM | 2015年 / 22卷 / 03期

关键词：

INDUCED MUSCLE TOXICITY; SKELETAL-MUSCLE; INDUCED MYOTOXICITY; RESPIRATORY-CHAIN; CELLS; RHABDOMYOLYSIS; SUSCEPTIBILITY; SIMVASTATIN; METABOLISM; CHILDHOOD;

D O I：

10.1016/j.cmet.2015.08.002

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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.

引用

页码：399 / 407

页数：9

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