Statin-Induced Myopathy Is Associated with Mitochondrial Complex III Inhibition.
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.
Department of Pharmacology and Toxicology, Radboud University Medical Center, Nijmegen 6500HB, the Netherlands; Center for Systems Biology and Bioenergetics, Nijmegen Center for Mitochondrial Disorders, Radboud University Medical Center, Nijmegen 6500HB, the Netherlands.
Tom J J
TJ
Schirris
Center for Systems Biology and Bioenergetics, Nijmegen Center for Mitochondrial Disorders, Radboud University Medical Center, Nijmegen 6500HB, the Netherlands; Nijmegen Center for Mitochondrial Disorders, Department of Pediatrics, Radboud University Medical Center, Nijmegen 6500HB, the Netherlands.
G Herma
GH
Renkema
Computational Discovery and Design Group, Center for Molecular and Biomolecular Informatics (CMBI), Radboud University Medical Center, Nijmegen 6500HB, the Netherlands.
Tina
T
Ritschel
Department of Neurology, Radboud University Medical Center, Nijmegen 6500HB, the Netherlands.
Nicol C
NC
Voermans
Department of Pharmacology and Toxicology, Radboud University Medical Center, Nijmegen 6500HB, the Netherlands.
Albert
A
Bilos
Department of Neurology, Radboud University Medical Center, Nijmegen 6500HB, the Netherlands.
Baziel G M
BG
van Engelen
Nijmegen Center for Mitochondrial Disorders, Department of Pediatrics, Radboud University Medical Center, Nijmegen 6500HB, the Netherlands.
Ulrich
U
Brandt
Center for Systems Biology and Bioenergetics, Nijmegen Center for Mitochondrial Disorders, Radboud University Medical Center, Nijmegen 6500HB, the Netherlands; Department of Biochemistry, Radboud University Medical Center, Nijmegen 6500HB, the Netherlands.
Werner J H
WJ
Koopman
Department of Pharmacology and Toxicology, Radboud University Medical Center, Nijmegen 6500HB, the Netherlands; Center for Systems Biology and Bioenergetics, Nijmegen Center for Mitochondrial Disorders, Radboud University Medical Center, Nijmegen 6500HB, the Netherlands.
Julien D
JD
Beyrath
Center for Systems Biology and Bioenergetics, Nijmegen Center for Mitochondrial Disorders, Radboud University Medical Center, Nijmegen 6500HB, the Netherlands; Nijmegen Center for Mitochondrial Disorders, Department of Pediatrics, Radboud University Medical Center, Nijmegen 6500HB, the Netherlands.
Richard J
RJ
Rodenburg
Center for Systems Biology and Bioenergetics, Nijmegen Center for Mitochondrial Disorders, Radboud University Medical Center, Nijmegen 6500HB, the Netherlands; Department of Biochemistry, Radboud University Medical Center, Nijmegen 6500HB, the Netherlands.
Peter H G M
PH
Willems
Center for Systems Biology and Bioenergetics, Nijmegen Center for Mitochondrial Disorders, Radboud University Medical Center, Nijmegen 6500HB, the Netherlands; Nijmegen Center for Mitochondrial Disorders, Department of Pediatrics, Radboud University Medical Center, Nijmegen 6500HB, the Netherlands. Electronic address: jan.smeitink@radboudumc.nl.
Jan A M
JA
Smeitink
Department of Pharmacology and Toxicology, Radboud University Medical Center, Nijmegen 6500HB, the Netherlands; Center for Systems Biology and Bioenergetics, Nijmegen Center for Mitochondrial Disorders, Radboud University Medical Center, Nijmegen 6500HB, the Netherlands. Electronic address: frans.russel@radboudumc.nl.
Frans G M
FG
Russel
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D019069:Cell Respiration / Q000187:drug effects; D002478:Cells, Cultured; D014450:Electron Transport Complex III / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000009:adverse effects* / Q000737:chemistry; D007783:Lactones / Q000009:adverse effects* / Q000737:chemistry; D051379:Mice; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008958:Models, Molecular; D009132:Muscles / Q000166:cytology / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009135:Muscular Diseases / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D032446:Myoblasts / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007783:Lactones; D000255:Adenosine Triphosphate; D014450:Electron Transport Complex III