Statin-Induced Myopathy Is Associated with Mitochondrial Complex III Inhibition

Cell Metabolism
Tom J J SchirrisFrans G M Russel

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.

References

Jan 1, 1994·Critical Reviews in Biochemistry and Molecular Biology·U Brandt, B Trumpower
Jul 1, 1997·Journal of the Neurological Sciences·J MourmansW Ruitenbeek
Dec 11, 1999·Nucleic Acids Research·H M BermanP E Bourne
Apr 16, 2002·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Thomayant PrueksaritanontThomas A Baillie
Dec 23, 2004·Journal of Thrombosis and Haemostasis : JTH·A ArduiniP Carminati
May 4, 2006·Muscle & Nerve·Georgirene D VladutiuPaul S Phillips
Mar 3, 2007·Clinical Chemistry·Antoon J M JanssenRichard J T Rodenburg
Jun 15, 2007·Lancet·Jane Armitage
Nov 10, 2007·The Journal of Clinical Investigation·Jun-ichi HanaiStewart H Lecker
Feb 5, 2008·Current Opinion in Pharmacology·Pascal SirventAlain Lacampagne
Feb 26, 2008·European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences·Ine Blankenberg SkottheimAnders Asberg
Jun 10, 2008·Nature Protocols·Andrey V KuznetsovWolfram S Kunz
Jul 25, 2008·The New England Journal of Medicine·UNKNOWN SEARCH Collaborative GroupR Collins
Nov 11, 2008·Bioorganic & Medicinal Chemistry·Patrick J CrowleyRussell Viner
May 27, 2009·The International Journal of Biochemistry & Cell Biology·Erich Gnaiger
May 5, 2010·Journal of Inherited Metabolic Disease·Richard J T Rodenburg
Feb 24, 2011·Expert Opinion on Drug Safety·Thura T Abd, Terry A Jacobson
Jan 25, 2012·Toxicology and Applied Pharmacology·P SirventJ Mercier
Jul 27, 2012·Journal of Chemical Information and Modeling·David J WoodTina Ritschel
Nov 28, 2012·Circulation·Beth A ParkerPaul D Thompson
Nov 30, 2012·Expert Review of Cardiovascular Therapy·James J DiNicolantonio
Apr 13, 2013·Molecular Diagnosis & Therapy·Camilla StormoMarianne K Kringen
Nov 2, 2013·Neuromuscular Disorders : NMD·M Needham, F L Mastaglia
Dec 10, 2013·Cell Metabolism·Kevin D Ballard, Paul D Thompson
Jan 16, 2014·Chemical Research in Toxicology·Junguk HurJane P F Bai
Feb 18, 2014·Translational Research : the Journal of Laboratory and Clinical Medicine·Dhiaa A TahaPavel Gershkovich
May 2, 2014·European Journal of Human Genetics : EJHG·G Herma RenkemaRichard J T Rodenburg
Jun 5, 2014·Clinical Pharmacology and Therapeutics·A AlfirevicM Pirmohamed
Sep 19, 2014·Nature·James S FloydBruce M Psaty

❮ Previous
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Citations

Jan 1, 2016·Lipids in Health and Disease·Maciej BanachAdrian Covic
Mar 20, 2016·Drug Safety : an International Journal of Medical Toxicology and Drug Experience·Iain P HargreavesSimon J R Heales
Apr 17, 2016·Translational Research : the Journal of Laboratory and Clinical Medicine·Dhiaa A TahaPavel Gershkovich
Apr 14, 2016·British Journal of Clinical Pharmacology·Corine EkhartFlorence van Hunsel
Dec 10, 2016·PloS One·Hae R ChungMarni D Boppart
Jan 21, 2017·European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences·Dhiaa A TahaPavel Gershkovich
Oct 14, 2017·American Journal of Cardiovascular Drugs : Drugs, Devices, and Other Interventions·Beth A Taylor
Sep 25, 2017·Clinical Pharmacology and Therapeutics·Nur Salwani BakarFarhad Kamali
Jan 20, 2018·Muscle & Nerve·Alba Ramos-FransiJaume Coll-Cantí
Jan 10, 2019·Cells·Helena XicoyGerard J M Martens
Jan 18, 2019·Circulation Research·Natalie C WardRobert H Eckel
Oct 19, 2017·The Journal of Clinical Endocrinology and Metabolism·Neeltje A E AllardSilvie Timmers
Apr 27, 2018·The Journal of Pharmacology and Experimental Therapeutics·Young LeeJaipal Singh
Mar 10, 2016·EMBO Molecular Medicine·Werner Jh KoopmanJan Am Smeitink
Dec 1, 2017·Journal of Muscle Research and Cell Motility·Jessica Pingel, Frank Suhr
Sep 20, 2019·Biomolecules·Maurizio Balestrino, Enrico Adriano
Aug 3, 2016·Clinical Medicine : Journal of the Royal College of Physicians of London·Anthony S Wierzbicki, Paul Grant
Oct 13, 2019·Acta Physiologica·Miljenko Valentin PanajatovicJamal Bouitbir
Dec 22, 2019·Journal of Clinical Medicine·Richard Myles Turner, Munir Pirmohamed
Feb 8, 2020·Journal of Inherited Metabolic Disease·Maaike C De VriesMichelangelo Mancuso
Feb 8, 2020·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Jessica HoppstädterAlexandra K Kiemer
Apr 30, 2019·Scandinavian Cardiovascular Journal : SCJ·John MunkhaugenEinar Husebye
Sep 8, 2019·Molecular Neurobiology·Helena XicoyGerard J M Martens
Apr 3, 2020·Expert Opinion on Drug Safety·Dragana NikolicManfredi Rizzo
Aug 29, 2019·Journal of Translational Medicine·Estela Lorza-GilHelena C F Oliveira
Aug 26, 2020·JCI Insight·Terence E RyanJoseph M McClung
Nov 2, 2016·Journal of Cell Science·Dania C Liemburg-ApersWerner J H Koopman
Aug 2, 2017·Journal of Clinical Medicine·Radha Ramachandran, Anthony S Wierzbicki
Dec 27, 2017·British Journal of Pharmacology·Elisa VenturiRebecca Sitsapesan
Jun 29, 2018·Oxidative Medicine and Cellular Longevity·Anna JaśkiewiczArkadiusz Orzechowski
Dec 5, 2018·Archives of Toxicology·François SinghJamal Bouitbir
Apr 6, 2019·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Charleston F ChristieEduardo N Maldonado
Nov 22, 2019·Physiological Reviews·Lando JanssenSilvie Timmers
Aug 14, 2020·Physiology·Benjamin F Miller, John P Thyfault

❮ Previous
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