title: The cardioprotective compound cloxyquin uncouples mitochondria and induces autophagy.
abstract: Mitochondrial quality control mechanisms have been implicated in protection against cardiac ischemia-reperfusion (IR) injury. Previously, cloxyquin (5-chloroquinolin-8-ol) was identified via phenotypic screening as a cardioprotective compound. Herein, cloxyquin was identified as a mitochondrial uncoupler in both isolated heart mitochondria and adult cardiomyocytes. Additionally, cardiomyocytes isolated from transgenic mice expressing green fluorescent protein-tagged microtubule-associated protein light chain 3 showed increased autophagosome formation with cloxyquin treatment. The autophagy inhibitor chloroquine abolished cloxyquin-induced cardioprotection in both cellular and perfused heart (Langendorff) models of IR injury. Finally, in an in vivo murine left anterior descending coronary artery occlusion model of IR injury, cloxyquin significantly reduced infarct size from 31.4 ± 3.4% to 16.1 ± 2.2%. In conclusion, the cardioprotective compound cloxyquin simultaneously uncoupled mitochondria and induced autophagy. Importantly, autophagy appears to be required for cloxyquin-induced cardioprotection.
authors.affiliation: Department of Pharmacology and Physiology, University of Rochester Medical Center, Rochester, New York;
authors.forename: Jimmy
authors.identifier: http://orcid.org/0000-0001-7869-8005
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Anesthesiology, University of Rochester Medical Center, Rochester, New York.
authors.forename: Sergiy M
authors.initials: SM
authors.lastname: Nadtochiy
authors.affiliation: Department of Anesthesiology, University of Rochester Medical Center, Rochester, New York.
authors.forename: William R
authors.initials: WR
authors.lastname: Urciuoli
authors.affiliation: Department of Anesthesiology, University of Rochester Medical Center, Rochester, New York paul_brookes@urmc.rochester.edu.
authors.forename: Paul S
authors.initials: PS
authors.lastname: Brookes
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D002738:Chloroquine / Q000494:pharmacology; D002739:Chloroquinolinols / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D000067268:Isolated Heart Preparation; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D008929:Mitochondria, Heart / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009203:Myocardial Infarction / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D020011:Protective Agents / Q000494:pharmacology*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D013997:Time Factors; D014475:Uncoupling Agents / Q000494:pharmacology*
chemical_list: D002739:Chloroquinolinols; D008869:Microtubule-Associated Proteins; D020011:Protective Agents; D011993:Recombinant Fusion Proteins; D014475:Uncoupling Agents; D049452:Green Fluorescent Proteins; D002738:Chloroquine; C519493:cloxyquin
keywords: 8-hydroxyquinoline; heart; ischemia; mitophagy; uncoupling