The cardioprotective compound cloxyquin uncouples mitochondria and induces autophagy
Open accessAbstract
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.
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Cloxyquin protects mouse cardiomyocytes against ischemia-reperfusion, an effect requiring autophagy.
“Indeed, the mitochondrial uncoupler cloxyquin (5-chloro-8-hydroxyquinoline) protects mouse cardiomyocytes against ischemia-reperfusion, an effect requiring autophagy [99].”
From Mitochondrial Uncoupling: A Key Controller of Biological Processes in Physiology and Diseases (2019) · cites this paper as [99]
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Klionsky, D. J., Abdel-Aziz, A. K., Abdelfatah, S., Abdellatif, M., Abdoli, A., Abel, S., Abeliovich, H., Abildgaard, M. H., Abudu, Y. P., Acevedo-Arozena, A., et al. (2021) · Autophagy · doi:10.1080/15548627.2020.1797280 · Cited by 2,622 · see citing works
Self-citationMitochondrial Uncoupling: A Key Controller of Biological Processes in Physiology and Diseases
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“Mechanistically, mitochondrial uncoupling induced by cloxyquin is accompanied by an increase in macroautophagy characterized by an increase in LC3-II abundance and in autophagosome number [99].”
BackgroundInfluentialAccumulation of Succinate in Cardiac Ischemia Primarily Occurs via Canonical Krebs Cycle Activity
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Self-citation
- Authors
- Zhang, J., Nadtochiy, S. M., Urciuoli, W. R., & Brookes, P. S.
- Affiliations
- University of Rochester Medicine (US)
- Corresponding author
- Brookes, Paul S.
- Venue
- American Journal of Physiology-Heart and Circulatory Physiology
- Publisher
- American Physiological Society
- Published
- 2016-01-01
- Volume
- 310
- Issue
- 1
- Pages
- H29-H38
- ISSN
- 0363-6135 (ISSN-L)
- 1522-1539
- PMC
- PMC4796459
- OpenAlex
- W2269587458
- Cited by
- 36
- References
- 50
- Citations by year
- 2026: 4 · 2025: 1 · 2024: 2 · 2023: 4 · 2022: 5 · 2021: 2 · 2020: 3 · 2019: 5 · 2018: 1 · 2017: 5 · 2016: 4
- FWCI
- 2.65
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- American Journal of Physiology-Heart and Circulatory Physiology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- HHS | National Institutes of Health (NIH) (R01 HL-071158, T32GM007356)
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Cardiac Ischemia and Reperfusion
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Keywords
- mitochondrial uncoupling, autophagy, cardioprotection, myocardial ischemia-reperfusion injury, chloroquine, cardiomyocytes, mitochondrial quality control, infarct size, coronary artery occlusion, LC3
- MeSH terms
- Isolated Heart Preparation, Animals, Autophagy, Chloroquine, Chloroquinolinols, Dose-Response Relationship, Drug, Male, Mice, Inbred C57BL, Mice, Transgenic, Microtubule-Associated Proteins, Mitochondria, Heart, Myocardial Infarction, Recombinant Fusion Proteins, Time Factors, Uncoupling Agents, Myocardial Reperfusion Injury, Protective Agents, Myocytes, Cardiac, Green Fluorescent Proteins
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