Cited by 986Cardiac Ischemia and ReperfusionMitochondrial Function and PathologyCell death mechanisms and regulation

Inhibiting Mitochondrial Fission Protects the Heart Against Ischemia/Reperfusion Injury

Ong, Sang-Bing, Subrayan, Sapna, Lim, Shiang Y., Yellon, Derek M., Davidson, Sean M., Hausenloy, Derek J.·2010·Circulation

Abstract

Background— Whether alterations in mitochondrial morphology affect the susceptibility of the heart to ischemia/reperfusion injury is unknown. We hypothesized that modulating mitochondrial morphology protects the heart against ischemia/reperfusion injury. Methods and Results— In response to ischemia, mitochondria in HL-1 cells (a cardiac-derived cell line) undergo fragmentation, a process that is dependent on the mitochondrial fission protein dynamin-related protein 1 (Drp1). Transfection of HL-1 cells with the mitochondrial fusion proteins mitofusin 1 or 2 or with Drp1 K38A , a dominant-negative mutant form of Drp1, increased the percentage of cells containing elongated mitochondria (65±4%, 69±5%, and 63±6%, respectively, versus 46±6% in control: n=80 cells per group; P <0.05), decreased mitochondrial permeability transition pore sensitivity (by 2.4±0.5-, 2.3±0.7-, and 2.4±0.3-fold, respectively; n=80 cells per group; P <0.05), and reduced cell death after simulated ischemia/reperfusion injury (11.6±3.9%, 16.2±3.9%, and 12.1±2.9%, respectively, versus 41.8±4.1% in control: n=320 cells per group; P <0.05). Treatment of HL-1 cells with mitochondrial division inhibitor-1, a pharmacological inhibitor of Drp1, replicated these beneficial effects. Interestingly, elongated interfibrillar mitochondria were identified in the adult rodent heart with confocal and electron microscopy, and in vivo treatment with mitochondrial division inhibitor-1 increased the percentage of elongated mitochondria from 3.6±0.5% to 14.5±2.8% ( P =0.023). Finally, treatment of adult murine cardiomyocytes with mitochondrial division inhibitor-1 reduced cell death and inhibited mitochondrial permeability transition pore opening after simulated ischemia/reperfusion injury, and in vivo treatment with mitochondrial division inhibitor-1 reduced myocardial infarct size in mice subject to coronary artery occlusion and reperfusion (21.0±2.2% with mitochondrial division inhibitor-1 versus 48.0±4.5% in control; n=6 animals per group; P <0.05). Conclusion— Inhibiting mitochondrial fission protects the heart against ischemia/reperfusion injury, suggesting a novel pharmacological strategy for cardioprotection.

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Crossref · 10.1161/circulationaha.109.906610

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Authors
Ong, S.-B., Subrayan, S., Lim, S. Y., Yellon, D. M., Davidson, S. M., & Hausenloy, D. J.
Affiliations
University College Hospital (GB)
Venue
Circulation
Published
2010-05-11
Volume
121
Issue
18
Pages
2012-2022
ISSN
  • 0009-7322 (ISSN-L)
  • 1524-4539
OpenAlex
W2085367705
Cited by
986
References
36
Citations by year
2026: 34 · 2025: 40 · 2024: 44 · 2023: 50 · 2022: 70 · 2021: 71 · 2020: 86 · 2019: 57 · 2018: 68 · 2017: 92 · 2016: 65 · 2015: 60 · 2014: 71 · 2013: 55 · 2012: 63
FWCI
38.33
Type
journal article
Language
en
Open access
closed
Locations
  • Circulation (publishedVersion)
  • PubMed (publishedVersion)
  • UCL Discovery (University College London) (submittedVersion)
Funders
  • British Heart Foundation
  • Medical Research Council
  • Biotechnology and Biological Sciences Research Council
Topics
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Cardiac Ischemia and Reperfusion
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
Keywords
mitochondrial fission, mitochondrial fragmentation, ischemia-reperfusion injury, cardioprotection, Drp1, mitofusin 1, mitofusin 2, mitochondrial permeability transition pore, cardiomyocyte death, myocardial infarct size, mitochondrial morphology, coronary artery occlusion, HL-1 cells
MeSH terms
Age Factors, Animals, Cardiotonic Agents, Cell Line, Male, Membrane Fusion, Mice, Inbred C57BL, Microscopy, Electron, Microtubule-Associated Proteins, Mitochondria, Transfection, Myocardial Reperfusion Injury, Cell Death, Microscopy, Confocal, GTP Phosphohydrolases, Myocytes, Cardiac, Dynamins, Green Fluorescent Proteins, Mitochondrial Membranes, Mice, Quinazolinones

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