Inhibiting Mitochondrial Fission Protects the Heart Against Ischemia/Reperfusion Injury
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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Prevention of mitochondrial fission is beneficial in kidneys and heart after acute ischemia/reperfusion injury in mice.
“For example, mitochondrial fission occurs in the kidneys and heart after acute ischemia/reperfusion injury in mice, and prevention of this process is beneficial (5, 32).”
From Mitochondrial Fission Contributes to Mitochondrial Dysfunction and Insulin Resistance in Skeletal Muscle (2012) · cites this paper as [32]
Mitochondrial fission occurs in kidneys and heart after acute ischemia/reperfusion injury in mice.
“For example, mitochondrial fission occurs in the kidneys and heart after acute ischemia/reperfusion injury in mice, and prevention of this process is beneficial (5, 32).”
From Mitochondrial Fission Contributes to Mitochondrial Dysfunction and Insulin Resistance in Skeletal Muscle (2012) · cites this paper as [32]
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“Therapeutic intervention on the cardiac Drp1 pathway has so far focused on inhibition of fission in acute ischemia-reperfusion, but low-level chronic activation to promote mitophagy and high ATP synthesis might be of benefit in the failing heart (42, 43).”
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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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