Transient mitochondrial permeability transition pore opening mediates preconditioning-induced protection
Abstract
BACKGROUND: Transient (low-conductance) opening of the mitochondrial permeability transition pore (mPTP) may limit mitochondrial calcium load and mediate mitochondrial reactive oxygen species (ROS) signaling. We hypothesize that transient mPTP opening and ROS mediate the protection associated with myocardial preconditioning and mitochondrial uncoupling. METHODS AND RESULTS: Isolated perfused rat hearts were subjected to 35 minutes of ischemia/120 minutes of reperfusion, and the infarct-risk-volume ratio was determined by tetrazolium staining. Inhibiting mPTP opening during the preconditioning phase with cyclosporine-A (CsA, 0.2 micromol/L) or sanglifehrin-A (SfA, 1.0 micromol/L) abolished the protection associated with ischemic preconditioning (IPC) (20.2+/-3.6% versus 45.9+/-2.5% with CsA, 49.0+/-7.1% with SfA; P<0.001); and pharmacological preconditioning with diazoxide (Dzx, 30 micromol/L) (22.1+/-2.7% versus 46.3+/-3.0% with CsA, 48.4+/-5.5% with SfA; P<0.001), CCPA (the adenosine A1-receptor agonist, 200 nmol/L) (24.9+/-4.5% versus 54.4+/-6.6% with CsA, 42.6+/-9.0% with SfA; P<0.001), or 2,4-dinitrophenol (DNP, the mitochondrial uncoupler, 50 micromol/L) (15.7+/-2.7% versus 40.8+/-5.5% with CsA, 34.3+/-3.1% with SfA; P<0.001), suggesting that mPTP opening during the preconditioning phase is required to mediate protection in these settings. Inhibiting ROS during the preconditioning protocols with N-mercaptopropionylglycine (MPG, 1 mmol/L) also abolished the protection associated with IPC (20.2+/-3.6% versus 47.1+/-3.8% with MPG; P<0.001), diazoxide (22.1+/-2.7% versus 56.3+/-3.8% with MPG; P<0.001), and DNP (15.7+/-2.7% versus 50.7+/-6.6% with MPG; P<0.001) but not CCPA (24.9+/-4.5% versus 26.5+/-8.4% with MPG; P=NS). Further experiments in adult rat myocytes demonstrated that diazoxide induced CsA-sensitive, low-conductance transient mPTP opening (represented by a 28+/-3% reduction in mitochondrial calcein fluorescence compared with control; P<0.01). CONCLUSIONS: We report that the protection associated with IPC, diazoxide, and mitochondrial uncoupling requires transient mPTP opening and ROS.
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Partial, short duration openings of mPTP can generate a pulse of H2O2, Ca2+ and superoxide that may serve as signals for several physiological processes.
“Partial, short duration openings of mPTP can generate a pulse of H2O2, Ca2+ and superoxide that may serve as signals for several physiological processes [11,12,13,69,70].”
From The mitochondrial permeability transition: Nexus of aging, disease and longevity (2021) · cites this paper as [11]
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References 19 · Cited by 366
- Authors
- Hausenloy, D., Wynne, A., Duchen, M., & Yellon, D.
- Affiliations
- University College London (GB)
- Venue
- Circulation
- Published
- 2004-04-13
- Volume
- 109
- Issue
- 14
- Pages
- 1714-1717
- ISSN
- 0009-7322 (ISSN-L)
- 1524-4539
- OpenAlex
- W2144553443
- Cited by
- 366
- References
- 19
- Citations by year
- 2026: 6 · 2025: 8 · 2024: 10 · 2023: 5 · 2022: 9 · 2021: 11 · 2020: 10 · 2019: 5 · 2018: 16 · 2017: 9 · 2016: 20 · 2015: 16 · 2014: 24 · 2013: 19 · 2012: 18
- FWCI
- 19.65
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Circulation (publishedVersion)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Funders
- Wellcome Trust
- British Heart Foundation
- 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 permeability transition pore, myocardial preconditioning, cardioprotection, mitochondrial reactive oxygen species, mitochondrial uncoupling, cyclosporine, sanglifehrin A, diazoxide, adenosine A1 receptor, 2,4-dinitrophenol, myocardial ischemia-reperfusion injury, infarct size
- MeSH terms
- Mitochondrial Permeability Transition Pore, Adenosine, Adrenergic alpha-Agonists, Animals, Cardiotonic Agents, Cells, Cultured, Diazoxide, Electric Conductivity, Ion Channels, Lactones, Male, Mitochondria, Heart, Oxidative Phosphorylation, Spiro Compounds, Uncoupling Agents, Vasodilator Agents, Signal Transduction, Myocardial Reperfusion Injury, Ion Channel Gating, Cyclosporine, Ion Transport, Myocardial Ischemia, Rats, Sprague-Dawley, Reactive Oxygen Species, Ischemic Preconditioning, Myocardial, 2,4-Dinitrophenol, Myocytes, Cardiac, Mitochondrial Membrane Transport Proteins, Macromolecular Substances, Rats, Adrenergic alpha-1 Receptor Agonists
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