Potassium channel openers are uncoupling protonophores: implication in cardioprotection
Abstract
Excessive build‐up of mitochondrial protonic potential is harmful to cellular homeostasis, and modulation of inner membrane permeability a proposed countermeasure. Here, we demonstrate that structurally distinct potassium channel openers, diazoxide and pinacidil, facilitated transmembrane proton translocation generating H+‐selective current through planar phospholipid membrane. Both openers depolarized mitochondria, activated state 4 respiration and reduced oxidative phosphorylation, recapitulating the signature of mitochondrial uncoupling. This effect was maintained in K+‐free conditions and shared with the prototypic protonophore 2,4‐dinitrophenol. Diazoxide, pinacidil and 2,4‐dinitrophenol, but not 2,4‐dinitrotoluene lacking protonophoric properties, preserved functional recovery of ischemic heart. The identified protonophoric property of potassium channel openers, thus, implicates a previously unrecognized component in their mechanism of cardioprotection.
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Mitochondrial proteins are also subject to attack by ROS.
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From Mitochondrial reactive oxygen species production in excitable cells: Modulators of mitochondrial and cell function (2009) · cites this paper as [157]
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RETRACTED: Direct effects of ursolic acid on oxidative phosphorylation of rat heart mitochondria
Liobikas, J., Bernatonienė, J., Majienė, D., Kuršvietienė, L., Masteiková, R., Kopustinskienė, D. M., Trumbeckaitė, S., & Savickas, A. (2011) · Biomedicine & Preventive Nutrition · doi:10.1016/j.bionut.2010.12.001
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Treatment of Mitochondrial-Based Cardiac Diseases. Targeting the Organelle
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Effect of thallium on mitochondria
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Structure and mechanism of cellular cation-transporters: Affinity-binding and murburn models
Manoj, K. M., Jaeken, L., Gideon, D. A., Tamagawa, H., & Kavdia, M. (2026) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2026.150614
- Authors
- Holmuhamedov, E. L., Jahangir, A., Oberlin, A., Komarov, A., Colombini, M., & Terzic, A.
- Affiliations
- Mayo Clinic (US)
- University of Maryland, College Park (US)
- Venue
- FEBS Letters
- Publisher
- Wiley
- Published
- 2004-05-31
- Volume
- 568
- Issue
- 1-3
- Pages
- 167-170
- ISSN
- 0014-5793 (ISSN-L)
- 1873-3468
- OpenAlex
- W2086991052
- Cited by
- 90
- References
- 43
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 1 · 2023: 1 · 2022: 4 · 2021: 1 · 2020: 1 · 2019: 1 · 2017: 5 · 2016: 4 · 2015: 2 · 2014: 2 · 2013: 3 · 2012: 4
- FWCI
- 8.09
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- FEBS Letters (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute on Aging (R01AG021201, AG-21201)
- National Heart, Lung, and Blood Institute (HL64822, R01HL064822)
- 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 › Ion channel regulation and function
- Keywords
- potassium channel openers, mitochondrial uncoupling, protonophores, diazoxide, pinacidil, 2,4-dinitrophenol, mitochondrial membrane potential, mitochondrial respiration, oxidative phosphorylation, ischemic heart, cardioprotection, proton translocation, inner membrane permeability
- MeSH terms
- Animals, Cardiotonic Agents, Diazoxide, Mitochondria, Heart, Oxidative Phosphorylation, Uncoupling Agents, Potassium Channels, Pinacidil, Rats
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