Multiprotein complex containing succinate dehydrogenase confers mitochondrial ATP-sensitive K + channel activity
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The mitochondrial ATP-sensitive K + (mitoK ATP ) channel plays a central role in protection of cardiac and neuronal cells against ischemia and apoptosis, but its molecular structure is unknown. Succinate dehydrogenase (SDH) is inhibited by mitoK ATP activators, fueling the contrary view that SDH, rather than mitoK ATP , is the target of cardioprotective drugs. Here, we report that SDH forms part of mitoK ATP functionally and structurally. Four mitochondrial proteins [mitochondrial ATP-binding cassette protein 1 (mABC1), phosphate carrier, adenine nucleotide translocator, and ATP synthase] associate with SDH. A purified IM fraction containing these proteins was reconstituted into proteoliposomes and lipid bilayers and shown to confer mitoK ATP channel activity. This channel activity is sensitive not only to mitoK ATP activators and blockers but also to SDH inhibitors. These results reconcile the controversy over the basis of ischemic preconditioning by demonstrating that SDH is a component of mitoK ATP as part of a macromolecular supercomplex. The findings also provide a tangible clue as to the structural basis of mitoK ATP channels.
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A model was presented that merges the two conflicting views, i.e., that complex II may be a component or regulator of the mitoKATP channel.
“Recently, a model was presented that merges these two conflicting views, i.e. that complex II may be a component or regulator of the mitoK ATP channel [44,156,157].”
From Differential effects of complex II on mitochondrial ROS production and their relation to cardioprotective pre- and postconditioning (2013) · cites this paper as [156]
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- Authors
- Ardehali, H., Chen, Z., Ko, Y., Mejía-Alvarez, R., & Marbán, E.
- Affiliations
- Johns Hopkins University (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2004-07-29
- Volume
- 101
- Issue
- 32
- Pages
- 11880-11885
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC511068
- OpenAlex
- W1964769632
- Cited by
- 215
- References
- 32
- Citations by year
- 2025: 3 · 2024: 2 · 2023: 4 · 2022: 3 · 2021: 12 · 2020: 5 · 2019: 3 · 2018: 5 · 2017: 3 · 2016: 5 · 2015: 5 · 2014: 7 · 2013: 11 · 2012: 14
- FWCI
- 8.90
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Heart, Lung, and Blood Institute (R37 HL-36957, R37HL036957)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Health Sciences › Medicine › Pathology and Forensic Medicine › Cardiac Ischemia and Reperfusion
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
- Keywords
- mitochondrial ATP-sensitive potassium channel, succinate dehydrogenase, protein complexes, mitochondrial supercomplexes, ischemic preconditioning, cardioprotection, phosphate transporters, adenine nucleotide translocase, ATP synthase, channel structure, proteoliposome reconstitution
- MeSH terms
- Adenosine Triphosphate, Animals, Electrophysiology, Liposomes, Mitochondria, Liver, Protein Binding, Succinate Dehydrogenase, Blotting, Western, Potassium Channels, Ischemic Preconditioning, Mitochondrial Proteins, Macromolecular Substances, Multiprotein Complexes, Rats
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