The mitochondrial ATP-sensitive K+ (mitoKATP) 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 mitoKATP activators, fueling the contrary view that SDH, rather than mitoKATP, 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 mitoKATP 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 mitoKATP as part of a macromolecular super-complex. The findings also provide a tangible clue as to the structural basis of mitoKATP channels.
|Original language||English (US)|
|Number of pages||6|
|Journal||Proceedings of the National Academy of Sciences of the United States of America|
|State||Published - Aug 10 2004|
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