Multiprotein complex containing succinate dehydrogenase confers mitochondrial ATP-sensitive K + channel activity

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Abstract
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.