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

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 super-complex. The findings also provide a tangible clue as to the structural basis of mitoK_ATP channels.