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 supercomplex. The findings also provide a tangible clue as to the structural basis of mitoK(ATP) channels.
Institute of Molecular Cardiobiology and Department of Radiology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Hossein
H
Ardehali
Zhenhui
Z
Chen
Young
Y
Ko
Rafael
R
Mejía-Alvarez
Eduardo
E
Marbán
D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D015153:Blotting, Western; D004594:Electrophysiology; D019194:Ischemic Preconditioning; D008081:Liposomes; D046911:Macromolecular Substances; D008930:Mitochondria, Liver / Q000737:chemistry / Q000201:enzymology / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000302:isolation & purification / Q000378:metabolism* / Q000502:physiology; D046912:Multiprotein Complexes; D015221:Potassium Channels / Q000378:metabolism*; D011485:Protein Binding; D051381:Rats; D013385:Succinate Dehydrogenase / Q000302:isolation & purification / Q000378:metabolism / Q000502:physiology*
D008081:Liposomes; D046911:Macromolecular Substances; D024101:Mitochondrial Proteins; D046912:Multiprotein Complexes; D015221:Potassium Channels; D000255:Adenosine Triphosphate; D013385:Succinate Dehydrogenase