Multiprotein complex containing succinate dehydrogenase confers mitochondrial ATP-sensitive K+ channel activity
Multiprotein complex containing succinate dehydrogenase confers mitochondrial ATP-sensitive K+ channel activity
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DOI：
10.1073/pnas.0401703101
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发表时间：
2004-08-10
影响因子：
11.1
通讯作者：
Marbán, E
中科院分区：
文献类型：
--
作者：
Ardehali, H;Chen, ZH;Marbán, E
线粒体 ATIP 敏感 K+ (mitoK(ATP)) 通道在保护心脏和神经元细胞免受缺血和凋亡方面发挥着核心作用，但其分子结构尚不清楚。琥珀酸脱氢酶 (SDH) 被 mitoK(ATP) 激活剂抑制，这引发了相反的观点，即 SDH，而不是 mitoK(ATP)，是心脏保护药物的靶点。在这里，我们报道 SDH 在功能和结构上构成 mitoK(ATP) 的一部分。四种线粒体蛋白 [线粒体 ATP 结合盒蛋白 1 (mABC1)、磷酸盐载体、腺嘌呤核苷酸转位蛋白和 ATP 合酶] 与 SDH 相关。含有这些蛋白质的纯化 IM 级分被重构为蛋白脂质体和脂质双层，并显示出赋予 mitoK(ATP) 通道活性。该通道活性不仅对 mitoK(ATP) 激活剂和阻断剂敏感，而且对 SDH 抑制剂也敏感。这些结果证明 SDH 是 mitoK(ATP) 的组成部分，是大分子超复合物的一部分，从而调和了关于缺血预处理基础的争议。这些发现还为 mitoK(ATP) 通道的结构基础提供了切实的线索。
The mitochondrial ATIP-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.