PDF(Pubmed)
Abstract：
The maintenance of cellular function relies on the close regulation of adenosine triphosphate (ATP) synthesis and hydrolysis. ATP hydrolysis by mitochondrial ATP Synthase (CV) is induced by loss of proton motive force and inhibited by the mitochondrial protein ATPase inhibitor (ATPIF1). The extent of CV hydrolytic activity and its impact on cellular energetics remains unknown due to the lack of selective hydrolysis inhibitors of CV. We find that CV hydrolytic activity takes place in coupled intact mitochondria and is increased by respiratory chain defects. We identified (+)-Epicatechin as a selective inhibitor of ATP hydrolysis that binds CV while preventing the binding of ATPIF1. In cells with Complex-III deficiency, we show that inhibition of CV hydrolytic activity by (+)-Epichatechin is sufficient to restore ATP content without restoring respiratory function. Inhibition of CV-ATP hydrolysis in a mouse model of Duchenne Muscular Dystrophy is sufficient to improve muscle force without any increase in mitochondrial content. We conclude that the impact of compromised mitochondrial respiration can be lessened using hydrolysis-selective inhibitors of CV.
摘要：
细胞功能的维持依赖于三磷酸腺苷(ATP)合成和水解的紧密调节。线粒体ATP合成酶（CV）的ATP水解是由质子动力损失引起的，并被线粒体蛋白ATP酶抑制剂（ATPIF1）抑制。由于缺乏CV的选择性水解抑制剂，CV水解活性的程度及其对细胞能量学的影响仍然未知。我们发现，CV水解活性发生在完整的线粒体中，并因呼吸链缺陷而增加。我们确定(+)-表儿茶素是ATP水解的选择性抑制剂,其结合CV,同时阻止ATPIF1的结合。在复合物III缺乏的细胞中，我们表明，（）-Epichatechin抑制CV水解活性足以恢复ATP含量而不恢复呼吸功能。在Duchenne肌营养不良的小鼠模型中抑制CV-ATP水解足以改善肌肉力,而线粒体含量没有任何增加。我们得出的结论是，使用CV的水解选择性抑制剂可以减轻线粒体呼吸受损的影响。
