Inhibition of ATP synthase reverse activity restores energy homeostasis in mitochondrial pathologies.
Inhibition of ATP synthase reverse activity restores energy homeostasis in mitochondrial pathologies.
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DOI：
10.15252/embj.2022111699
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发表时间：
2023-05-15
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--
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细胞功能的维持依赖于三磷酸腺苷（ATP）合成和水解的密切调节。线粒体ATP合酶（CV）的ATP水解由质子动力的丧失诱导，并被线粒体蛋白ATP酶抑制剂（ATPIF 1）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水解活性发生在耦合完整的线粒体和呼吸链缺陷增加。我们鉴定了（+）-表儿茶素作为ATP水解的选择性抑制剂，其结合CV，同时阻止ATPIF 1的结合。在复合物-III缺乏的细胞中，我们发现（+）-表儿茶素对CV水解活性的抑制足以恢复ATP含量，而不恢复呼吸功能。在杜氏肌营养不良症小鼠模型中抑制CV-ATP水解足以改善肌肉力量，而不会增加线粒体含量。我们得出结论，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。ATP合酶的反向活性发生在健康的线粒体中，并且随着呼吸链功能障碍而增加。在杜氏肌营养不良模型中，单独抑制ATP水解足以防止ATP耗竭，恢复细胞功能并改善肌肉力量。
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. Reverse activity of ATP synthase occurs in healthy mitochondria and is increased with respiratory chain dysfunction. Inhibition of ATP hydrolysis, alone, is sufficient to prevent ATP depletion, restore cellular function and improve muscle strength in model of Duchenne Muscular Dystrophy.
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影响因子：
4.7
作者：
Dubinin MV;Starinets VS;Talanov EY;Mikheeva IB;Belosludtseva NV;Serov DA;Tenkov KS;Belosludtseva EV;Belosludtsev KN
通讯作者：
Belosludtsev KN
影响因子：
5.6
作者：
Bason JV;Runswick MJ;Fearnley IM;Walker JE
通讯作者：
Walker JE
影响因子：
3.3
作者：
Blaauw, Bert;Agatea, Lisa;Reggiani, Carlo
通讯作者：
Reggiani, Carlo
DOI：
10.1007/978-1-4939-3810-0_1
发表时间：
2016-01-01
期刊：
SKELETAL MUSCLE REGENERATION IN THE MOUSE: METHODS AND PROTOCOLS
影响因子：
--
作者：
Call, Jarrod A.;Lowe, Dawn A.
通讯作者：
Lowe, Dawn A.
影响因子：
5.5
作者：
Borrelli, KW;Vitalis, A;Guallar, V
通讯作者：
Guallar, V