Department of Internal Medicine (Endocrinology), Yale University, New Haven, CT, USA.
Department of Human Nutrition and Hospitality Management, University of Alabama, Tuscaloosa, AL, USA.
Cell Death Dis. 2019 Jun 13;10(6):469. doi: 10.1038/s41419-019-1679-x.
Familial Parkinson's disease (PD) protein DJ-1 mutations are linked to early onset PD. We have found that DJ-1 binds directly to the FF ATP synthase β subunit. DJ-1's interaction with the β subunit decreased mitochondrial uncoupling and enhanced ATP production efficiency while in contrast mutations in DJ-1 or DJ-1 knockout increased mitochondrial uncoupling, and depolarized neuronal mitochondria. In mesencephalic DJ-1 KO cultures, there was a progressive loss of neuronal process extension. This was ameliorated by a pharmacological reagent, dexpramipexole, that binds to ATP synthase, closing a mitochondrial inner membrane leak and enhancing ATP synthase efficiency. ATP synthase c-subunit can form an uncoupling channel; we measured, therefore, ATP synthase F (β subunit) and c-subunit protein levels. We found that ATP synthase β subunit protein level in the DJ-1 KO neurons was approximately half that found in their wild-type counterparts, comprising a severe defect in ATP synthase stoichiometry and unmasking c-subunit. We suggest that DJ-1 enhances dopaminergic cell metabolism and growth by its regulation of ATP synthase protein components.
家族性帕金森病（PD）蛋白 DJ-1 突变与早发性 PD 有关。我们发现 DJ-1 直接与 FF ATP 合酶β亚基结合。DJ-1 与β亚基的相互作用降低了线粒体解偶联并增强了 ATP 产生效率，而 DJ-1 突变或 DJ-1 敲除则增加了线粒体解偶联，并使神经元线粒体去极化。在中脑 DJ-1 KO 培养物中，神经元突起的延伸逐渐丧失。一种与 ATP 合酶结合的药理学试剂 dexpramipexole 可改善这种情况，它可关闭线粒体内膜漏并提高 ATP 合酶效率。ATP 合酶 c 亚基可形成解偶联通道；因此，我们测量了 ATP 合酶 F（β亚基）和 c 亚基蛋白水平。我们发现，DJ-1 KO 神经元中的 ATP 合酶β亚基蛋白水平约为其野生型对应物的一半，这构成了 ATP 合酶计量比的严重缺陷，并使 c 亚基暴露。我们认为，DJ-1 通过调节 ATP 合酶蛋白成分来增强多巴胺能细胞的代谢和生长。
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