氧化呼吸链蛋白乙酰化修饰紊乱介导的线粒体功能障碍在帕金森病中的作用及机制研究

线粒体功能障碍是帕金森病（PD）多巴胺神经元退变的核心致病机制之一。近年来的研究表明线粒体蛋白的乙酰化和去乙酰化修饰对线粒体功能调控至关重要。我们通过对黑质组织蛋白进行乙酰化蛋白质组学及实验验证发现，线粒体蛋白尤其是氧化呼吸链的多个亚基如Ndufb6、Uqcrc2、ATP5O及ATP5J的乙酰化水平在PD模型小鼠中显著增加。我们也发现介导线粒体蛋白乙酰化修饰的乙酰辅酶A乙酰转移酶1（ACAT1）自身的乙酰化修饰和去乙酰化酶SIRT3的表达在PD模型中显著改变。我们推测，这些蛋白的乙酰化增加及修饰酶异常与PD的线粒体功能障碍机制密切相关。我们拟在PD动物模型和细胞模型中，运用生物学、组学、基因工程小鼠及药理学等方法，阐明线粒体蛋白乙酰化修饰异常对线粒体功能的影响及其在PD中的作用和机制。通过本项目的实施，我们的研究将进一步完善PD中的线粒体功能障碍机理，为PD的干预治疗提供新思路和新靶标。

Mitochondrial dysfunction is one of the key pathological factors for dopaminergic neuronal degeneration in Parkinson’s disease (PD). Recent studies have shown that acetylation and deacetylation of mitochondrial proteins are critical for the regulation of mitochondrial function. Our preliminary data indicated that the acetylation on some specific lysine residues of many mitochondrial proteins, especially some subunits in oxidative respiratory chain such as Ndufb6, Uqcrc2, ATP5O and ATP5J was dramatically elevated in substantia nigra of PD mouse models that was subjected to quantitative analysis of acetylation proteomics and verified with biochemical analysis. Moreover, we also found that the protein acetylation of acetyl-CoA acetyltransferase (ACAT1) and the expression of deacetylase SIRT3 that mediate the acetylation modification of mitochondrial proteins was significantly changed in PD models. We suppose that abnormal acetylation of these mitochondrial proteins and the related modification enzymes may be tightly involved in mitochondrial dysfunction of PD pathogenesis. We will elucidate the molecular mechanism of abnormal acetylation of these proteins as well as the roles of abnormal acetylation-mediated mitochondrial dysfunction in PD pathogenesis through multiple approaches including biology, omics analysis, genetically engineered mice and pharmacology. Our study will further extend our understanding in mechanism of mitochondrial dysfunction in PD pathogenesis, and provide new ideas and novel targets for intervention strategies of PD.