Parkinson’s disease (PD) is a progressive neurodegenerative disease characterized by mitochondrial dysfunction and accumulation of alpha-synuclein (α-Syn)-containing protein aggregates known as Lewy bodies (LB). Here, we investigated the entry of α-Syn into mitochondria to cause mitochondrial dysfunction and loss of cellular fitness in vivo. We show that α-Syn expressed in yeast and human cells is constitutively imported into mitochondria. In a transgenic mouse model, the level of endogenous α-Syn accumulation in mitochondria of dopaminergic neurons and microglia increases with age. The imported α-Syn is degraded by conserved mitochondrial proteases, most notably NLN and PITRM1 (Prd1 and Cym1 in yeast, respectively). α-Syn in the mitochondrial matrix that is not degraded interacts with respiratory chain complexes, leading to loss of mitochondrial DNA (mtDNA), mitochondrial membrane potential and cellular fitness decline. Importantly, enhancing mitochondrial proteolysis by increasing levels of specific proteases alleviated these defects in yeast, human cells, and a PD model of mouse primary neurons. Together, our results provide a direct link between α-synuclein-mediated cellular toxicity and its import into mitochondria and reveal potential therapeutic targets for the treatment of α-synucleinopathies.

帕金森病 (PD) 是一种进行性神经退行性疾病，其特征是线粒体功能障碍和含有 α-突触核蛋白 (α-Syn) 的蛋白质聚集体（称为路易体 (LB)）的积累。在这里，我们研究了 α-Syn 进入线粒体导致线粒体功能障碍和体内细胞适应性丧失的情况。我们表明，在酵母和人类细胞中表达的 α-Syn 被组成型导入线粒体中。在转基因小鼠模型中，多巴胺能神经元和小胶质细胞线粒体中内源 α-Syn 积累的水平随着年龄的增长而增加。导入的 α-Syn 会被保守的线粒体蛋白酶降解，最显着的是 NLN 和 PITRM1（分别是酵母中的 Prd1 和 Cym1）。线粒体基质中未降解的 α-Syn 与呼吸链复合物相互作用，导致线粒体 DNA (mtDNA) 损失、线粒体膜电位和细胞适应性下降。重要的是，通过增加特定蛋白酶的水平来增强线粒体蛋白水解作用，可以减轻酵母、人类细胞和小鼠原代神经元 PD 模型中的这些缺陷。总之，我们的结果提供了 α-突触核蛋白介导的细胞毒性与其进入线粒体之间的直接联系，并揭示了治疗 α-突触核蛋白病的潜在治疗靶点。