帕金森病(Parkinson's disease, PD)是一种常见的神经退行性疾病,其特征是中脑黑质多巴 胺能神经元的进行性丢失。近年来,铜死亡(cuproptosis)作为一种新发现的程序性细胞死亡方式, 在PD发病机制中的作用逐渐受到关注。铜死亡的核心机制是过量铜离子与三羧酸循环中的脂酰 化蛋白结合,导致蛋白质异常聚集和铁硫簇蛋白丢失,引发线粒体蛋白毒性应激。本文系统综述了 铜死亡对神经元关键细胞器———线粒体、内质网和溶酶体的影响及其机制。铜死亡通过破坏线粒 体呼吸链功能、加剧氧化应激、抑制线粒体自噬,干扰内质网蛋白质折叠与钙稳态,以及损害溶酶体 酸化和自噬-溶酶体途径,加剧多巴胺能神经元的损伤与死亡。本文从铜死亡与细胞器功能障碍之 间的交互网络出发,以期为PD的机制研究和治疗提供新的方向。

Parkinson's disease (PD) is a common neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons in the substantia nigra of the midbrain. In recent years, cuproptosis,a newly discovered form of programmed cell death,has gradually gained attention for its role in the pathogenesis of PD.The core mechanism of cuproptosis involves the binding of excessive copper ions to lipoylated proteins in the tricarboxylic acid (TCA) cycle,leading to abnormal protein aggregation and loss of iron-sulfur cluster proteins, thereby triggering mitochondrial proteotoxic stress.This article systematically reviews the impact of cuproptosis on key neuronal organelles-mitochondria,the endoplasmic reticulum ,and lysosomes and its molecular mechanisms.Cuproptosis exacerbates the damage and death of dopaminergic neurons by disrupting mitochondrial respiratory chain function, intensifying oxidative stress, inhibiting mitophagy, interfering with endoplasmic reticulum protein folding and calcium homeostasis, as well as impairing lysosomal acidification and the autophagy-lysosome pathway. Understanding the interactive network between cuproptosis and organelle dysfunction may provide new potential targets for PD treatment strategies.