Mitochondrial calcium dysfunction contributes to autophagic cell death induced by MPP⁺ via AMPK pathway

Parkinson's disease (PD) is a progressive neurodegenerative disease characterized by the loss of dopaminergic neurons in the substantia nigra. Prevailing evidence suggests that abnormal autophagy and mitochondrial dysfunction participate in the process of PD. However, many damages of neuronal functions are regulated by intracellular Ca²⁺ signaling and the contribution of mitochondrial Ca²⁺ to the process of neurodegeneration is still unclear. MPP⁺, the metabolite of a neurotoxin MPTP, causes symptom of PD in animal models by selectively destroying dopaminergic neurons in substantia nigra. Here we report that mitochondrial Ca²⁺ uniporter (MCU) participated in MPP⁺-induced autophagic cell death in SH-SY5Y cells. Pharmacological agonist of MCU or exogenous expressed MCU can partially reduce MPP⁺-induced autophagic cell death. Down-regulation of MCU enhanced autophagic cell death via AMPK activation, which was independent of Beclin1 and PI3K. These findings show that the mitochondrial calcium dyshomeostasis contributes to MPP⁺-induced neuronal degeneration, and MCU may be a potential therapeutic target of PD through the prevention of pathological autophagy.