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

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

  • Biochem Biophys Res Commun. 2019 Feb 5;509(2):390-394. doi: 10.1016/j.bbrc.2018.12.148.
Menglan Zhao 1,  Jialong Chen 1,  Kanmin Mao 1,  Hua She 2,  Yixian Ren 1,  Chen Gui 1,  Xian Wu 1,  Fei Zou 3,  Wenjun Li 4
Affiliations

Affiliations

  • 1 Department of Occupational Health and Occupational Medicine, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, Guangdong, China.
  • 2 Department of Pharmacology, Emory University School of Medicine, Atlanta, GA, Georgia.
  • 3 Department of Occupational Health and Occupational Medicine, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, Guangdong, China. Electronic address: feizoudean@hotmail.com.
  • 4 Department of Occupational Health and Occupational Medicine, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, Guangdong, China. Electronic address: cjlwj@smu.edu.cn.
PMID: 30594390 DOI: 10.1016/j.bbrc.2018.12.148
Abstract

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.

Keywords

AMPK; Autophagy; Calcium; MCU; MPP(+).

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