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Mitochondrial calcium dysfunction contributes to autophagic cell death induced by MPP + via AMPK pathway.
- Source :
-
Biochemical and biophysical research communications [Biochem Biophys Res Commun] 2019 Feb 05; Vol. 509 (2), pp. 390-394. Date of Electronic Publication: 2018 Dec 26. - Publication Year :
- 2019
-
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 Ca <superscript>2+</superscript> signaling and the contribution of mitochondrial Ca <superscript>2+</superscript> to the process of neurodegeneration is still unclear. MPP <superscript>+</superscript> , 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 Ca <superscript>2+</superscript> uniporter (MCU) participated in MPP <superscript>+</superscript> -induced autophagic cell death in SH-SY5Y cells. Pharmacological agonist of MCU or exogenous expressed MCU can partially reduce MPP <superscript>+</superscript> -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 <superscript>+</superscript> -induced neuronal degeneration, and MCU may be a potential therapeutic target of PD through the prevention of pathological autophagy.<br /> (Copyright © 2018 Elsevier Inc. All rights reserved.)
- Subjects :
- 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine metabolism
AMP-Activated Protein Kinases genetics
Autophagosomes drug effects
Autophagosomes metabolism
Autophagy genetics
Beclin-1 genetics
Beclin-1 metabolism
Biotransformation
Calcium Channels genetics
Calcium Channels metabolism
Calcium Signaling
Cell Line, Tumor
Cell Survival drug effects
Gene Expression Regulation
Humans
Lysosomes drug effects
Lysosomes metabolism
Mitochondria metabolism
Mitochondria pathology
Neurons metabolism
Neurons pathology
Phosphatidylinositol 3-Kinases genetics
Phosphatidylinositol 3-Kinases metabolism
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine pharmacology
AMP-Activated Protein Kinases metabolism
Autophagy drug effects
Calcium metabolism
Mitochondria drug effects
Neurons drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 1090-2104
- Volume :
- 509
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Biochemical and biophysical research communications
- Publication Type :
- Academic Journal
- Accession number :
- 30594390
- Full Text :
- https://doi.org/10.1016/j.bbrc.2018.12.148