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Parkin Promotes Mitophagic Cell Death in Adult Hippocampal Neural Stem Cells Following Insulin Withdrawal

Title
Parkin Promotes Mitophagic Cell Death in Adult Hippocampal Neural Stem Cells Following Insulin Withdrawal
Authors
Park, HyunheeChung, Kyung MinAn, Hyun-KyuGim, Ji-EunHong, JihyunWoo, HanwoongCho, BongkiMoon, CheilYu, Seong-Woon
DGIST Authors
Cho, Bongki; Moon, CheilYu, Seong-Woon
Issue Date
2019-02
Citation
Frontiers in Molecular Neuroscience, 12
Type
Article
Article Type
Article
Author Keyword
autophagy-dependent cell death; c-Jun; hippocampal neural stem cells; mitophagy; Parkin
Keyword
AUTOPHAGOSOME FORMATION; MECHANISMS; UBIQUITIN; PROTEIN; NEUROGENESIS; MITOCHONDRIA; DISEASE; DEGRADATION; INFUSION; CALCIUM
ISSN
1662-5099
Abstract
Regulated cell death (RCD) plays a fundamental role in human health and disease. Apoptosis is the best-studied mode of RCD, but the importance of other modes has recently been gaining attention. We have previously demonstrated that adult rat hippocampal neural stem (HCN) cells undergo autophagy-dependent cell death (ADCD) following insulin withdrawal. Here, we show that Parkin mediates mitophagy and ADCD in insulin-deprived HCN cells. Insulin withdrawal increased the amount of depolarized mitochondria and their colocalization with autophagosomes. Insulin withdrawal also upregulated both mRNA and protein levels of Parkin, gene knockout of which prevented mitophagy and ADCD. c-Jun is a transcriptional repressor of Parkin and is degraded by the proteasome following insulin withdrawal. In insulin-deprived HCN cells, Parkin is required for Ca 2+ accumulation and depolarization of mitochondria at the early stages of mitophagy as well as for recognition and removal of depolarized mitochondria at later stages. In contrast to the pro-death role of Parkin during mitophagy, Parkin deletion rendered HCN cells susceptible to apoptosis, revealing distinct roles of Parkin depending on different modes of RCD. Taken together, these results indicate that Parkin is required for the induction of ADCD accompanying mitochondrial dysfunction in HCN cells following insulin withdrawal. Since impaired insulin signaling is implicated in hippocampal deficits in various neurodegenerative diseases and psychological disorders, these findings may help to understand the mechanisms underlying death of neural stem cells and develop novel therapeutic strategies aiming to improve neurogenesis and survival of neural stem cells. © 2019 Park, Chung, An, Gim, Hong, Woo, Cho, Moon and Yu.
URI
http://hdl.handle.net/20.500.11750/9636
DOI
10.3389/fnmol.2019.00046
Publisher
Frontiers Media S.A.
Related Researcher
  • Author Yu, Seong-Woon Laboratory of Neuronal Cell Death
  • Research Interests Molecular mechanisms of neuronal cell death and neurodegeneration
Files:
Collection:
Companion Diagnostics and Medical Technology Research Group1. Journal Articles
Department of Brain and Cognitive SciencesMoon Lab1. Journal Articles
Department of Brain and Cognitive SciencesLaboratory of Neuronal Cell Death1. Journal Articles


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