PMID- 34213839
OWN - NLM
STAT- MEDLINE
DCOM- 20220202
LR  - 20220202
IS  - 1582-4934 (Electronic)
IS  - 1582-1838 (Print)
IS  - 1582-1838 (Linking)
VI  - 25
IP  - 15
DP  - 2021 Aug
TI  - The molecular mechanism underlying mitophagy-mediated hippocampal neuron 
      apoptosis in diabetes-related depression.
PG  - 7342-7353
LID - 10.1111/jcmm.16763 [doi]
AB  - Diabetes-related depression (DD) is a major complication of diabetes mellitus. 
      Our previous studies indicated that glutamate (Glu) and hippocampal neuron 
      apoptosis are key signal and direct factor leading to diabetes-related 
      depression, respectively. However, the accurate pathogenesis remains to be 
      unclear. We hypothesized that diabetes-related depression might be associated 
      with the mitophagy-mediated hippocampal neuron apoptosis, triggered by aberrant 
      Glu-glutamate receptor2 (GluR2)-Parkin pathway. To testify this hypothesis, here 
      the rat model of DD in vivo and in vitro were both established so as to uncover 
      the potential mechanism of DD based on mitophagy and apoptosis. We found that DD 
      rats exhibit an elevated glutamate levels followed by monoamine neurotransmitter 
      deficiency and depressive-like behaviour, and DD modelling promoted autophagosome 
      formation and caused mitochondrial impairment, eventually leading to hippocampal 
      neuron apoptosis via aberrant Glu-GluR2-Parkin pathway. Further, in vitro study 
      demonstrated that the simulated DD conditions resulted in an abnormal glutamate 
      and monoamine neurotransmitter levels followed by autophagic flux increment, 
      mitochondrial membrane potential reduction and mitochondrial reactive oxygen 
      species and lactic dehydrogenase elevation. Interestingly, both GluR2 and 
      mammalian target of rapamycin (mTOR) receptor blocker aggravated 
      mitophagy-induced hippocampal neuron apoptosis and abnormal expression of 
      apoptotic protein. In contrast, both GluR2 and mTOR receptor agonist ameliorated 
      those apoptosis in simulated DD conditions. Our findings revealed that 
      mitophagy-mediated hippocampal neuron apoptosis, triggered by aberrant 
      Glu-GluR2-Parkin pathway, is responsible for depressive-like behaviour and 
      monoamine neurotransmitter deficiency in DD rats. This work provides promising 
      molecular targets and strategy for the treatment of DD.
CI  - (c) 2021 The Authors. Journal of Cellular and Molecular Medicine published by 
      Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.
FAU - Liu, Jian
AU  - Liu J
AD  - The First Hospital, Hunan University of Chinese Medicine, Hunan Province, 
      Changsha, China.
FAU - Liu, Lin
AU  - Liu L
AD  - The First Hospital, Hunan University of Chinese Medicine, Hunan Province, 
      Changsha, China.
FAU - Han, Yuan-Shan
AU  - Han YS
AD  - The First Hospital, Hunan University of Chinese Medicine, Hunan Province, 
      Changsha, China.
FAU - Yi, Jian
AU  - Yi J
AD  - The First Hospital, Hunan University of Chinese Medicine, Hunan Province, 
      Changsha, China.
FAU - Guo, Chun
AU  - Guo C
AD  - The First Hospital, Hunan University of Chinese Medicine, Hunan Province, 
      Changsha, China.
FAU - Zhao, Hong-Qing
AU  - Zhao HQ
AD  - Institute of Innovation and Applied Research, Hunan University of Chinese 
      Medicine, Hunan Province, Changsha, China.
AD  - Key Laboratory of Chinese Material Medical Power and Innovation Drugs Established 
      by Provincial and Ministry, Hunan University of Chinese Medicine, Hunan Province, 
      Changsha, China.
FAU - Ling, Jia
AU  - Ling J
AD  - Institute of Innovation and Applied Research, Hunan University of Chinese 
      Medicine, Hunan Province, Changsha, China.
AD  - Key Laboratory of Chinese Material Medical Power and Innovation Drugs Established 
      by Provincial and Ministry, Hunan University of Chinese Medicine, Hunan Province, 
      Changsha, China.
FAU - Wang, Yu-Hong
AU  - Wang YH
AUID- ORCID: 0000-0003-2285-6339
AD  - Institute of Innovation and Applied Research, Hunan University of Chinese 
      Medicine, Hunan Province, Changsha, China.
AD  - Key Laboratory of Chinese Material Medical Power and Innovation Drugs Established 
      by Provincial and Ministry, Hunan University of Chinese Medicine, Hunan Province, 
      Changsha, China.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20210702
PL  - England
TA  - J Cell Mol Med
JT  - Journal of cellular and molecular medicine
JID - 101083777
RN  - 0 (Neurotransmitter Agents)
RN  - 0 (Receptors, AMPA)
RN  - EC 2.3.2.27 (Ubiquitin-Protein Ligases)
RN  - EC 2.3.2.27 (parkin protein)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - P6W5IXV8V9 (glutamate receptor ionotropic, AMPA 2)
SB  - IM
MH  - Animals
MH  - *Apoptosis
MH  - Cells, Cultured
MH  - Depression/etiology/*metabolism
MH  - Diabetes Mellitus, Experimental/*complications/psychology
MH  - Hippocampus/cytology/*metabolism
MH  - Male
MH  - *Mitophagy
MH  - Neurons/drug effects/metabolism
MH  - Neurotransmitter Agents/*metabolism
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Receptors, AMPA/agonists/metabolism
MH  - TOR Serine-Threonine Kinases/antagonists & inhibitors/metabolism
MH  - Ubiquitin-Protein Ligases/metabolism
PMC - PMC8335699
OTO - NOTNLM
OT  - Apoptosis
OT  - Diabetes-related depression
OT  - GluR2
OT  - Glutamate
OT  - Hippocampal neuron
OT  - Mitophagy
OT  - Parkin
COIS- All authors declare that they have no competing interests.
EDAT- 2021/07/03 06:00
MHDA- 2022/02/03 06:00
PMCR- 2021/08/01
CRDT- 2021/07/02 12:29
PHST- 2021/06/03 00:00 [revised]
PHST- 2020/12/17 00:00 [received]
PHST- 2021/06/11 00:00 [accepted]
PHST- 2021/07/03 06:00 [pubmed]
PHST- 2022/02/03 06:00 [medline]
PHST- 2021/07/02 12:29 [entrez]
PHST- 2021/08/01 00:00 [pmc-release]
AID - JCMM16763 [pii]
AID - 10.1111/jcmm.16763 [doi]
PST - ppublish
SO  - J Cell Mol Med. 2021 Aug;25(15):7342-7353. doi: 10.1111/jcmm.16763. Epub 2021 Jul 
      2.