PMID- 36273635
OWN - NLM
STAT- MEDLINE
DCOM- 20221122
LR  - 20221122
IS  - 1879-3169 (Electronic)
IS  - 0378-4274 (Linking)
VI  - 372
DP  - 2023 Jan 1
TI  - PGAM5 regulates DRP1-mediated mitochondrial fission/mitophagy flux in lipid 
      overload-induced renal tubular epithelial cell necroptosis.
PG  - 14-24
LID - S0378-4274(22)01764-7 [pii]
LID - 10.1016/j.toxlet.2022.10.003 [doi]
AB  - The pathophysiology of renal lipid toxicity caused by excess adiposity is not 
      well-understood. Necroptosis, a regulated form of cell death, is involved in 
      injuring renal tubular epithelial cells (RTECs). Phosphoglycerate mutase 5 
      (PGAM5) is a key downstream effector of necroptosis. This study investigated the 
      underlying mechanism of PGAM5 in promoting lipid-induced necroptosis in RTECs. 
      HK2 cells (an immortalized proximal tubule epithelial cell line) were exposed to 
      oleic acid (OA) to mimic the lipid overload environment in vitro. We found that 
      OA suppressed HK2 cell proliferation, triggered cytoskeleton rupture and cell 
      death. In OA-treated cells, upregulated expression of necroptosis pathway 
      proteins, phosphorylated receptor-interacting protein-1/3 (pRIPK1/3), 
      phosphorylated mixed lineage kinase domain-like protein (pMLKL), PGAM5, 
      phosphorylated dynamin-related protein 1 (pDRP1(S616)), and downregulated 
      pDRP1(S637) expression were observed. This was accompanied by mitochondrial 
      dysfunction (mitochondrial ROS overproduction and decreased mitochondrial 
      membrane potential) and increased cellular necrosis, as reflected by Annexin V/ 
      Propidium Iodide (PI) labeling. OA also induced the accumulation of LC3II and 
      P62, blocking autophagosome fusion with lysosomes. Knockdown of PGAM5 could 
      prevent these OA-induced changes. We propose inhibition of PGAM5 protects 
      lipid-induced RTECs from necroptosis by reducing DRP1-mediated mitochondrial 
      fission and improving mitophagy flux.
CI  - Copyright (c) 2022 The Authors. Published by Elsevier B.V. All rights reserved.
FAU - Dan Sang
AU  - Dan Sang
AD  - Department of Endocrinology, The Eighth Affiliated Hospital, Sun Yat-sen 
      University, Shenzhen, Guangdong 518033, People's Republic of China.
FAU - Duan, Xinyue
AU  - Duan X
AD  - Department of Cardiology, The Eighth Affiliated Hospital, Sun Yat-sen University, 
      Shenzhen, Guangdong 518033, People's Republic of China.
FAU - Yu, Xiaoli
AU  - Yu X
AD  - Oncology Department, The Eighth Affiliated Hospital, Sun Yat-sen University, 
      Shenzhen, Guangdong 518033, People's Republic of China.
FAU - Zang, Jiabin
AU  - Zang J
AD  - Department of Cardiology, The Eighth Affiliated Hospital, Sun Yat-sen University, 
      Shenzhen, Guangdong 518033, People's Republic of China.
FAU - Liu, Lan
AU  - Liu L
AD  - Department of Endocrinology, The Eighth Affiliated Hospital, Sun Yat-sen 
      University, Shenzhen, Guangdong 518033, People's Republic of China.
FAU - Wu, Guifu
AU  - Wu G
AD  - Department of Cardiology, The Eighth Affiliated Hospital, Sun Yat-sen University, 
      Shenzhen, Guangdong 518033, People's Republic of China; Guangdong Innovative 
      Engineering and Technology Research Center for Assisted Circulation, Shenzhen, 
      Guangdong 518033, People's Republic of China. Electronic address: 
      wuguifu@mail.sysu.edu.cn.
LA  - eng
PT  - Journal Article
DEP - 20221020
PL  - Netherlands
TA  - Toxicol Lett
JT  - Toxicology letters
JID - 7709027
RN  - EC 5.4.2.11 (Phosphoglycerate Mutase)
RN  - 0 (Lipids)
RN  - 0 (Mitochondrial Proteins)
SB  - IM
MH  - *Mitophagy
MH  - *Mitochondrial Dynamics
MH  - Necroptosis
MH  - Phosphoglycerate Mutase/metabolism
MH  - Epithelial Cells/metabolism
MH  - Lipids
MH  - Mitochondrial Proteins/genetics/metabolism
OTO - NOTNLM
OT  - Dynamin-related protein 1(DRP1)
OT  - Lipid-nephrotoxicity
OT  - Mitophagy
OT  - Necroptosis
OT  - Phosphoglycerate mutase 5 (PGAM5)
COIS- Declaration of Competing Interest The authors declare that they have no known 
      competing financial interests or personal relationships that could have appeared 
      to influence the work reported in this paper.
EDAT- 2022/10/24 06:00
MHDA- 2022/11/23 06:00
CRDT- 2022/10/23 19:34
PHST- 2022/05/12 00:00 [received]
PHST- 2022/10/02 00:00 [revised]
PHST- 2022/10/18 00:00 [accepted]
PHST- 2022/10/24 06:00 [pubmed]
PHST- 2022/11/23 06:00 [medline]
PHST- 2022/10/23 19:34 [entrez]
AID - S0378-4274(22)01764-7 [pii]
AID - 10.1016/j.toxlet.2022.10.003 [doi]
PST - ppublish
SO  - Toxicol Lett. 2023 Jan 1;372:14-24. doi: 10.1016/j.toxlet.2022.10.003. Epub 2022 
      Oct 20.