PMID- 36180832
OWN - NLM
STAT- MEDLINE
DCOM- 20221004
LR  - 20230824
IS  - 1689-1392 (Electronic)
IS  - 1425-8153 (Print)
IS  - 1425-8153 (Linking)
VI  - 27
IP  - 1
DP  - 2022 Sep 30
TI  - Inhibition of CISD2 promotes ferroptosis through ferritinophagy-mediated ferritin 
      turnover and regulation of p62-Keap1-NRF2 pathway.
PG  - 81
LID - 10.1186/s11658-022-00383-z [doi]
LID - 81
AB  - BACKGROUND: CDGSH iron sulfur domain 2 (CISD2) is an iron-sulfur protein with a 
      [2Fe-2S] cluster, which is critical for cell proliferation and iron homeostasis. 
      It has been demonstrated that aberrant expression of CISD2 is associated with the 
      progression of multiple cancers. However, the underlying mechanism of CISD2 in 
      regulating tumorigenesis remains obscure. METHODS: Bioinformatics strategies were 
      used to investigate the protein interaction network and functional annotation of 
      CISD2. In the functional experiment, cell viability was measured by CCK-8 kit. 
      The levels of cellular reactive oxygen species (ROS), intracellular free iron, 
      lipid peroxides, and lysosomal activity were determined by DCF-DA, RPA, 
      C11-BODIPY, and cathepsin B staining, respectively. The glutathione (GSH) content 
      was determined using a GSH assay kit. RESULTS: We showed that knockdown of CISD2 
      significantly accelerated the Erastin-induced ferroptotic cell death with excess 
      lipid peroxidation, GSH exhaustion, and iron accumulation, while overexpression 
      of CISD2 hindered the sensitivity to Erastin. Further assays via confocal 
      microscopy and western blot exhibited that CISD2 knockdown markedly enhanced the 
      lysosomal activity, and activated ferritinophagy under the exposure of Erastin. 
      Pharmacological inhibition of lysosomal function could inhibit the degradation of 
      ferritin heavy chain (FTH), and attenuate the phenotypes of ferroptosis, such as 
      accelerated iron accumulation and lipid peroxidation. Notably, we found that 
      Erastin-induced compensatory elevation of nuclear factor erythroid 2-related 
      factor 2 (NRF2) could be eliminated in CISD2 depletion cells. Mechanically, CISD2 
      knockdown promoted the degradation of autophagy adaptor p62 and resulted in an 
      increased binding affinity of Keap1 with NRF2, thus leading to the increased 
      ubiquitination and subsequent degradation of NRF2. Enforced expression of NRF2 
      reversed the sensitivity of shCISD2 cells to ferroptosis both in vitro and 
      in vivo. Conversely, enforced expression of Keap1 exacerbated the degradation of 
      NRF2, reduced the transcriptional expression of FTH and heme oxygenase 1 (HO-1), 
      increased the oxidative damage, and thus further facilitated ferroptosis. 
      CONCLUSION: Taken together, our current results illustrated two parallel 
      mechanisms involved in the shCISD2-mediated ferroptosis. One was that shCISD2 
      enhanced the accumulation of free iron via ferritinophagy-dependent ferritin 
      turnover; the other was that CISD2 depletion induced the inhibition of the 
      p62-Keap1-NRF2 pathway, which resulted in oxidative stress and ferroptosis.
CI  - (c) 2022. The Author(s).
FAU - Li, Yanchun
AU  - Li Y
AD  - Department of Central Laboratory, Affiliated Hangzhou First People's Hospital, 
      Zhejiang University School of Medicine, Hangzhou, 310006, Zhejiang, China.
AD  - Department of Clinical Laboratory, Laboratory Medicine Center, Zhejiang 
      Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical 
      College), Hangzhou, 310014, Zhejiang, China.
FAU - Xu, Bing
AU  - Xu B
AD  - Department of Clinical Laboratory, Hangzhou Women's Hospital, Hangzhou, 310016, 
      Zhejiang, China.
FAU - Ren, Xueying
AU  - Ren X
AD  - Department of Laboratory Medicine, The Second Affiliated Hospital of Zhejiang 
      Chinese Medical University, 310005, Hangzhou, Zhejiang, China.
FAU - Wang, Luyang
AU  - Wang L
AD  - Department of Clinical Laboratory, Laboratory Medicine Center, Zhejiang 
      Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical 
      College), Hangzhou, 310014, Zhejiang, China.
FAU - Xu, Yaqing
AU  - Xu Y
AD  - Department of Clinical Laboratory, Laboratory Medicine Center, Zhejiang 
      Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical 
      College), Hangzhou, 310014, Zhejiang, China.
FAU - Zhao, Yefeng
AU  - Zhao Y
AD  - Department of Clinical Laboratory, Laboratory Medicine Center, Zhejiang 
      Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical 
      College), Hangzhou, 310014, Zhejiang, China.
FAU - Yang, Chen
AU  - Yang C
AD  - Department of Clinical Laboratory, Laboratory Medicine Center, Zhejiang 
      Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical 
      College), Hangzhou, 310014, Zhejiang, China.
FAU - Yuan, Chen
AU  - Yuan C
AD  - Department of Clinical Laboratory, Laboratory Medicine Center, Zhejiang 
      Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical 
      College), Hangzhou, 310014, Zhejiang, China.
FAU - Li, Huanjuan
AU  - Li H
AD  - Department of Clinical Laboratory, Laboratory Medicine Center, Zhejiang 
      Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical 
      College), Hangzhou, 310014, Zhejiang, China.
FAU - Tong, Xiangmin
AU  - Tong X
AD  - Department of Clinical Laboratory, Laboratory Medicine Center, Zhejiang 
      Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical 
      College), Hangzhou, 310014, Zhejiang, China. tongxiangmin@163.com.
FAU - Wang, Ying
AU  - Wang Y
AD  - Department of Central Laboratory, Affiliated Hangzhou First People's Hospital, 
      Zhejiang University School of Medicine, Hangzhou, 310006, Zhejiang, China. 
      nancywangying@163.com.
FAU - Du, Jing
AU  - Du J
AUID- ORCID: 0000-0001-7519-8531
AD  - Department of Clinical Laboratory, Laboratory Medicine Center, Zhejiang 
      Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical 
      College), Hangzhou, 310014, Zhejiang, China. dujing1@hmc.edu.cn.
LA  - eng
GR  - 82102938/National Natural Science Foundation of China/
PT  - Letter
DEP - 20220930
PL  - England
TA  - Cell Mol Biol Lett
JT  - Cellular & molecular biology letters
JID - 9607427
RN  - 0 (Iron-Sulfur Proteins)
RN  - 0 (Kelch-Like ECH-Associated Protein 1)
RN  - 0 (Lipid Peroxides)
RN  - 0 (NF-E2-Related Factor 2)
RN  - 0 (Reactive Oxygen Species)
RN  - 70FD1KFU70 (Sulfur)
RN  - 9007-73-2 (Ferritins)
RN  - 9013-31-4 (Apoferritins)
RN  - E1UOL152H7 (Iron)
RN  - EC 1.14.14.18 (Heme Oxygenase-1)
RN  - EC 3.4.22.1 (Cathepsin B)
RN  - GAN16C9B8O (Glutathione)
RN  - M03GIQ7Z6P (Sincalide)
SB  - IM
EIN - Cell Mol Biol Lett. 2023 Aug 24;28(1):69. PMID: 37620770
MH  - Apoferritins
MH  - Cathepsin B/metabolism
MH  - Ferritins/genetics
MH  - *Ferroptosis
MH  - Glutathione/metabolism
MH  - Heme Oxygenase-1/metabolism
MH  - Iron/metabolism
MH  - *Iron-Sulfur Proteins
MH  - Kelch-Like ECH-Associated Protein 1/genetics/metabolism
MH  - Lipid Peroxides/metabolism
MH  - NF-E2-Related Factor 2/metabolism
MH  - Reactive Oxygen Species/metabolism
MH  - Sincalide/metabolism
MH  - Sulfur/metabolism
PMC - PMC9523958
OTO - NOTNLM
OT  - Autophagy
OT  - CISD2
OT  - Ferritinophagy
OT  - Ferroptosis
OT  - Iron
COIS- The authors declare that there is no conflict of interest.
EDAT- 2022/10/01 06:00
MHDA- 2022/10/05 06:00
PMCR- 2022/09/30
CRDT- 2022/09/30 23:44
PHST- 2022/06/11 00:00 [received]
PHST- 2022/09/02 00:00 [accepted]
PHST- 2022/09/30 23:44 [entrez]
PHST- 2022/10/01 06:00 [pubmed]
PHST- 2022/10/05 06:00 [medline]
PHST- 2022/09/30 00:00 [pmc-release]
AID - 10.1186/s11658-022-00383-z [pii]
AID - 383 [pii]
AID - 10.1186/s11658-022-00383-z [doi]
PST - epublish
SO  - Cell Mol Biol Lett. 2022 Sep 30;27(1):81. doi: 10.1186/s11658-022-00383-z.