Disrupting CISD2 function in cancer cells primarily impacts mitochondrial labile iron levels and triggers TXNIP expression.
CISD2
Cancer
Ferroptosis
Iron homeostasis
Iron-sulfur cluster [Fe–S]
Mitochondria
NAF-1
Oxidative stress
Reactive oxygen species (ROS)
TXNIP
Journal
Free radical biology & medicine
ISSN: 1873-4596
Titre abrégé: Free Radic Biol Med
Pays: United States
ID NLM: 8709159
Informations de publication
Date de publication:
20 11 2021
20 11 2021
Historique:
received:
28
07
2021
revised:
14
09
2021
accepted:
15
09
2021
pubmed:
22
9
2021
medline:
24
11
2021
entrez:
21
9
2021
Statut:
ppublish
Résumé
The CISD2 (NAF-1) protein plays a key role in regulating cellular homeostasis, aging, cancer and neurodegenerative diseases. It was found to control different calcium, reactive oxygen species (ROS), and iron signaling mechanisms. However, since most studies of CISD2 to date were conducted with cells that constitutively lack, overexpress, or contain mutations in CISD2, the relationships between these different signaling processes are unclear. To address the hierarchy of signaling events occurring in cells upon CISD2 disruption, we developed an inducible system to express CISD2, or the dominant-negative H114C inhibitor of CISD2, in human breast cancer cells. Here, we report that inducible disruption of CISD2 function causes an immediate disruption in mitochondrial labile iron (mLI), and that this disruption results in enhanced mitochondrial ROS (mROS) levels. We further show that alterations in cytosolic and ER calcium levels occur only after the changes in mLI and mROS levels happen and are unrelated to them. Interestingly, disrupting CISD2 function resulted in the enhanced expression of the tumor suppressor thioredoxin-interacting protein (TXNIP) that was dependent on the accumulation of mLI and associated with ferroptosis activation. CISD2 could therefore regulate the expression of TXNIP in cancer cells, and this regulation is dependent on alterations in mLI levels.
Identifiants
pubmed: 34547371
pii: S0891-5849(21)00725-5
doi: 10.1016/j.freeradbiomed.2021.09.013
pmc: PMC8761261
mid: NIHMS1742977
pii:
doi:
Substances chimiques
CISD2 protein, human
0
Carrier Proteins
0
Membrane Proteins
0
Reactive Oxygen Species
0
TXNIP protein, human
0
Iron
E1UOL152H7
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
92-104Subventions
Organisme : NIGMS NIH HHS
ID : R01 GM111364
Pays : United States
Informations de copyright
Copyright © 2021 Elsevier Inc. All rights reserved.
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