Identification of Frataxin as a regulator of ferroptosis.
Ferroptosis
Frataxin
Iron-sulfur cluster
Mitochondria
Journal
Redox biology
ISSN: 2213-2317
Titre abrégé: Redox Biol
Pays: Netherlands
ID NLM: 101605639
Informations de publication
Date de publication:
05 2020
05 2020
Historique:
received:
27
11
2019
revised:
15
02
2020
accepted:
28
02
2020
pubmed:
15
3
2020
medline:
22
6
2021
entrez:
15
3
2020
Statut:
ppublish
Résumé
Ferroptosis is a newly discovered form of non-apoptotic regulated cell death and is characterized by iron-dependent and lipid peroxidation. Due to the enhanced dependence on iron in cancer cells, induction of ferroptosis is becoming a promising therapeutic strategy. However, the precise underlying molecular mechanism and regulation process of ferroptosis remains largely unknown. In the present study, we demonstrate that the protein Frataxin (FXN) is a key regulator of ferroptosis by modulating iron homeostasis and mitochondrial function. Suppression of FXN expression specifically repressed the proliferation, destroyed mitochondrial morphology, impeded Fe-S cluster assembly and activated iron starvation stress. Moreover, suppression of FXN expression significantly enhanced erastin-induced cell death through accelerating free iron accumulation, lipid peroxidation and resulted in dramatic mitochondria morphological damage including enhanced fragmentation and vanished cristae. In addition, this type of cell death was confirmed to be ferroptosis, since it could be pharmacologically restored by ferroptotic inhibitor Fer-1 or GSH, but not by inhibitors of apoptosis, necrosis. Vice versa, enforced expression of FXN blocked iron starvation response and erastin-induced ferroptosis. More importantly, pharmacological or genetic blocking the signal of iron starvation could completely restore the resistance to ferroptosis in FXN knockdown cells and xenograft graft in vivo. This paper suggests that FXN is a novel ferroptosis modulator, as well as a potential provided target to improve the antitumor activity based on ferroptosis.
Identifiants
pubmed: 32169822
pii: S2213-2317(19)31475-2
doi: 10.1016/j.redox.2020.101483
pmc: PMC7068686
pii:
doi:
Substances chimiques
Iron-Binding Proteins
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
101483Commentaires et corrections
Type : ErratumIn
Informations de copyright
Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of competing interest The authors declare that there is no conflict of interest.
Références
Free Radic Biol Med. 2018 Dec;129:454-462
pubmed: 30339884
Hepatology. 2016 Jan;63(1):173-84
pubmed: 26403645
Mol Cell Oncol. 2015 May 26;2(4):e1054549
pubmed: 27308510
J Biol Chem. 2003 Oct 17;278(42):40612-20
pubmed: 12902335
Cell Res. 2016 Sep;26(9):1021-32
pubmed: 27514700
J Biol Chem. 2018 May 25;293(21):8297-8311
pubmed: 29523684
Free Radic Biol Med. 2010 Feb 1;48(3):411-20
pubmed: 19932164
J Bioenerg Biomembr. 2008 Oct;40(5):445-56
pubmed: 18843528
Free Radic Biol Med. 2019 Mar;133:1-2
pubmed: 30736912
Free Radic Biol Med. 2019 Mar;133:153-161
pubmed: 30217775
Rev Physiol Biochem Pharmacol. 2018;174:25-65
pubmed: 28828516
Sci Rep. 2017 Dec 15;7(1):17667
pubmed: 29247214
Mol Cell. 2019 Jan 17;73(2):354-363.e3
pubmed: 30581146
Cell. 2012 May 25;149(5):1060-72
pubmed: 22632970
Redox Biol. 2017 Apr;11:254-262
pubmed: 28012440
J Hematol Oncol. 2019 Mar 29;12(1):34
pubmed: 30925886
Proc Natl Acad Sci U S A. 2019 Sep 24;116(39):19421-19430
pubmed: 31511419
Cerebellum. 2017 Aug;16(4):840-851
pubmed: 28456899
Int J Hematol. 2018 Jan;107(1):44-54
pubmed: 29139060
Free Radic Biol Med. 2019 Mar;133:130-143
pubmed: 30268886
Hum Mol Genet. 2000 May 1;9(8):1219-26
pubmed: 10767347
J Pharmacol Exp Ther. 2019 Apr;369(1):47-54
pubmed: 30635474
Nat Rev Cancer. 2013 May;13(5):342-55
pubmed: 23594855
Cell Death Dis. 2016 May 26;7:e2237
pubmed: 27228352
Nature. 2017 Nov 30;551(7682):639-643
pubmed: 29168506
Metallomics. 2017 Nov 15;9(11):1483-1500
pubmed: 28879348
Kidney Int. 2019 Aug;96(2):291-301
pubmed: 31005270
Ann N Y Acad Sci. 2016 Mar;1368(1):149-61
pubmed: 26890363
Nucleic Acids Res. 2004 Aug 10;32(14):e115
pubmed: 15304544
FEBS Lett. 2018 Mar;592(5):718-727
pubmed: 29197070
Cancer Cell. 2019 Jun 10;35(6):830-849
pubmed: 31105042
Antioxid Redox Signal. 2018 Dec 20;29(18):1809-1829
pubmed: 28967283
ACS Chem Biol. 2018 Apr 20;13(4):1013-1020
pubmed: 29512999
Cell. 2019 May 30;177(6):1507-1521.e16
pubmed: 31031004
Free Radic Biol Med. 2017 Jul;108:610-626
pubmed: 28433662
Free Radic Biol Med. 2019 Feb 1;131:356-369
pubmed: 30557609
Am J Pathol. 2017 Dec;187(12):2858-2875
pubmed: 28935570
Redox Biol. 2019 May;23:101107
pubmed: 30692038
Autophagy. 2016 Aug 2;12(8):1425-8
pubmed: 27245739
Sci Rep. 2017 Aug 29;7(1):9840
pubmed: 28852135
Antioxid Redox Signal. 2013 Nov 1;19(13):1481-93
pubmed: 23350650