Cellular degradation systems in ferroptosis

In eukaryotic cells, macromolecular homeostasis requires selective degradation of damaged units by the ubiquitin-proteasome system (UPS) and autophagy. Thus, dysfunctional degradation systems contribute to multiple pathological processes. Ferroptosis is a type of iron-dependent oxidative cell death...

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Bibliographic Details
Published in:Cell death and differentiation 2021-04, Vol.28 (4), p.1135-1148
Main Authors: Chen, Xin, Yu, Chunhua, Kang, Rui, Kroemer, Guido, Tang, Daolin
Format: Article
Language:English
Subjects:
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Animals
Antioxidants
Apoptosis
Autophagic Cell Death - physiology
Autophagy
Autophagy - physiology
Biochemistry
Biomedical and Life Sciences
Cell Biology
Cell Cycle Analysis
Cell death
Circadian rhythms
Degradation
Ferritin
Ferroptosis
Ferroptosis - physiology
Glutathione
HMGB1 protein
Homeostasis
Humans
Life Sciences
Lipid peroxidation
Lipids
Lysosomes - metabolism
Lysosomes - pathology
Macromolecules
Molecular Chaperones - metabolism
Phagocytosis
Proteasomes
Repressors
Review
Review Article
Signal Transduction - physiology
Stem Cells
TOR protein
Ubiquitin
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Summary:In eukaryotic cells, macromolecular homeostasis requires selective degradation of damaged units by the ubiquitin-proteasome system (UPS) and autophagy. Thus, dysfunctional degradation systems contribute to multiple pathological processes. Ferroptosis is a type of iron-dependent oxidative cell death driven by lipid peroxidation. Various antioxidant systems, especially the system xc − -glutathione-GPX4 axis, play a significant role in preventing lipid peroxidation-mediated ferroptosis. The endosomal sorting complex required for transport-III (ESCRT-III)–dependent membrane fission machinery counteracts ferroptosis by repairing membrane damage. Moreover, cellular degradation systems play a dual role in regulating the ferroptotic response, depending on the cargo they degrade. The key ferroptosis repressors, such as SLC7A11 and GPX4, are degraded by the UPS. In contrast, the overactivation of selective autophagy, including ferritinophagy, lipophagy, clockophagy and chaperone-mediated autophagy, promotes ferroptotic death by degrading ferritin, lipid droplets, circadian proteins, and GPX4, respectively. Autophagy modulators (e.g., BECN1, STING1/TMEM173, CTSB, HMGB1, PEBP1, MTOR, AMPK, and DUSP1) also determine the ferroptotic response in a context-dependent manner. In this review, we provide an updated overview of the signals and mechanisms of the degradation system regulating ferroptosis, opening new horizons for disease treatment strategies.
ISSN:1350-9047
1476-5403
DOI:10.1038/s41418-020-00728-1