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Review
. 2022 Sep 23:9:1003340.
doi: 10.3389/fnut.2022.1003340. eCollection 2022.

Crosstalk between regulated necrosis and micronutrition, bridged by reactive oxygen species

Lei Zhang  1   2   3 , Jinting Liu  1   2   3 , Ziyan Dai  1   2   3 , Jia Wang  1   2   3 , Mengyang Wu  1   2   3 , Ruicong Su  1   2   3 , Di Zhang  1   2   3
Affiliations
Review

Crosstalk between regulated necrosis and micronutrition, bridged by reactive oxygen species

Lei Zhang et al. Front Nutr. .

Abstract

The discovery of regulated necrosis revitalizes the understanding of necrosis from a passive and accidental cell death to a highly coordinated and genetically regulated cell death routine. Since the emergence of RIPK1 (receptor-interacting protein kinase 1)-RIPK3-MLKL (mixed lineage kinase domain-like) axis-mediated necroptosis, various other forms of regulated necrosis, including ferroptosis and pyroptosis, have been described, which enrich the understanding of pathophysiological nature of diseases and provide novel therapeutics. Micronutrients, vitamins, and minerals, position centrally in metabolism, which are required to maintain cellular homeostasis and functions. A steady supply of micronutrients benefits health, whereas either deficiency or excessive amounts of micronutrients are considered harmful and clinically associated with certain diseases, such as cardiovascular disease and neurodegenerative disease. Recent advance reveals that micronutrients are actively involved in the signaling pathways of regulated necrosis. For example, iron-mediated oxidative stress leads to lipid peroxidation, which triggers ferroptotic cell death in cancer cells. In this review, we illustrate the crosstalk between micronutrients and regulated necrosis, and unravel the important roles of micronutrients in the process of regulated necrosis. Meanwhile, we analyze the perspective mechanism of each micronutrient in regulated necrosis, with a particular focus on reactive oxygen species (ROS).

Keywords: ferroptosis; iron; necroptosis; pyroptosis; reactive oxygen species; selenium; vitamins; zinc.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Molecular mechanisms of regulated necrosis. (A) Necroptosis. Activation of TNFR1 by TNFα induces the formation of complex I, which contains RIPK1, TRADD, TRAF2/5, and cIAP1/2. Then, RIPK1 is ubiquitinated by cIAP1/2 to form K63-ubiquitin chains, which is removed by A20. The formed K63 uboquitination recruits LUBAC to complex I, where LUBAC catalyzes the formation of M1-ubiquitin chain on RIPK1, which is removed by CYLD. K63 ubiquitination of RIPK1 promotes the formation of necrosome, which subsequently phosphorylates MLKL to initiate necroptosis. Whereas, M1 ubiquitination induces the assembly of complex IIa, which initiates apoptosis. When caspase 8 is inhibited, necroptosis is triggered via activation of necrosome. (B) Ferroptosis. Aberrant buildup of ROS induces lipid peroxidation, which leads to ferroptosis. Intracellular ferrous ion (Fe2+) catalyzes lipid peroxidation via Fenton reaction and LOXs. GPX4, in turn, hydrolyses lipid peroxides, converting them to corresponding lipid alcohols. The antioxidant activity of GPX4 requires the participation of GSH, whose synthesis depends on cystine/glutamate antiporter system Xc–. inhibition of GPX4 or system Xc– initiates ferroptosis. (C) Pyroptosis. PAMPs and DAMPs activate inflammasome assembly. Inflammaspme sensor (NLRP3) interacts with ASC, which recruits pro-caspase 1. Pro-caspase 1 is activated by autocleavage. Activated casapse 1 not only cleaves GSDMD to induce pyroptosis, but also processes the precursors of IL-1β/IL-18 to mature IL-1β/IL-18, which are released through the pores formed by N-GSDMD.
FIGURE 2
FIGURE 2
Selenium (Se) antagnized regulated necrosis. (A) Necroptosis. Se deficiency promotes necroptosis by manipulating microRNAs, which target specific proteins involving in necroptosis signaling, MAPK signaling, and PI3K/AKT signaling. (B) Ferroptosis. To begin the synthesis of selenocysteine (Sec), seryl-tRNA synthetase (SerRS) attaches serine (Ser) to tRNASec. Then, Ser-tRNASec is phosphorylated by O-phosphoseryl-tRNASec kinase (PSTK) at seryl group to generate phosphoseryl—tRNASec (P-Ser-tRNASec). Finally, Sep(O-phosphoserine) tRNA:Sec [selenocysteine] tRNA synthase (SEPSECS) converts P-Ser-tRNASec into selenocysteinyl (Sec)-tRNASec with the participation of selenophosphate (SeP), which is the main Se donor in the process, produced by selenophosphate synthetase 2 (SEPHS2). Synthesized Sec is then incorporated into GPX4, which inhibits the lipid peroxidation and blocks ferroptosis. Selenoprotein P (SelP) transports Se across the membrane. The increased Se upregulates the expression of GPX4 through transcriptional coactivators, TRAP2C and Sp1.
FIGURE 3
FIGURE 3
Iron metabolism and ferroptosis. Ferric state of iron (Fe3+) is bound to transferrin (Tf) in serum. Transferrin receptor 1 (TfR1) recognizes and binds the complex, which facilitates the endocytosis of ferric iron. The six-transmembrane epithelial antigen of the prostate-3 (Steap3) and acidic environment of the endosome jointly promote the reduction and release of ferrous iron (Fe2+). Divalent metal transporter 1 (DMT1) transports ferrous iron to cytoplasm, which is tightly controlled by ferritin. Autophagy (or ferritinophagy) selectively degrades ferritin with the coordination of nuclear receptor coactivator 4 (NCOA4), whose downregulation releases ferrous iron to activate lipid peroxidation, ultimately leading to ferroptosis. In addition, ferrous iron also triggers mitochondria-derived ROS through siderofexin (SFXN1). Ferroportin1 (FPN) can transport ferrous iron out of cell, which decreases the intracellular concentration of ferrous iron.
FIGURE 4
FIGURE 4
Dual roles of zinc (Zn) in regulated necrosis. ZIP transports Zn from ER to cytosol, which increases Zn level in cytoplasm. The increased Zn inhibits GPX4 and its cofactor GSH, and disturbs the intracellular iron homeostasis, which jointly trigger the accumulation of ROS and lead to ferroptosis. In addition, Zinc finger protein, YY2 inhibits GSH, which also activates ferroptosis. Besides ferroptosis, Zn and zinc finger proteins, ZFP91 and Sp1, facilitate activation of RIPK3 dependent necroptosis. Meanwhile, Zn activates NLRP3 inflammasome. Zinc finger proteins, ZNF377, GLI1, and Sp1 also induce pyroptosis. In the contrary, Zn upregulates GPX4 and GSH through NRF2 and HO-1 to counteract ferroptosis. ZNF498 and A20 also antagonize ferroptosis and necroptosis, respectively.
FIGURE 5
FIGURE 5
Vitamins and regulated necrosis. (A) Vitamin E. Vitamin E (VitE) attenuates regulated necrosis through downregulating the intracellular ROS. As lipophilic antioxidants, VitE can directly remove the lipid peroxides that accumulate in the cell. Meanwhile, VitE inhibits the activity of LOXs, which also blocks the lipid peroxidation. (B) Vitamin D. Vitamin D (VitD) activates vitamin D receptor (VDR), which (i) inhibits the formation of necrosome to block necroptosis; (ii) upregulates the expression of GPX4 to inhibit lipid peroxidation and resultant ferroptosis; (iii) inactivates inflammasome directly or via autophagy to inhibit pyroptosis. (C) Vitamin C. Vitamin C (VitC) upregulates the expression of RIPK1, RIPK3, and MLKL, which triggers necroptosis. In addition, VitC triggers lipid peroxidation by (i) inactivating GPX4: (ii) increasing the intracellular ferrous iron. The accumulated lipid peroxides lead to ferroptosis.
FIGURE 6
FIGURE 6
Crosstalk between prooxidant and antioxidant micronutrients in regulated necrosis process. Iron, as a prooxidant, catalyzes generation of ROS via Fenton reaction and LOXs. The antioxidant micronutrients counteract iron-mediated ROS production. Among them, selenium (Se) enhances GPX4 activity, and vitamin E (VitE) inhibits the activity of LOXs. Zinc (Zn) and vitamin D (VitD) attenuate iron-dependent ROS by modulating iron metabolism associated proteins. On the other hand, vitamin C (VitC) not only facilitates reduction of iron ion, but also upregulates iron metabolism associated proteins via IRP-IRE system, which jointly increase the cellular uptake of iron.
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References

    1. Riedl SJ, Shi Y. Molecular mechanisms of caspase regulation during apoptosis. Nat Rev Mol Cell Biol. (2004) 5:897–907. 10.1038/nrm1496 - DOI - PubMed
    1. Meier P, Finch A, Evan G. Apoptosis in development. Nature. (2000) 407:796–801. 10.1038/35037734 - DOI - PubMed
    1. Favaloro B, Allocati N, Graziano V, Di Ilio C, De Laurenzi V. Role of apoptosis in disease. Aging. (2012) 4:330–49. 10.18632/aging.100459 - DOI - PMC - PubMed
    1. Syntichaki P, Tavernarakis N. Death by necrosis. Uncontrollable catastrophe, or is there order behind the chaos? EMBO Rep. (2002) 3:604–9. 10.1093/embo-reports/kvf138 - DOI - PMC - PubMed
    1. Proskuryakov SY, Konoplyannikov AG, Gabai VL. Necrosis: a specific form of programmed cell death? Exp Cell Res. (2003) 283:1–16. 10.1016/s0014-482700027-7 - DOI - PubMed
-