Polybrominated Diphenyl Ethers Quinone Induces NCOA4-Mediated Ferritinophagy through Selectively Autophagic Degradation of Ferritin

Dong, Wenjing; Ya, Tan; Qi, Qin; Yang, Benhui; Zhu, Qiqi; Liu, Xu; Liu, Zixuan; Song, Erqun; Song, Yang

doi:10.1021/acs.chemrestox.9b00350

Cited by 25 publications

(11 citation statements)

References 32 publications

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“…mRNA expression of NCOA4, which is a selective cargo receptor known to guide ferritin to the autolysosome, rapidly decreased after 2 h of hypoxia and reached significance after 4 h (Fig. 1L) [ 18 , 19 ]. The decrease of NCOA4 mRNA may suggest a link between ferritinophagy and hypoxia.…”

Section: Resultsmentioning

confidence: 99%

“…Iron release from ferritins is regulated by a process known as ferritinophagy. Ferritinophagy is mediated by nuclear receptor coactivator 4 (NCOA4), which directly binds FTH and transfers the complex to the autolysosome for degradation [ [15] , [16] , [17] , [18] ]. NCOA4 has, in contrast to FTH, a low affinity to FTL indicating that ferritinophagy is predominantly regulated via the NCOA4-FTH system [ 19 ].…”

Section: Introductionmentioning

confidence: 99%

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Hypoxia inhibits ferritinophagy, increases mitochondrial ferritin, and protects from ferroptosis

et al. 2020

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Cellular iron, at the physiological level, is essential to maintain several metabolic pathways, while an excess of free iron may cause oxidative damage and/or provoke cell death. Consequently, iron homeostasis has to be tightly controlled. Under hypoxia these regulatory mechanisms for human macrophages are not well understood. Hypoxic primary human macrophages reduced intracellular free iron and increased ferritin expression, including mitochondrial ferritin (FTMT), to store iron. In parallel, nuclear receptor coactivator 4 (NCOA4), a master regulator of ferritinophagy, decreased and was proven to directly regulate FTMT expression. Reduced NCOA4 expression resulted from a lower rate of hypoxic NCOA4 transcription combined with a micro RNA 6862-5p-dependent degradation of NCOA4 mRNA, the latter being regulated by c-jun N-terminal kinase (JNK). Pharmacological inhibition of JNK under hypoxia increased NCOA4 and prevented FTMT induction. FTMT and ferritin heavy chain (FTH) cooperated to protect macrophages from RSL-3-induced ferroptosis under hypoxia as this form of cell death is linked to iron metabolism. In contrast, in HT1080 fibrosarcome cells, which are sensitive to ferroptosis, NCOA4 and FTMT are not regulated. Our study helps to understand mechanisms of hypoxic FTMT regulation and to link ferritinophagy and macrophage sensitivity to ferroptosis.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Hypoxia inhibits ferritinophagy, increases mitochondrial ferritin, and protects from ferroptosis

et al. 2020

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“…There is a fundamental difference in molecular mechanism between ferroptosis and other cell death, including apoptosis, necrosis and autophagy (Gao et al, 2016). Ferroptosis is morphologically manifest by smaller mitochondria with condensed membrane and reduced or vanished cristae (Dong et al, 2019;Park & Chung, 2019). Increasing evidences show that ferroptosis serves a crucial role in cancer cell death among various cancer types including CRC (Chen et al, 2020;Guo et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Role of ferroptosis-related genes in prognostic prediction and tumor immune microenvironment in colorectal carcinoma

Yang

Huang

Cao

et al. 2021

PeerJ

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Background and Aim Colorectal cancer (CRC) ranks the second most common cause of cancer-related mortality worldwide. Ferroptosis, a recently discovered form of programmed cell death different from other, raises promising novel opportunities for therapeutic intervention of CRC. This study intended to systematically assess the prognosis value and multiple roles of the ferroptosis-related genes in the tumor immune microenvironment of CRC. Materials and Methods Of 1,192 CRC patients with complete information from the public datasets (TCGA CRC, GEO GSE39582 and GSE17538 cohorts) were selected for analysis. Firstly, K-means consensus clustering was performed to identify ferroptosis-associated subtypes in CRC patients. Subsequently, we constructed a risk signature based on ferroptosis-related genes in TCGA cohort and acquired its validation in two GEO cohorts. Additionally, we established a nomogram integrating the risk signature and clinical factors to improve risk assessment of CRC patients. Results Five molecular subtypes were identified by consensus clustering for ferroptosis-related genes. There were significant differences in the overall survival, immune cells infiltration status and PD1/PD-L1 mRNA among the five clusters. Then, a risk signature based on the ten-gene was constructed which could distinguish effectively high-risk group among CRC patients in both training and validation sets. The high-risk patients were more likely to have an inhibitory immune microenvironment and lower stemness features. A prognostic nomogram integrated risk signature and clinicopathological features could be used as a more accurate prognostic prediction visualization tool than TNM stage alone. Conclusion This ferroptosis risk signature may accurately differentiate between different risk populations and predict the prognosis of CRC. Besides, this study elucidated the crucial role of ferroptosis in tumor immune microenvironment.

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“…In addition, their further peroxidase-oxidated products, quinones, may occur. Previously, our studies have demonstrated a highly reactive metabolite, PBDEs quinone (PBDEQ), exposure results in ROS production in cells, accompanied by autophagy, apoptosis, and DNA damage. , However, it is currently unknown whether PBDEQ causes pyroptosis or activates inflammasome. In the present study, we demonstrated the pyroptosis and NLRP3 inflammasome activation induced by PBDEQ in J774A.1 macrophages.…”

Section: Introductionmentioning

confidence: 99%

Polybrominated Diphenyl Ether Quinone Exposure Induces Atherosclerosis Progression via CD36-Mediated Lipid Accumulation, NLRP3 Inflammasome Activation, and Pyroptosis

Wang

Fang

Liu

et al. 2021

Chem. Res. Toxicol.

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Polybrominated diphenyl ethers (PBDEs) are used worldwide in brominated flame retardants. Although due to the forbiddance of their application, PBDEs continuously exist in the environment due to their persistence. Therefore, it is important to expand the understanding of their potential toxicities and human risks. The underlying cardiovascular toxicological mechanisms of PBDEs are still largely unknown. Our previous studies indicated that PBDE quinone-type metabolite (PBDEQ) exposure causes reactive oxygen species (ROS)-driven cytotoxicity and various types of programmed cell death. Here, we first reported PBDEQ exposure induces atherosclerosis progression in bone marrow-derived macrophages (BMDMs) isolated from wild-type C57BL/6 or CD36 −/− mice and J774A.1 macrophage models. First, we found that PBDEQ exposure induced lipid accumulation in oxidized low-density lipid (Ox-LDL)-treated J774A.1 macrophages. Consistently, in J774A.1 macrophages, PBDEQ exposure resulted in NLR family pyrin domain containing 3 (NLRP3) inflammasome activation and pyroptosis. CD36, a scavenger receptor responsible for the mediation of Ox-LDL uptake, was upregulated upon PBDEQ treatment. On the contrary, genetic knockout of CD36 or CD36 silencing by small interfering RNA efficiently attenuates PBDEQ-promoted lipid accumulation in BMDMs and J774A.1 macrophages. These findings highlight the effect of CD36 on the cardiovascular toxicity of PBDEs, which provides a better understanding of the pro-atherosclerosis effect of PBDEs.

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Polybrominated Diphenyl Ethers Quinone Induces NCOA4-Mediated Ferritinophagy through Selectively Autophagic Degradation of Ferritin

Cited by 25 publications

References 32 publications

Hypoxia inhibits ferritinophagy, increases mitochondrial ferritin, and protects from ferroptosis

Hypoxia inhibits ferritinophagy, increases mitochondrial ferritin, and protects from ferroptosis

Role of ferroptosis-related genes in prognostic prediction and tumor immune microenvironment in colorectal carcinoma

Polybrominated Diphenyl Ether Quinone Exposure Induces Atherosclerosis Progression via CD36-Mediated Lipid Accumulation, NLRP3 Inflammasome Activation, and Pyroptosis

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