Mitochondrial oxidative stress mediated Fe-induced ferroptosis via the NRF2-ARE pathway

Chen, Guanghui; Song, Chang-Chun; Pantopoulos, Kostas; Wei, Xiaolei; Zheng, Heng; Luo, Zhi

doi:10.1016/j.freeradbiomed.2022.01.012

Cited by 165 publications

(75 citation statements)

References 51 publications

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“…Furthermore, ML385, an Nrf2 inhibitor, not only downregulated GPx4 expression in SK-Hep1 ρ 0 cells but also significantly attenuated SK-Hep1 ρ 0 cell resistance to erastin (Fig. 1 H, I), supporting the role of Nrf2-dependent GPx4 induction in SK-Hep1 ρ 0 cells resistance against ferroptosis [ 18 , 19 ]. SK-Hep1 ρ 0 cell death by ML385 was abrogated by Fer-1 (Fig.…”

Section: Resultsmentioning

confidence: 82%

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Mitochondrial event as an ultimate step in ferroptosis

Ikeda

Ide

et al. 2022

Cell Death Discov.

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In ferroptosis, the roles of mitochondria have been controversial. To explore the role of mitochondrial events in ferroptosis, we employed mitochondrial DNA-depleted ρ0 cells that are resistant to cell death due to enhanced expression of antioxidant enzymes. Expression of mitochondrial-type GPx4 (mGPx4) but no other forms of GPx4 was increased in SK-Hep1 ρ0 cells. Likely due to high mGPx4 expression, SK-Hep1 ρ0 cells were resistant to ferroptosis by erastin inhibiting xCT channel. In contrast, SK-Hep1 ρ0 cells were susceptible to cell death by a high concentration of RSL3 imposing ferroptosis by GPx4 inhibition. Accumulation of cellular ROS and oxidized lipids was observed in erastin- or RSL3-treated SK-Hep1 ρ+ cells but not in erastin-treated SK-Hep1 ρ0 cells. Mitochondrial ROS and mitochondrial peroxidized lipids accumulated in SK-Hep1 ρ+ cells not only by RSL3 but also by erastin acting on xCT on the plasma membrane. Mitochondrial ROS quenching inhibited SK-Hep1 ρ+ cell death by erastin or a high dose of RSL3, suggesting a critical role of mitochondrial ROS in ferroptosis. Ferroptosis by erastin or RSL3 was inhibited by a more than 20-fold lower concentration of MitoQ, a mitochondrial ROS quencher, compared to DecylQ, a non-targeting counterpart. Ferroptosis of SK-Hep1 ρ+ cells by erastin or RSL3 was markedly inhibited by a VDAC inhibitor, accompanied by significantly reduced accumulation of mitochondria ROS, total peroxidized lipids, and mitochondrial peroxidized lipids, strongly supporting the role of mitochondrial events in ferroptotic death and that of VDAC in mitochondrial steps of ferroptosis induced by erastin or RSL3. SK-Hep1 ρ+ cell ferroptosis by sorafenib was also suppressed by mitochondrial ROS quenchers, accompanied by abrogation of sorafenib-induced mitochondrial ROS and mitochondrial peroxidized lipid accumulation. These results suggest that SK-Hep1 ρ0 cells are resistant to ferroptosis due to upregulation of mGPx4 expression and mitochondrial events could be the ultimate step in determining final cell fate.

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Section: Resultsmentioning

confidence: 82%

“…To study the mechanism of GPx4 induction in SK-Hep1 ρ 0 cells, we studied Nrf2, a master regulator of antioxidant responses and a transcriptional regulator of GPx4 [ 18 , 19 ]. Nrf2 expression was markedly increased in SK-Hep1 ρ 0 cells (Fig.…”

Section: Resultsmentioning

confidence: 99%

Mitochondrial event as an ultimate step in ferroptosis

Ikeda

Ide

et al. 2022

Cell Death Discov.

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“…Meantime, we found that the gene expression of keap1 was declined, but the gene expression of nrf2 was increased with the increment of dietary mixed plant protein levels; moreover, compared to other three groups, yellow catfish fed the control and RM10 diet had lowest Nrf2 protein expression but the highest Keap1 protein expression. Nrf2, an important transcriptional factor, regulates the expression of many antioxidative genes through the direct binding to the antioxidant response element (ARE) of target genes' promoters [12,52]. Keap1 can bind with Nrf2 protein, prevents its translocation to the nucleus, and promotes its ubiquitination-proteasomal Aquaculture Nutrition degradation [12,53].…”

Section: Discussionmentioning

confidence: 99%

“…Nrf2, an important transcriptional factor, regulates the expression of many antioxidative genes through the direct binding to the antioxidant response element (ARE) of target genes' promoters [12,52]. Keap1 can bind with Nrf2 protein, prevents its translocation to the nucleus, and promotes its ubiquitination-proteasomal Aquaculture Nutrition degradation [12,53]. Studies indicated that phenolic compounds can induce oxidative stress by regulating Keap1 and Nrf2 [9].…”

Section: Discussionmentioning

confidence: 99%

Fish Meal Replacement by Mixed Plant Protein in the Diets for Juvenile Yellow Catfish Pelteobagrus fulvidraco: Effects on Growth Performance and Health Status

Han

Luo

et al. 2022

Aquaculture Nutrition

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Increasing dietary replacement levels of fish meal by alternative plant proteins are of value for aquaculture. Here, a 10-week feeding experiment was undertaken to explore the effects of fish meal replacement by mixed plant protein (at a 2 : 3 ratio of cottonseed meal to rapeseed meal) on growth performance, oxidative and inflammatory responses, and mTOR pathway of yellow catfish Pelteobagrus fulvidraco. Yellow catfish ( 2.38 ± 0.1 g , mean ± SEM ) were randomly divided into 15 indoors fiberglass tanks, 30 fish each tank, and fed five isonitrogenous (44% crude protein) and isolipidic (9% crude fat) diets with fish meal replaced by mixed plant protein at 0% (the control), 10% (RM10), 20% (RM20), 30% (RM30), and 40% (RM40), respectively. Among five groups, fish fed the control, and RM10 diets tended to have higher growth performance, higher protein content, and lower lipid content in livers. Dietary mixed plant protein substitute increased hepatic free gossypol content and damaged liver histology and reduced the serum total essential amino acids, total nonessential amino acids, and total amino acid contents. Yellow catfish fed the control, and RM10 diets tended to have higher antioxidant capacity. Dietary mixed plant protein replacement tended to promote proinflammatory responses and inhibited mTOR pathway. Based on the second regression analysis of SGR against mixed plant protein substitutes, the optimal replacement level of fish meal by mixed plant protein was 8.7%.

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“…On one hand, Nrf2 can regulate the expression of GPX4 protein, while GPX4 overexpression results in ferroptosis resistance ( Fan et al, 2017 ; Cui et al, 2021 ; Gao et al, 2022 ). On the other hand, Nrf2 can directly bind with the antioxidant-responsive element (ARE) sequence of the SLC7A11 subunit promoter, increasing the expression of SLC7A11 and increasing the GSH level to inhibit ferroptosis ( Carpi-Santos and Calaza, 2018 ; Dong et al, 2020 ; Chen et al, 2022 ). Nrf2 regulates the intracellular free iron content by activating iron metabolism-related genes (SLC40A1).…”

Section: Molecular Mechanisms Of Ferroptosismentioning

confidence: 99%

Ferroptosis: A new therapeutic target for bladder cancer

et al. 2022

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Bladder cancer (BC) is the most frequent type of urinary system cancer. The prognosis of BC is poor due to high metastasis rates and multidrug resistance. Hence, development of novel therapies targeting BC cell death is urgently needed. As a novel cell death type with strong antitumor potential, ferroptosis has been investigated by many groups for its potential in BC treatment. As an iron-dependent cell death process, ferroptosis is characterized by excessive oxidative phospholipids. The molecular mechanisms of ferroptosis include iron overload and the system Xc-GSH-GPX4 signaling pathway. A recent study revealed that ferroptosis is involved in the metastasis, treatment, and prognosis of BC. Herein, in this review, we comprehensively summarize the mechanism of ferroptosis, address newly identified targets involved in ferroptosis, and discuss the potential of new clinical therapies targeting ferroptosis in BC.

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Mitochondrial oxidative stress mediated Fe-induced ferroptosis via the NRF2-ARE pathway

Cited by 165 publications

References 51 publications

Mitochondrial event as an ultimate step in ferroptosis

Mitochondrial event as an ultimate step in ferroptosis

Fish Meal Replacement by Mixed Plant Protein in the Diets for Juvenile Yellow Catfish Pelteobagrus fulvidraco: Effects on Growth Performance and Health Status

Ferroptosis: A new therapeutic target for bladder cancer

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