GPX4 at the Crossroads of Lipid Homeostasis and Ferroptosis

Forcina, Giovanni C.; Dixon, Scott J.

doi:10.1002/pmic.201800311

Cited by 515 publications

(294 citation statements)

References 135 publications

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“…Intriguingly, as a lipid peroxidase, GPX4 is the only peroxidase that reduces toxic lipid peroxides to non-toxic lipid alcohols in animal cells, and this task is achieved with the critical involvement of two glutathione (GSH) molecules [93]. This process prevents the iron-dependent formation of toxic lipid-ROS, and the functional inactivation of GPX4 results in an increased lipid-ROS accumulation and subsequent lipid peroxidation [94]. Indeed, current insights into the role of GPX4 has further improved our understanding of this selenoprotein in tissue redox homeostasis [95][96][97][98][99].…”

Section: Expression Of Gpx1 Gpx3 Gpx4 Selenof Bcl-2 and P21mentioning

confidence: 99%

“…Indeed, current insights into the role of GPX4 has further improved our understanding of this selenoprotein in tissue redox homeostasis [95][96][97][98][99]. Together with its role in lipid peroxidation, GPX4 is also considered as an essential regulator of physiologically important signaling lipids, and a balance between both of these functions is critical in maintaining homeostasis within a given cell (reviewed in [94]). To this effect, recent research has indeed shown that GPX4 is implicated in regulating ferroptosis (a form of necrotic cell death) in different epithelial cells lines, potentially by enzymatic scavenging of hydroperoxy lipids [100].…”

Section: Expression Of Gpx1 Gpx3 Gpx4 Selenof Bcl-2 and P21mentioning

confidence: 99%

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Dietary Selenium Supplementation Ameliorates Female Reproductive Efficiency in Aging Mice

et al. 2019

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Female reproductive (ovarian) aging is distinctively characterized by a markedly reduced reproductive function due to a remarkable decline in quality and quantity of follicles and oocytes. Selenium (Se) has been implicated in playing many important biological roles in male fertility and reproduction; however, its potential roles in female reproduction, particularly in aging subjects, remain poorly elucidated. Therefore, in the current study we used a murine model of female reproductive aging and elucidated how different Se-levels might affect the reproductive efficiency in aging females. Our results showed that at the end of an 8-week dietary trial, whole-blood Se concentration and blood total antioxidant capacity (TAOC) were significantly reduced in Se-deficient (0.08 mg Se/kg; Se-D) mice, whereas both of these biomarkers were significantly higher in inorganic (0.33 mg/kg; ISe-S) and organic (0.33 mg/kg; OSe-S) Se-supplemented groups. Similarly, compared to the Se-D group, Se supplementation significantly ameliorated the maintenance of follicles and reduced the rate of apoptosis in ovaries. Meanwhile, the rate of in vitro-produced embryos resulting from germinal vesicle (GV) oocytes was also significantly improved in Se-supplemented (ISe-S and OSe-S) groups compared to the Se-D mice, in which none of the embryos developed to the hatched blastocyst stage. RT-qPCR results revealed that mRNA expression of Gpx1, Gpx3, Gpx4, Selenof, p21, and Bcl-2 genes in ovaries of aging mice was differentially modulated by dietary Se levels. A considerably higher mRNA expression of Gpx1, Gpx3, Gpx4, and Selenof was observed in Se-supplemented groups compared to the Se-D group. Similarly, mRNA expression of Bcl-2 and p21 was significantly lower in Se-supplemented groups. Immunohistochemical assay also revealed a significantly higher expression of GPX4 in Se-supplemented mice. Our results reasonably indicate that Se deficiency (or marginal levels) can negatively impact the fertility and reproduction in females, particularly those of an advancing age, and that the Se supplementation (inorganic and organic) can substantiate ovarian function and overall reproductive efficiency in aging females.

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Section: Expression Of Gpx1 Gpx3 Gpx4 Selenof Bcl-2 and P21mentioning

confidence: 99%

Section: Expression Of Gpx1 Gpx3 Gpx4 Selenof Bcl-2 and P21mentioning

confidence: 99%

Dietary Selenium Supplementation Ameliorates Female Reproductive Efficiency in Aging Mice

et al. 2019

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“…More specifically, we show that an elevated pool of Fe 2+ iron characterizes PDA and other KRAS driven malignancies. Ferroaddiction comes at a cost however (Dixon et al, 2012), since labile Fe 2+ promotes intracellular Fenton chemistry, in turn resulting in elevated intracellular reactive oxygen species (ROS) (Dizdaroglu and Jaruga, 2012;Inoue and Kawanishi, 1987) and ferroptosis-associated lipid peroxidation that in turn engenders dependence on ROS-detoxifying enzymes like GPX4 (Forcina and Dixon, 2019;Liu et al, 2018) and FSP1 (Bersuker et al, 2019;Doll et al, 2019). Our studies in KRAS-driven cells and tumors directly link oncogenic KRAS to elevated Fe 2+ and a vulnerability to ferroptosis (Dixon et al, 2012).…”

Section: Discussionmentioning

confidence: 74%

Exploiting KRAS-driven Ferroaddiction in Cancer Through Ferrous Iron-Activatable Drug Conjugates (FeADC)

Jiang

Muir

Gonciarz

et al. 2020

Preprint

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KRAS mutations cause a quarter of cancer mortality and currently are not sensitive to any targeted, FDA-approved agents. Several inhibitors of the MAPK pathway are FDA approved but exhibit low clinical tolerability at doses needed to adequately extinguish KRAS signaling. We discovered an avidity for ferrous iron (Fe 2+ ) induced by and dependent on oncogenic KRAS signaling. We leveraged an FDA-approved MEK inhibitor to produce a prototypical Ferrous Iron-Activatable Drug Conjugate (FeADC) and with this novel agent achieved MAPK blockade in tumor cells while sparing normal tissues. These improvements allowed sustainable, effective treatment of tumor bearing animals with superior tolerability. Iron-activated therapeutics are unknown outside of antiparasitic therapy but may hold significant promise for the treatment of KRAS-driven solid tumors.driven PDA xenografts as compared to breast cancer xenografts with wt KRAS (Figure 1E). To assess levels of reduced iron in the same tumors, we used 18 F-TRX, our recently described (Muir et al., 2019) oxidation-state specific radiotracer for Fe 2+ . We found that the mKRAS-driven PDA tumors were enriched in Fe 2+ as compared to the wt KRAS tumors, mirroring our findings with 68 Ga (Figure S1A). Together these findings suggest that increased iron uptake and iron reduction are common in PDA and associated with poor patient prognosis.

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“…2B ). Although the significance of mitochondrial and nuclear Gpx4 remains to be determined (45), cytosolic Gpx4 has been identified as a central regulator of ferroptosis (11). We thus evaluated Gpx4 expression and localization in the gravid uterus and placenta exposed to DHT and INS.…”

Section: Resultsmentioning

confidence: 99%

Induction of hyperandrogenism and insulin resistance differentially modulates ferroptosis in uterine and placental tissues of pregnant rats

Zhang

Jia

et al. 2020

Preprint

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Ferroptosis, a form of regulated necrotic cell death, plays roles in diverse physiological processes and diseases. Women with polycystic ovary syndrome (PCOS) have hyperandrogenism and insulin resistance (HAIR) and an increased risk of miscarriage and placental dysfunction during pregnancy. However, whether maternal HAIR alters mechanisms leading to ferroptosis in the gravid uterus and placenta remains unknown. Previous studies in rats showed that maternal exposure to 5α-dihydrotestosterone (DHT) and insulin (INS) from gestational day 7.5 to 13.5 induces HAIR and subsequently leads to placental insufficiency and fetal loss. We therefore hypothesized that maternal HAIR triggers ferroptosis in the uterus and placenta in association with fetal loss in pregnant rats. Compared with controls, we found that co-exposure to DHT and INS led to decreased levels of Gpx4 and glutathione (GSH), increased GSH+glutathione disulfide (GSSG) and malondialdehyde (MDA), aberrant expression of ferroptosis-associated genes (Acsl4, Tfrc, Slc7a11, and Gclc), increased iron deposition, and activated ERK/p38/JNK phosphorylation in the gravid uterus. However, in the placenta, DHT and INS exposure only partially altered the expression of ferroptosis-related markers (e.g., region-dependent Gpx4, GSH+GSSG, MDA, Gls2 and Slc7a11 mRNAs, and phosphorylated p38 levels). In the uteri co-exposed to DHT and INS, we also observed shrunken mitochondria with electron-dense cristae, which are key features of ferroptosis-related mitochondrial morphology, as well as increased expression of Dpp4, a mitochondria-encoded gene responsible for ferroptosis induction. In contrast, in placentas co-exposed to DHT and INS we found decreased expression of Dpp4 mRNA and increased expression of Cisd1 mRNA (a mitochondria-encoded iron-export factor). Further, DHT+INS-exposed pregnant rats exhibited decreased apoptosis in the uterus and increased necroptosis in the placenta. Our findings suggest that maternal HAIR causes the activation of ferroptosis in the gravid uterus and placenta, although this is mediated via different mechanisms operating at the molecular and cellular levels. Furthermore, our data suggest other cell death pathways may play a role in coordinating or compensating for HAIR-induced ferroptosis when the gravid uterus and placenta are dysfunctional.

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GPX4 at the Crossroads of Lipid Homeostasis and Ferroptosis

Cited by 515 publications

References 135 publications

Dietary Selenium Supplementation Ameliorates Female Reproductive Efficiency in Aging Mice

Dietary Selenium Supplementation Ameliorates Female Reproductive Efficiency in Aging Mice

Exploiting KRAS-driven Ferroaddiction in Cancer Through Ferrous Iron-Activatable Drug Conjugates (FeADC)

Induction of hyperandrogenism and insulin resistance differentially modulates ferroptosis in uterine and placental tissues of pregnant rats

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