Mitochondrial rescue prevents glutathione peroxidase-dependent ferroptosis

Jelinek, Anja; Heyder, Lukas; Daude, Michael; Plessner, Matthias; Krippner, Sylvia; Grosse, Robert; Diederich, Wibke E.; Culmsee, Carsten

doi:10.1016/j.freeradbiomed.2018.01.019

Cited by 256 publications

(224 citation statements)

References 34 publications

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“…They synthesized MitoQ, a ubiquinone (coenzyme Q 10 ) molecule conjugated with TPP that selectively accumulates in mitochondria [76], and many researchers have reported various antioxidant therapeutic strategies using MitoQ to date. For example, in order to verify a therapeutic effect protects against oxidative cell death (such as cerebral ischemia), MitoQ was treated with neuronal HT22 cells [77].…”

Section: Mitochondria-targeted Delivery Of Antioxidants Using the Tppmentioning

confidence: 99%

Therapeutic Strategies for Regulating Mitochondrial Oxidative Stress

et al. 2020

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There have been many reports on the relationship between mitochondrial oxidative stress and various types of diseases. This review covers mitochondrial targeting photodynamic therapy and photothermal therapy as a therapeutic strategy for inducing mitochondrial oxidative stress. We also discuss other mitochondrial targeting phototherapeutic methods. In addition, we discuss anti-oxidant therapy by a mitochondrial drug delivery system (DDS) as a therapeutic strategy for suppressing oxidative stress. We also describe cell therapy for reducing oxidative stress in mitochondria. Finally, we discuss the possibilities and problems associated with clinical applications of mitochondrial DDS to regulate mitochondrial oxidative stress.Biomolecules 2020, 10, 83 2 of 23 Parkinson's and Alzheimer's diseases, by the direct neutralization of ROS and by suppressing inflammation [5,6]. Furthermore, CoQ 10 , a potent ubiquinone antioxidant, has been reported to show significant protective effects on mitochondria of the pancreatic beta cells during the oxidative stress induced by the chronic use of tacrolimus [7]. Due to the highly hydrophobic characteristics and the fact that most of the antioxidant molecules accumulate in a nonspecific manner, a high dose is needed to obtain the desired effects. Thus, the selective delivery of this compound would be expected to further strengthen its effectivity.In the context of cancer therapy, mitochondrial ROS were found to play an important role as a signaling molecule in controlling cell proliferation by virtue of its ability to regulate the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) signaling pathway [8]. Moreover, antioxidant activity, such as GSH and thioredoxin, was also reported to be essential for the initiation of and the progression of cancer. Inhibition of the antioxidant activity resulted in a significant reduction in tumor progression and metastasis [9][10][11]. These findings suggest that cancer cells are maintained under conditions of ROS stress and that antioxidant supplementation may be irrelevant for cancer therapy [12][13][14]. However, ROS interact with several major biologically active molecules such as proteins, lipids, and nucleic acids, leading to irreversible oxidative damage and the further induction of lethal effects for the cells. Therefore, promoting ROS production could be a promising strategy for treating tumors. There are numerous methods that can be employed to promote ROS levels in cancers, i.e., depleting or inhibiting antioxidant activity [15,16] and inhibiting the mitochondrial respiratory system [17], and producing an excessive amount of ROS through photochemical reactions. The latter effort shows a high selectivity for tumor cells, making it more encouraging in contrast to other efforts.This review focuses on therapeutic strategies for regulating mitochondrial oxidative stress. The main theme includes therapeutic strategies designed to induce oxidative stress and suppress mitochondrial oxidative stress (Figure 1). As ...

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Section: Mitochondria-targeted Delivery Of Antioxidants Using the Tppmentioning

confidence: 99%

Therapeutic Strategies for Regulating Mitochondrial Oxidative Stress

et al. 2020

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“…GSH is the most decreased cellular metabolite during ferroptosis, and GSH depletion causes loss of cellular antioxidant and inhibition of GPXs [13,42]. Ferroptosis induces GSH depletion, disrupted GPX4 function and ROS production [14,19,43]. Inhibition of GPX4 leads to the induction of ferroptosis [44], especially in drug-resistant tumors [45,46].…”

Section: Discussionmentioning

confidence: 99%

“…GPX4, an antioxidant defense enzyme is functional to repair oxidative damage to lipids and is a leading inhibitor of ferroptosis [18]. Ferroptosis is featured with GSH depletion, disrupted GPX4 redox defense, in ammation and detrimental lipid ROS formation [19,20]. However, whether GPX4-mediated ferroptosis is promising for ge tinib resistance in TNBC has not been reported.…”

Section: Introductionmentioning

confidence: 99%

Role of GPX4-Mediated Ferroptosis in the Sensitivity of Triple Negative Breast Cancer Cells to Gefitinib

Song

Wang

Liu

et al. 2020

Preprint

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Background: Gefitinib exhibits antitumor activity in the patients with breast cancer, but the resistance to gefitinib in triple negative breast cancer (TNBC) is a new concern. Glutathione peroxidase 4 (GPX4) is a leading regulator of ferroptosis, which is of importance for the survival of TNBC cells. This study investigated GPX4-mediated ferroptosis in gefitinib sensitivity in TNBC.Methods: Gefitinib resistant TNBC cells MDA-MB-231/Gef and HS578T/Gef were constructed, and treated with lentivirus sh-GPX4 and ferroptosis inhibitor ferrostatin-1. GPX4 expression, cell viability and apoptosis were detected. Malondialdehyde (MDA), glutathione (GSH), reactive oxygen species (ROS) levels were evaluated. The levels of ferroptosis-related proteins ACSL4, PTGS2, NOX1 and FTH1 were detected. Subcutaneous tumor model was established in nude mice, and gefitinib was intraperitoneally injected. Apoptosis was detected by TUNEL staining and Ki-67 expression was detected by immunohistochemistry.Results: GPX4 was increased in gefitinib-resistant cells. After silencing GPX4, the inhibition rate of cell viability increased, the limitation of colony formation ability reduced, apoptosis rate increased, and the sensitivity of cells to gefitinib was improved. After silencing GPX4, MDA level and ROS production were significantly increased, while GSH level was decreased. Silencing GPX4 promoted ferroptosis. After inhibition of ferroptosis by ferrostatin-1, it revealed that inhibition of GPX4 promoted gefitinib sensitivity by promoting cell ferroptosis. In vivo experiments also showed that inhibition of GPX4 enhanced the anticancer effect of gefitinib through promoting ferroptosis.Conclusion: Inhibition of GPX4 stimulated ferroptosis and thus enhanced TNBC cell sensitivity to gefitinib.

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“…Mitochondria play a protective role in the regulation of exhausted GSH-induced ferroptosis (26, 27). In women with PCOS and miscarriage (24, 28), as well as in pregnant PCOS-like rodents with fetal loss (18, 19, 29, 30), there is mounting evidence for mitochondrial abnormalities and oxidative damage.…”

Section: Introductionmentioning

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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Mitochondrial rescue prevents glutathione peroxidase-dependent ferroptosis

Cited by 256 publications

References 34 publications

Therapeutic Strategies for Regulating Mitochondrial Oxidative Stress

Therapeutic Strategies for Regulating Mitochondrial Oxidative Stress

Role of GPX4-Mediated Ferroptosis in the Sensitivity of Triple Negative Breast Cancer Cells to Gefitinib

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

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