Aerobic pyruvate metabolism sensitizes cells to ferroptosis primed by GSH depletion

Vučković, Ana-Marija; Venerando, Rina; Tibaldi, Elena; Bosello-Travain, Valentina; Roveri, Antonella; Bordin, Luciana; Miotto, Giovanni; Cozza, Giorgio; Toppo, Stefano; Maiorino, Matilde; Ursini, Fulvio

doi:10.1016/j.freeradbiomed.2021.02.045

Cited by 23 publications

(12 citation statements)

References 38 publications

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“…Recent studies also demonstrated the role of dihydrolipoyl residue of PDH in ROS generation and ferroptosis. In contrast to KGDH, silencing of the E3 subunit of PDH increased the pro-ferroptotic effect of either glucose or its metabolite pyruvate, while downregulation of the E1 subunit, which catalyzes the first step of the overall process, has an anti-ferroptotic effect [ 34 ]. This study suggested non-enzymatic oxidation (autoxidation) of DHLA that is known to produce superoxide [ 11 , 35 ].…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies demonstrated protective effects of ETC inhibition on erastin- or cysteine deprivation (CD)-induced ferroptosis in mouse embryonic fibroblasts that were associated with accumulation of lipid peroxides [ 7 ]. Interestingly, no significant effects of antimycin A and FCCP on erastin-induced ferroptosis were found in HT-1080 cells [ 34 ]. The opposite effects of ETC and OXPHOS inhibition on cell death induced by RSL3 and erastin/CD can be explained by the differences in the mechanisms of action of these ferroptotic factors as well as in cell types (cancer vs. non-cancer cells).…”

Section: Discussionmentioning

confidence: 99%

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Elucidating the contribution of mitochondrial glutathione to ferroptosis in cardiomyocytes

et al. 2021

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Ferroptosis is a programmed iron-dependent cell death associated with peroxidation of lipids particularly, phospholipids. Several studies suggested a possible contribution of mitochondria to ferroptosis although the mechanisms underlying mitochondria-mediated ferroptotic pathways remain elusive. Reduced glutathione (GSH) is a central player in ferroptosis that is required for glutathione peroxidase 4 to eliminate oxidized phospholipids. Mitochondria do not produce GSH, and although the transport of GSH to mitochondria is not fully understood, two carrier proteins, the dicarboxylate carrier (DIC, SLC25A10 ) and the oxoglutarate carrier (OGC, SLC25A11 ) have been suggested to participate in GSH transport. Here, we elucidated the role of DIC and OGC as well as mitochondrial bioenergetics in ferroptosis in H9c2 cardioblasts. Results showed that mitochondria are highly sensitive to ferroptotic stimuli displaying fragmentation, and lipid peroxidation shortly after the onset of ferroptotic stimulus. Inhibition of electron transport chain complexes and oxidative phosphorylation worsened RSL3-induced ferroptosis. LC-MS/MS analysis revealed a dramatic increase in the levels of pro-ferroptotic oxygenated phosphatidylethanolamine species in mitochondria in response to RSL3 (ferroptosis inducer) and cardiac ischemia-reperfusion. Inhibition of DIC and OGC aggravated ferroptosis and increased mitochondrial ROS, membrane depolarization, and GSH depletion. Dihydrolipoic acid, an essential cofactor for several mitochondrial multienzyme complexes, attenuated ferroptosis and induced direct reduction of pro-ferroptotic peroxidized phospholipids to hydroxy-phospholipids in vitro . In conclusion, we suggest that ferroptotic stimuli diminishes mitochondrial bioenergetics and stimulates GSH depletion and glutathione peroxidase 4 inactivation leading to ferroptosis.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Elucidating the contribution of mitochondrial glutathione to ferroptosis in cardiomyocytes

et al. 2021

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“…Increased iron uptake and mobilization lead to the deposition of intracellular iron in ferroptosis. Third, mitochondria regulate energetic metabolism in ferroptosis [ 21 , 71 ]. Temporary activation of aerobic respiration is associated with oxidative injury to mitochondria in ferroptosis.…”

Section: The Fundamental Roles Of Organelles In Ferroptosismentioning

confidence: 99%

Targeting ferroptosis in acute kidney injury

Yuan

2022

Cell Death Dis

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Acute kidney injury (AKI) is a major public health problem with high incidence and mortality. As a form of programmed cell death (PCD), ferroptosis could be considered as a process of iron accumulation and enhanced lipid peroxidation. Recently, the fundamental roles of ferroptosis in AKI have attracted much attention. The network mechanism of ferroptosis in AKI and its roles in the AKI to chronic kidney disease (CKD) transition is complicated and multifactorial. Strategies targeting ferroptosis show great potential. Here, we review the research progress on ferroptosis and its participation in AKI. We hope that this work will provide clues for further studies of ferroptosis in AKI.

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“…In addition to GPX4 inhibition, intracellular GSH depletion is another key driver of ferroptosis induction [ 31 ]. GSH functions as a co-factor that enables GPX4 to eliminate lipid peroxides from cells [ 32 ]. GSH synthesis depends on system Xc- by exchanging extracellular cystine for intracellular glutamate.…”

Section: Discussionmentioning

confidence: 99%

JUND/linc00976 promotes cholangiocarcinoma progression and metastasis, inhibits ferroptosis by regulating the miR-3202/GPX4 axis

et al. 2022

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Long noncoding RNAs (lncRNAs) are a novel class of noncoding RNAs that have emerged as critical regulators and biomarkers in various cancers. Nevertheless, the expression profile and mechanistic function of lncRNAs in cholangiocarcinoma (CCA) remain unclear. Herein, we examined the expression levels of linc00976 in clinical specimens and cell lines using reverse transcription-quantitative PCR. In total, 50 patients with CCA were enrolled to analyze the correlation between linc00976 expression and clinical characteristics of CCA. Loss- and gain-of-function experiments were performed to investigate the biological effects of linc00976 on proliferation, ferroptosis, migration, and invasion of CCA cells in vitro and in vivo. In situ hybridization, RNA immunoprecipitation, bioinformatic databases, RNA pull-down assay, a dual-luciferase reporter assay, mRNA sequencing, chromatin immunoprecipitation–PCR, and rescue experiments were performed to elucidate the underlying mechanisms of linc00976-induced competitive endogenous RNA regulatory networks. We characterized a novel and abundant lncRNA, linc00976, that functions as a pro-oncogenic regulator of CCA progression. Compared with normal controls, linc00976 was dramatically upregulated in CCA tissue samples and cell lines. Patients with CCA exhibiting high linc00976 expression had a highly advanced clinical stage, substantial lymph node metastasis, and poor overall survival. Knockdown of linc00976 significantly repressed proliferation and metastasis and promoted ferroptosis of CCA cells both in vitro and in vivo, whereas linc00976 overexpression exerted the opposite effect. Mechanistically, linc00976 competitively interacted with miR-3202 to upregulate GPX4 expression, thus contributing to the malignant biological behavior of CCA cells. Moreover, we demonstrated that JUND specifically interacts with the linc00976 promoter and activates linc00976 transcription. Accordingly, JUND promotes linc00976 transcription, and linc00976 plays a crucial role in accelerating CCA tumorigenesis and metastasis and inhibiting ferroptosis by modulating the miR-3202/GPX4 axis. These findings suggest that targeting linc00976 may afford a promising therapeutic strategy for patients with CCA.

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Aerobic pyruvate metabolism sensitizes cells to ferroptosis primed by GSH depletion

Cited by 23 publications

References 38 publications

Elucidating the contribution of mitochondrial glutathione to ferroptosis in cardiomyocytes

Elucidating the contribution of mitochondrial glutathione to ferroptosis in cardiomyocytes

Targeting ferroptosis in acute kidney injury

JUND/linc00976 promotes cholangiocarcinoma progression and metastasis, inhibits ferroptosis by regulating the miR-3202/GPX4 axis

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