Ferritinophagy-mediated ferroptosis is involved in sepsis-induced cardiac injury

Li, Ning; Wang, Wei; Zhou, Haoming; Wu, Qin; Duan, Mingxia; Liu, Chen; Wu, Hongyan; Deng, Wei; Shen, Difei

doi:10.1016/j.freeradbiomed.2020.08.009

Cited by 384 publications

(298 citation statements)

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“…In addition, the peroxidation of the mitochondrial phospholipid cardiolipin initiates apoptosis while the accumulation of peroxidised phosphatidyl ethanolamines (PE) promote the cellular necrosis, ferroptosis (Bersuker et al, 2019; Conrad and Pratt, 2019; Doll et al, 2017, 2019; Kagan et al, 2017; Wiernicki et al, 2020; Yang et al, 2016). Specifically, the dysregulation of lipid peroxidation processes is associated with various human pathologies such as cancer chemoresistance, brain and ischemia injuries, neurological alterations, metabolic diseases as well as tuberculosis susceptibility (Amaral et al, 2019; Dar et al, 2018; Li et al, 2020; Meunier and Neyrolles, 2019; Stockwell et al, 2020; Zhu et al, 2019). In this context, the enzymes glutathione peroxidase 4 (GPX4) and ferroptosis-suppressor protein-1 (FSP1) that belongs to the CoQ antioxidant system, detoxify phospholipid hydroperoxide accumulation, hence allowing lipid peroxide amounts to be balancedin cells (Bersuker et al, 2019; Dixon et al, 2012; Doll et al, 2019; Friedmann Angeli et al, 2014; Yang et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

Phospholipid peroxidation fuels ExoU phospholipase-dependent cell necrosis and supportsPseudomonas aeruginosa-driven pathology

Bagayoko

Leon-Icaza

Pinilla

et al. 2021

Preprint

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Regulated cell necrosis supports immune and anti-infectious strategies of the body; however, dysregulation of these processes drives pathological organ damage. Pseudomonas aeruginosa expresses a phospholipase, ExoU that triggers pathological host cell necrosis through a poorly characterized pathway. Here, we investigated the molecular and cellular mechanisms of ExoU-mediated necrosis. We show that cellular peroxidised phospholipids enhance ExoU phospholipase activity, which drives necrosis of immune and non-immune cells. Conversely, both the endogenous lipid peroxidation regulator GPX4 and the pharmacological inhibition of lipid peroxidation delay ExoU-dependent cell necrosis and improve bacterial elimination in vitro and in vivo. Our findings also pertain to the ExoU-related phospholipase from the bacterial pathogen Burkholderia thailandensis, suggesting that exploitation of peroxidised phospholipids might be a conserved virulence mechanism among various microbial phospholipases. Overall, our results identify an original lipid peroxidation-based virulence mechanism as a strong contributor of microbial phospholipase-driven pathology.

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Section: Introductionmentioning

confidence: 99%

Phospholipid peroxidation fuels ExoU phospholipase-dependent cell necrosis and supportsPseudomonas aeruginosa-driven pathology

Bagayoko

Leon-Icaza

Pinilla

et al. 2021

Preprint

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“…NCOA4 mediated regulation of SFXN1 was also reported in a recent study addressing the role of ferritinophagy in sepsis-induced cardiac injury [91]. In this study, SFXN1 was shown to be upregulated at the mRNA level in LPS-treated cardiomyocytes, but whether this upregulation results from a transcriptional activation or an enhanced stability of mRNA was not studied.…”

Section: Sfxn1 and Ferritinophagymentioning

confidence: 54%

“…Recently, SFXN1 was shown to participate in LPS-induced ferroptosis in H9c2 cardiomyocytes, a process depending of NCO4A-mediated ferritinophagy [91]. Li et al showed an LPS-and NCOA4-dependent upregulation of SFXN1 and documented the role of SFXN1 in LPS-induced ferroptosis.…”

Section: Sfxn Cell Death and Ferroptosismentioning

confidence: 99%

Insights into the Roles of the Sideroflexins/SLC56 Family in Iron Homeostasis and Iron-Sulfur Biogenesis

et al. 2021

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Sideroflexins (SLC56 family) are highly conserved multi-spanning transmembrane proteins inserted in the inner mitochondrial membrane in eukaryotes. Few data are available on their molecular function, but since their first description, they were thought to be metabolite transporters probably required for iron utilization inside the mitochondrion. Such as numerous mitochondrial transporters, sideroflexins remain poorly characterized. The prototypic member SFXN1 has been recently identified as the previously unknown mitochondrial transporter of serine. Nevertheless, pending questions on the molecular function of sideroflexins remain unsolved, especially their link with iron metabolism. Here, we review the current knowledge on sideroflexins, their presumed mitochondrial functions and the sparse—but growing—evidence linking sideroflexins to iron homeostasis and iron-sulfur cluster biogenesis. Since an imbalance in iron homeostasis can be detrimental at the cellular and organismal levels, we also investigate the relationship between sideroflexins, iron and physiological disorders. Investigating Sideroflexins’ functions constitutes an emerging research field of great interest and will certainly lead to the main discoveries of mitochondrial physio-pathology.

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“…AKR1C3 has been proven to inhibit lipid peroxidation to promote ferroptosis and has increased expression in zero-valent iron (ZVI)-induced ferroptosis [40]. The increase in PTGS2 has been con rmed by many studies as one of the hallmarks of the occurrence of ferroptosis [41], [42]. G6PD is involved in the pentose phosphate pathway [43].…”

Section: Discussionmentioning

confidence: 99%

A ferroptosis-associated gene signature for the prediction of prognosis and therapeutic response in luminal-type breast carcinoma

Peng

Zhang

et al. 2021

Preprint

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Background: Ferroptosis is a new form of regulated cell death (RCD), and its emergence has provided a new approach to the progression and drug resistance of breast cancer (BRCA). However, there is still a great gap in the study of ferroptosis-related genes in BRCA, especially luminal-type BRCA patients.Methods: We downloaded the mRNA expression profiles and corresponding clinical data of BRCA patients from the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) and The Cancer Genome Atlas (TCGA) databases. Then, we built a prognostic multigene signature with ferroptosis-related differentially expressed genes (DEGs) in the METABRIC cohort and validated it in the TCGA cohort. The predictive value of this signature was investigated in terms of mutations, copy number variations (CNVs), the immune microenvironment and the probability of a response to immunotherapy and chemotherapy.Findings: The patients were divided into a high-risk group and a low-risk group by the ferroptosis-associated gene signature, and the high-risk group had a worse overall survival (OS). The risk score based on the 10 ferroptosis-related gene-based signature was determined to be an independent prognostic predictor in both the METABRIC and TCGA cohorts (HR, 1.41, 95% CI, 1.14-1.76, P = 0.002; HR, 2.19, 95% CI, 1.13-4.26, P= 0.02). Gene set enrichment analysis indicated that the term “cytokine-cytokine receptor interaction” was enriched in the high-risk score subgroup. Moreover, the immune infiltration scores of most immune cells were significantly different between the two groups, and the low-risk group was much more sensitive to immunotherapy and six drugs might have potential therapeutic implications in high- risk group. In addition, we found that amplifications on chromosome 11 accompanied by the deletion of chromosome 1 were enriched in the high-risk subgroup. Finally, a nomogram incorporating a classifier based on the 10 ferroptosis-related genes, tumor stage, age and histologic grade was established. This nomogram showed a favorable discriminating ability and might contribute to clinical decision-making for luminal-type breast carcinoma.

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Ferritinophagy-mediated ferroptosis is involved in sepsis-induced cardiac injury

Cited by 384 publications

References 50 publications

Phospholipid peroxidation fuels ExoU phospholipase-dependent cell necrosis and supportsPseudomonas aeruginosa-driven pathology

Phospholipid peroxidation fuels ExoU phospholipase-dependent cell necrosis and supportsPseudomonas aeruginosa-driven pathology

Insights into the Roles of the Sideroflexins/SLC56 Family in Iron Homeostasis and Iron-Sulfur Biogenesis

A ferroptosis-associated gene signature for the prediction of prognosis and therapeutic response in luminal-type breast carcinoma

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