Cold stress‐induced ferroptosis involves the
            <scp>ASK</scp>
            1‐p38 pathway

Hattori, Kazuki; Ishikawa, Hiroyasu; Sakauchi, Chihiro; Takayanagi, Saki; Naguro, Isao; Ichijo, Hidenori

doi:10.15252/embr.201744228

Cited by 112 publications

(98 citation statements)

References 55 publications

(80 reference statements)

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“…These findings indicate that the molecular mechanism of cold stress-triggered liver graft damage was likely to be distinct from apoptosis, necrosis, or necroptosis. Since recent reports have demonstrated tissue-specific importance of ASK1/ p-p38 signaling in cold-stress cell damage (10,11), we focused on the ASK1/p-p38 axis in our model. Interestingly, the markedly increased hepatic ASK1 and p-p38 expression seen after cold storage (4°C/18 hours) in WT livers decreased in OLT at 3 hours after reperfusion ( Figure 3C).…”

Section: Resultsmentioning

confidence: 99%

“…Apoptosis signal-regulating kinase 1 (ASK1), a member of the MAP3K family, becomes activated by a wide range of extra-and intracellular stressors. Activation of p38 MAPK was reported in cold-induced tissue injury (9,10), whereas a recent study has identified tissuespecific contribution of ASK1 and p-p38 pathways in cell death signaling (11). The role of the ASK1/p-p38 axis in the mechanism of liver transplant damage has not been studied before.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Hepatic CEACAM1 expression indicates donor liver quality and prevents early transplantation injury

Nakamura¹,

Kageyama²,

Kaldas³

et al. 2020

Journal of Clinical Investigation

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Hepatic CEACAM1 expression indicates donor liver quality and prevents early transplantation injury

Nakamura¹,

Kageyama²,

Kaldas³

et al. 2020

Journal of Clinical Investigation

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“…Ferroptosis is a newly discovered form of regulated cell death that plays a major role in various diseases, including tumor, stoke, cold stress, acute kidney failure, and neural degeneration. 13,18,[29][30][31][32] As in TBI, a recent study reported that ferroptotic death possibly occurs at early time points after TBI in the pediatric rat CCI model due to elevated levels of 15-HpETE-PE in the brain cortex and hippocampus, along with increased expression of 15LO2 and decreased levels of GPX4. 19 However, the precise role of ferroptosis in adult rodents remains unknown.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of ferroptosis attenuates tissue damage and improves long‐term outcomes after traumatic brain injury in mice

et al. 2018

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Summary Aims Ferroptosis, a new form of iron‐dependent programmed cell death, has been shown to be involved in a range of diseases. However, the role of ferroptosis in traumatic brain injury (TBI) has yet to be elucidated. We aimed to investigate whether ferroptosis is induced after TBI and whether the inhibition of ferroptosis would protect against traumatic brain injury in a controlled cortical impact injury (CCI) mouse model. Methods After establishing the TBI model in mice, we determined the biochemical and morphological changes associated with ferroptosis, including iron accumulation with Perl's staining, neuronal cell death with Fluoro‐Jade B (FJB) staining, iron metabolism dysfunction with Western blotting, reactive oxygen species (ROS) accumulation with malondialdehyde (MDA) assays, and shrunken mitochondria with transmission electron microscopy. Furthermore, a specific inhibitor of ferroptosis, ferrostatin‐1(fer‐1), was administrated by cerebral ventricular injection after CCI. We used cresyl violet (CV) staining to assess lesion volume, along with the Morris water maze and beam walk test to evaluate long‐term outcomes. Results TBI was followed by iron accumulation, dysfunctional iron metabolism, the upregulation of ferroptosis‐related genes, reduced glutathione peroxidase (GPx) activity, and the accumulation of lipid‐reactive oxygen species (ROS). Three days (d) after TBI, transmission electron microscopy (TEM) confirmed that the mitochondria had shrunk a typical characteristic of ferroptosis. Importantly, the administration of Fer‐1 by cerebral ventricular injection significantly reduced iron deposition and neuronal degeneration while attenuating injury lesions and improving long‐term motor and cognitive function. Conclusion This study demonstrated an effective method with which to treat TBI by targeting ferroptosis.

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“…Taking into consideration that the MAPK signaling pathway, including ERK, p38, and c-JUN NH 2 -terminal kinase (JNK) is involved in the execution of ferroptosis in other cells (10, 49), we evaluated whether co-exposure to DHT and INS may be linked to activation of the MAPK signaling pathway in the gravid uterus and placenta. As shown in Figure 4A , in the gravid uterus DHT+INS exposure resulted in an increased abundance of phosphorylated ERK1/2 (p-ERK1/2) and decreased total ERK1/2, which subsequently resulted in an increased p-ERK1/2:ERK1/2 ratio.…”

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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Cold stress‐induced ferroptosis involves the ASK 1‐p38 pathway

Cited by 112 publications

References 55 publications

Hepatic CEACAM1 expression indicates donor liver quality and prevents early transplantation injury

Hepatic CEACAM1 expression indicates donor liver quality and prevents early transplantation injury

Inhibition of ferroptosis attenuates tissue damage and improves long‐term outcomes after traumatic brain injury in mice

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

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