Neutrophil extracellular traps drive intestinal microvascular endothelial ferroptosis by impairing Fundc1-dependent mitophagy

Chu, Chengnan; Wang, Xinyu; Yang, Chao; Chen, Fang; Shi, Lin; Xu, Weiqi; Wang, Kai; Liu, Baochen; Wang, Chenyang; Sun, Dongping; Ding, Weiwei

doi:10.1016/j.redox.2023.102906

Cited by 37 publications

(8 citation statements)

References 69 publications

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“…Endothelial cell ferroptosis play a significant role in cerebral ischemia injury. 15 , 16 Numerous studies have investigated the safety and therapeutic efficacy of the iron chelator and antioxidant drugs, such as deferoxamine (DFO) or N-acetylcysteine (NAC), in patients experiencing ischemic stroke. In individuals with moderate hematoma volume (HV) after intracerebral hemorrhage (ICH), a higher proportion of those treated with DFO attained a modified Rankin Scale score of 0–2 compared to those receiving a placebo, although this effect was not statistically significant for patients with small or large HVs.…”

Section: Discussionmentioning

confidence: 99%

Piezo1 Knockout Improves Post-Stroke Cognitive Dysfunction by Inhibiting the Interleukin-6 (IL-6)/Glutathione Peroxidase 4 (GPX4) Pathway

Tang,

Xie,

Wang

et al. 2024

JIR

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Background: Cerebral infarction often results in post-stroke cognitive impairment, which impairs the quality of life and causes longterm disability. Astrocytes, the most abundant glial cells in the central nervous system, have a crucial role in cerebral ischemia and neuroinflammation. We explored the possible advantages of interleukin-6 (IL-6), a powerful pro-inflammatory cytokine produced by astrocytes, for post-stroke cognitive function. Methods: Mendelian randomization was applied to analyze the GWAS database of stroke patients, obtaining a causal relationship between IL-6 and stroke. Further validation of this relationship and its mechanisms was conducted. Using a mouse model of cerebral infarction, we demonstrated a significant increase in IL-6 expression in astrocytes surrounding the ischemic lesion. This protective effect of Piezo1 knockout was attributed to the downregulation of matrix metalloproteinases and upregulation of tight junction proteins, such as occludin and zonula occludens-1 (ZO-1). Results: Two-step Mendelian randomization revealed that IL-6 exposure is a risk factor for stroke. Moreover, we conducted behavioral assessments and observed that Piezo1 knockout mice that received intranasal administration of astrocyte-derived IL-6 showed notable improvement in cognitive function compared to control mice. This enhancement was associated with reduced neuronal cell death and suppressed astrocyte activation, preserving ZO-1. Conclusion:Our study shows that astrocyte-derived IL-6 causes cognitive decline after stroke by protecting the blood-brain barrier. This suggests that piezo1 knockout may reduce cognitive impairment after brain ischemia. Further research on the mechanisms and IL-6 delivery methods may lead to new therapies for post-stroke cognition.

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Section: Discussionmentioning

confidence: 99%

Piezo1 Knockout Improves Post-Stroke Cognitive Dysfunction by Inhibiting the Interleukin-6 (IL-6)/Glutathione Peroxidase 4 (GPX4) Pathway

Tang,

Xie,

Wang

et al. 2024

JIR

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“…Similarly, FUNDC1, a signi cant receptor protein mediating mitophagy under hypoxia [50] , can be dephosphorylated by the action of PGAM5 [51] , which activates the PGAM5/FUNDC1 signaling pathway and thus promotes mitophagy to mitigate oxidative stress injury [19,52] .…”

Section: Discussionmentioning

confidence: 99%

Electroacupuncture inhibited neuronal apoptosis through PGAM5/FUNDC1-dependent mitophagy after ischemic stroke

Zhou,

Peng,

Zhou

et al. 2024

Preprint

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Neuronal apoptosis persists throughout ischemic stroke and leads to massive neuron loss, which severely hampers the recovery of neurological function. Clinical evidence has confirmed that EA effectively improves neurological function after stroke, but the undergoing mechanism still needs to be fully clarified. In this study we found that apoptosis and autophagy were activated after ischemic stroke, howerver EA further upregulated autophagy and inhibit neuronal apoptosis. Furthermore, the neuroprotective effect of EA was associated with the activation of mitophagy. Mechanistically, EA upregulated the expression of PGAM5 to promote FUNDC1 dephosphorylation, and then enhanced the affinity of FUNDC1 with LC3, ultimately activating PGAM5/FUNDC1-dependent mitophagy. Enhanced mitochondrial autophagy reduced the release of ROS and Cytc from damaged mitochondria, inhibited the activation of Caspase3 and subsequent neuronal apoptosis. Meanwhile, it also upregulated the level of FUNDC1 and further promoted mitophagy through the PGAM5/FUNDC1 pathway. Notably, inhibition of mitophagy by lateral ventricle injection of 3-MA significantly reversed the neuroprotective effect of EA. In summary, activating mitophagy by EA to inhibit neuronal apoptosis is a potential mechanism in post-stroke neurorepair.

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“…Endothelial damage is a major reason for microcirculatory dysfunction, microthrombosis, and organ dysfunction. Neutrophil extracellular traps inhibit mitophagy by inducing FUNDC1 phosphorylation to lead to endothelial ferroptosis, which can be reversed by urolithin A [ 151 ].…”

Section: Molecular Pathways Of Mitophagymentioning

confidence: 99%

Mechanism and role of mitophagy in the development of severe infection

Ma,

Han,

Zhan

2024

Cell Death Discov.

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Mitochondria produce adenosine triphosphate and potentially contribute to proinflammatory responses and cell death. Mitophagy, as a conservative phenomenon, scavenges waste mitochondria and their components in the cell. Recent studies suggest that severe infections develop alongside mitochondrial dysfunction and mitophagy abnormalities. Restoring mitophagy protects against excessive inflammation and multiple organ failure in sepsis. Here, we review the normal mitophagy process, its interaction with invading microorganisms and the immune system, and summarize the mechanism of mitophagy dysfunction during severe infection. We highlight critical role of normal mitophagy in preventing severe infection.

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Neutrophil extracellular traps drive intestinal microvascular endothelial ferroptosis by impairing Fundc1-dependent mitophagy

Cited by 37 publications

References 69 publications

Piezo1 Knockout Improves Post-Stroke Cognitive Dysfunction by Inhibiting the Interleukin-6 (IL-6)/Glutathione Peroxidase 4 (GPX4) Pathway

Piezo1 Knockout Improves Post-Stroke Cognitive Dysfunction by Inhibiting the Interleukin-6 (IL-6)/Glutathione Peroxidase 4 (GPX4) Pathway

Electroacupuncture inhibited neuronal apoptosis through PGAM5/FUNDC1-dependent mitophagy after ischemic stroke

Mechanism and role of mitophagy in the development of severe infection

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