Acute high‐altitude hypoxia exposure causes neurological deficits via formaldehyde accumulation

Wang, Xiaoyin; Sun, Haochen; Cui, Lili; Wang, Xian; Ren, Chang­hong; Tong, Zhiqian; Ji, Xunming

doi:10.1111/cns.13849

Cited by 15 publications

(13 citation statements)

References 59 publications

(104 reference statements)

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“…Studies have shown that HA exposure elicits remarkable alterations in iron metabolism, leading to disturbances in iron homeostasis and giving rise to toxicities such as inflammation, oxidative stress, and ferroptosis [ 7 , 8 , 9 , 10 , 12 ]. Yet, as far as we know, no relevant study has examined these effects on adipose tissue during HA treatment.…”

Section: Discussionmentioning

confidence: 99%

“…Ferroptosis is a novel kind of self-regulated cell death characterized by excessive iron-dependent oxidative stress and lipid peroxidation [ 22 , 23 ]. Acute exposure to HA may induce neuronal iron elevation and ferroptosis, subsequently leading to neurological deficits [ 12 ]. We investigated alterations in the ferroptosis signaling pathway in the adipose tissue of HA mice.…”

Section: Discussionmentioning

confidence: 99%

“…Iron homeostasis is vital to health and is maintained in a balanced state under normal conditions [ 6 ]. However, numerous studies revealed that HA hypoxia exposure induced significant changes in iron metabolism (uptake, storage, and efflux), causing iron homeostasis imbalance and even leading to toxicities such as oxidative stress [ 7 , 8 , 9 ], inflammatory response [ 10 , 11 ], and ferroptosis [ 12 ], an iron-dependent programmed cell death marked by ROS accumulation. As reported, chronic HA hypoxia causes brain iron accumulation and dysfunctional iron metabolism, inducing oxidative stress and apoptosis, and ultimately triggering cognitive impairment [ 7 ].…”

Section: Introductionmentioning

confidence: 99%

“…Moreover, HA exposure aggravated oxidative damage by producing MDA and inhibiting antioxidant enzyme activities in the liver, which could be reversed by iron supplementation with Fe-glycinate chelate (Fe-Gly) [ 8 ]. Better yet, acute HA exposure induced neuronal ferroptosis by iron elevation and formaldehyde accumulation, subsequently inducing neurological deficits [ 12 ].…”

Section: Introductionmentioning

confidence: 99%

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High-Altitude Hypoxia Exposure Induces Iron Overload and Ferroptosis in Adipose Tissue

et al. 2022

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High altitude (HA) has become one of the most challenging environments featuring hypobaric hypoxia, which seriously threatens public health, hence its gradual attraction of public attention over the past decade. The purpose of this study is to investigate the effect of HA hypoxia on iron levels, redox state, inflammation, and ferroptosis in adipose tissue. Here, 40 mice were randomly divided into two groups: the sea-level group and HA hypoxia group (altitude of 5000 m, treatment for 4 weeks). Total iron contents, ferrous iron contents, ROS generation, lipid peroxidation, the oxidative enzyme system, proinflammatory factor secretion, and ferroptosis-related biomarkers were examined, respectively. According to the results, HA exposure increases total iron and ferrous iron levels in both WAT and BAT. Meanwhile, ROS release, MDA, 4-HNE elevation, GSH depletion, as well as the decrease in SOD, CAT, and GSH-Px activities further evidenced a phenotype of redox imbalance in adipose tissue during HA exposure. Additionally, the secretion of inflammatory factors was also significantly enhanced in HA mice. Moreover, the remarkably changed expression of ferroptosis-related markers suggested that HA exposure increased ferroptosis sensitivity in adipose tissue. Overall, this study reveals that HA exposure is capable of inducing adipose tissue redox imbalance, inflammatory response, and ferroptosis, driven in part by changes in iron overload, which is expected to provide novel preventive targets for HA-related illness.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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High-Altitude Hypoxia Exposure Induces Iron Overload and Ferroptosis in Adipose Tissue

et al. 2022

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“…As an environment featuring hypobaric hypoxia, high altitude (HA) exposure increased ferroptosis sensitivity in adipose tissue with elevated levels of iron, ROS, MDA, and 4-HNE, as well as GSH depletion [ 134 ]. Acute high-altitude hypoxia exposure in mice leads to cerebral formaldehyde accumulation to induce neuronal ferroptosis [ 135 ]. A recent study suggested that hypobaric hypoxia at high-altitude induces both apoptosis and ferroptosis via the JNK signaling pathway by depleting keratin 18 (Krt18) and elevating JNK3 (MAPK10), as well as increasing ASCL4 for ferroptosis [ 136 ].…”

Section: The Mechanism and Regulation Of Ferroptosis Modulated By Hyp...mentioning

confidence: 99%

Ferroptosis Regulated by Hypoxia in Cells

Zheng

Liang

Zhang

2023

Cells

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Ferroptosis is an oxidative damage-related, iron-dependent regulated cell death with intracellular lipid peroxide accumulation, which is associated with many physiological and pathological processes. It exhibits unique features that are morphologically, biochemically, and immunologically distinct from other regulated cell death forms. Ferroptosis is regulated by iron metabolism, lipid metabolism, anti-oxidant defense systems, as well as various signal pathways. Hypoxia, which is found in a group of physiological and pathological conditions, can affect multiple cellular functions by activation of the hypoxia-inducible factor (HIF) signaling and other mechanisms. Emerging evidence demonstrated that hypoxia regulates ferroptosis in certain cell types and conditions. In this review, we summarize the basic mechanisms and regulations of ferroptosis and hypoxia, as well as the regulation of ferroptosis by hypoxia in physiological and pathological conditions, which may contribute to the numerous diseases therapies.

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Impairment of Autophagic Flux After Hypobaric Hypoxia Potentiates Oxidative Stress and Cognitive Function Disturbances in Mice

Dai,

Feng,

et al. 2023

Neurosci. Bull.

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Acute hypobaric hypoxic brain damage is a potentially fatal high-altitude sickness. Autophagy plays a critical role in ischemic brain injury, but its role in hypobaric hypoxia (HH) remains unknown. Here we used an HH chamber to demonstrate that acute HH exposure impairs autophagic activity in both the early and late stages of the mouse brain, and is partially responsible for HH-induced oxidative stress, neuronal loss, and brain damage. The autophagic agonist rapamycin only promotes the initiation of autophagy. By proteome analysis, a screen showed that protein dynamin2 (DNM2) potentially regulates autophagic flux. Overexpression of DNM2 significantly increased the formation of autolysosomes, thus maintaining autophagic flux in combination with rapamycin. Furthermore, the enhancement of autophagic activity attenuated oxidative stress and neurological deficits after HH exposure. These results contribute to evidence supporting the conclusion that DNM2-mediated autophagic flux represents a new therapeutic target in HH-induced brain damage.

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Acute high‐altitude hypoxia exposure causes neurological deficits via formaldehyde accumulation

Cited by 15 publications

References 59 publications

High-Altitude Hypoxia Exposure Induces Iron Overload and Ferroptosis in Adipose Tissue

High-Altitude Hypoxia Exposure Induces Iron Overload and Ferroptosis in Adipose Tissue

Ferroptosis Regulated by Hypoxia in Cells

Impairment of Autophagic Flux After Hypobaric Hypoxia Potentiates Oxidative Stress and Cognitive Function Disturbances in Mice

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