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

Abstract

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.

Iron: The silent culprit in your adipose tissue

“…Emerging research suggests that increased markers of ferroptosis in adipose tissue may contribute to a phenotype of adipose tissue dysfunction characterized by heightened inflammation and cellular senescence. This effect can result in the attenuation of the ability to store lipids in white adipose tissue and reduced thermogenic activity in brown adipose tissue 69–72 . However, it is essential to conduct further studies to fully understand the significance of ferroptosis in adipose tissue physiology.…”

“…This effect can result in the attenuation of the ability to store lipids in white adipose tissue and reduced thermogenic activity in brown adipose tissue. [69][70][71][72] However, it is essential to conduct further studies to fully understand the significance of ferroptosis in adipose tissue physiology.…”

Ferroptosis Regulated by Hypoxia in Cells

“…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 ].…”

Frontiers and hotspots of adipose tissue and NAFLD: a bibliometric analysis from 2002 to 2022

“…Ferroptosis is associated with the progression of oxidative stress and lipid peroxidation in NAFLD. Glutathione peroxidase 4 (GPX4) plays a pivotal role in inhibiting ferroptosis by scavenging lipid peroxidation (Tong et al, 2022;Zhang et al, 2022). Under hypoxic conditions, iron homeostasis in WAT and BAT is dysregulated, leading to a significant decrease in GPX4 expression in subcutaneous WAT and interscapular BAT, which exacerbates lipid peroxidation.…”