Impairment of Autophagic Flux After Hypobaric Hypoxia Potentiates Oxidative Stress and Cognitive Function Disturbances in Mice
Shuhui Dai1,2 · Yuan Feng1 · Chuanhao Lu1 · Hongchen Zhang1 · Wenke Ma1,3 · Wenyu Xie1 · Xiuquan Wu1 · Peng Luo1 · Lei Zhang1 · Fei Fei4 · Zhou Fei1 · Xia Li11 Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi’an 710000, China
2 National Translational Science Center for Molecular Medicine and Department of Cell Biology, Fourth Military Medical University, Xi’an 710000, China
3 Department of Neurosurgery, The Central Hospital of Baoji, Baoji 721000, China
4 Department of Ophthalmology, Xijing Hospital, Fourth Military Medical University, Xi’an 710000, China
Abstract
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.
Keywords
Autophagy; Proteomics; Oxidative stress; Hypobaric hypoxia; Brain injury
