TMEM175 downregulation participates in impairment of the autophagy related lysosomal dynamics following neonatal hypoxic‐ischemic brain injury

Abstract

AbstractThe mechanism underlying long‐term cognitive impairment caused by neonatal hypoxic‐ischemic brain injury (HIBI) remains unclear. Autophagy is a closely related mechanism and may play a role in this process. We aimed to investigate the role of lysosomal transmembrane protein 175 (TMEM175) in the autophagy‐lysosome pathway in neonatal rats with HIBI. A neonatal rat model of HIBI was established, hypoxia was induced, followed by left common carotid artery ligation. Expression levels of TMEM175 and the corresponding proteins involved in autophagy flux and the endolysosomal system fusion process were measured. Rats were administered TMEM175 plasmid via intracerebroventricular injection to induce overexpression. Brain damage and cognitive function were then assessed. TMEM175 was downregulated in the hippocampal tissue, and the autophagy‐lysosome pathway was impaired following HIBI in neonatal rats. Overexpression of TMEM175 significantly mitigated neuronal injury and improved long‐term cognitive and memory function in neonatal rats with HIBI. We found that improvement in the autophagy‐lysosome pathway and endolysosomal system homeostasis, which are TMEM175 related, occurred via regulation of lysosomal membrane dynamic fusion. TMEM175 plays a critical role in maintaining the autophagy‐lysosome pathway and endolysosomal homeostasis, contributing to the amelioration of neuronal injury and impaired long‐term cognitive function following neonatal HIBI.