Copper aggravated synaptic damage after traumatic brain injury by downregulating BNIP3-mediated mitophagy

作者：Hanxiao Chang, Weiwei Zhang, Lei Xu, Zheng Li, Chao Lin, Yuqi Shen, Guangjian Zhang, Lei Mao, Chencheng Ma, Ning Liu, Hua Lu · 发表于：Autophagy · 年份：2024 · DOI：10.1080/15548627.2024.2409613 · 被引用次数：17 · 研究领域：Trace Elements in Health、Alzheimer's disease research and treatments、Mitochondrial Function and Pathology

Synaptic damage is a crucial pathological process in traumatic brain injury. However, the mechanisms driving this process remain poorly understood. In this report, we demonstrate that the accumulation of damaged mitochondria, resulting from impaired mitphagy, plays a significant role in causing synaptic damage. Moreover, copper induced downregulation of BNIP3 is a key player in regulating mitophagy. DMSA alleviates synaptic damage and mitochondrial dysfunction by promoting urinary excretion of copper. Mechanistically, we find that copper downregulate BNIP3 by increasing the nuclear translocation of NFKB, which is triggered by TRIM25-mediated ubiquitination-dependent degradation of NFKBIA. Our study underscores the importance of copper accumulation in the regulation of BNIP3-mediated mitophagy and suggests that therapeutic targeting of the copper-TRIM25-NFKB-BNIP3 axis holds promise to attenuate synaptic damage after traumatic brain injury.