COX5A 通过纠正线粒体稳态失衡缓解脑外伤引发的小鼠神经损伤

COX5A Relieves Traumatic Brain Injury-Induced Neurological Damage in Mice by Correcting Mitochondrial Homeostasis Imbalance

摘要

目的 探讨细胞色素c氧化酶亚基5A（cytochrome c oxidase subunit 5A，COX5A）过表达对创伤性脑损伤（traumatic brain injury，TBI）小鼠的神经保护作用及其与线粒体功能的关系。方法 将4～6周龄C57BL/6J野生型（wild type，WT）小鼠及同龄COX5A过表达（COX5A-UP）转基因小鼠随机分为WT+假手术组、WT+TBI组、COX5A-UP+假手术组和COX5A-UP+TBI组（n = 12，雌雄各半），采用可控皮质冲击法制备TBI模型。术后14 d评估神经行为学表现、脑含水量、海马突触体线粒体氧消耗率、ATP、活性氧、丙二醛、线粒体膜电位及线粒体超微结构。结果 与WT+假手术组相比，WT+TBI组神经功能和行为学表现受损，脑含水量升高，突触体线粒体能量代谢下降、氧化应激增强，并出现线粒体形态破坏（P ＜ 0.05）。与WT+TBI组相比，COX5A-UP+TBI组上述神经行为学异常、脑水肿及线粒体功能和结构损伤均改善（P ＜ 0.05）。结论 COX5A过表达可减轻TBI诱导的神经功能损伤，其作用可能与改善突触体线粒体功能障碍和维持线粒体结构稳态有关。

Abstract

Objective To investigate the neuroprotective effect of cytochrome c oxidase subunit 5A (COX5A) overexpression in mice with traumatic brain injury (TBI) and its association with mitochondrial function. Methods C57BL/6J wild-type (WT) mice aged 4–6 weeks and age-matched COX5A-overexpressing (COX5A-UP) transgenic mice were randomly divided into WT+sham operation group, WT+TBI group, COX5A-UP+sham operation group, and COX5A-UP+TBI group (n = 12 per group, male:female = 1:1). The TBI model was established using the controlled cortical impact method. At 14 days after surgery, neurological and behavioral performance, brain water content, oxygen consumption rate of hippocampal synaptosomal mitochondrial, ATP levels, reactive oxygen species, malondialdehyde, mitochondrial membrane potential and mitochondrial ultrastructure were examined. Results Compared with the WT+sham group, WT+TBI group showed impaired neurological and behavioral performance, increased brain water content, reduced mitochondrial energy metabolism, enhanced oxidative stress and mitochondrial morphological damage (P ＜ 0.05). Compared with the WT+TBI group, the COX5A-UP+TBI group showed improvements in these neurological, behavioral, edema-related and mitochondrial abnormalities (P ＜ 0.05). Conclusion COX5A overexpression alleviates TBI-induced neurological impairment, and this effect may be associated with amelioration of synaptosomal mitochondrial dysfunction and preservation of mitochondrial structural homeostasis.

关键词

细胞色素c氧化酶亚基5A / 创伤性脑损伤 / 线粒体稳态失衡 / 神经保护 / 小鼠模型 / 行为学

Key words

COX5A / Traumatic brain injury / Mitochondrial dyshomeostasis / Neuroprotection / Mouse model / Behavior

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基金资助

国家自然科学基金(82560226)

昆明医科大学特色学科团队病理学团队(2024XKTDTS11)