Traumatic brain injury-induced changes in gene expression and functional activity of mitochondrial cytochrome c oxidase
Traumatic brain injury-induced changes in gene expression and functional activity of mitochondrial cytochrome c oxidase
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DOI：
10.1089/08977150152693692
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发表时间：
2001-10-01
影响因子：
4.2
通讯作者：
Phillips, LL
中科院分区：
文献类型：
--
作者：
Harris, LK;Black, RT;Phillips, LL
据记录，创伤性脑损伤 (TBI) 对中枢神经系统代谢产生有害影响，包括葡萄糖利用的改变和线粒体氧化磷酸化的抑制。对线粒体代谢的研究还提供了证据，证明 TBI 后电子传递链的细胞色素氧化酶复合物（复合物 IV）的活性降低，线粒体状态 3 呼吸频率立即（1 小时）降低，这种情况可以在受伤后持续长达 14 天。使用差异显示方法筛选基因表达的差异，我们发现细胞色素 c 氧化酶 H (COII)（复合物 IV 的线粒体编码亚基）在 TBI 后上调。由于 COH 在呼吸链中携带细胞色素 c 的结合位点，并且由于它是链电子传递到分子氧所需的，从而驱动 ATP 的产生，因此我们假设 TBI 引起的代谢功能障碍直接改变 COII 基因表达，可能会影响损伤后恢复过程中发生的突触可塑性。为了检验这一假设，我们记录了损伤后 7 天的 COII mRNA 表达和复合物 IV（细胞色素 C 氧化酶）功能活性，重点关注与突触重组最密切相关的长期损伤后时期。对中央液体冲击 TBI 和联合 TBI 以及双侧内嗅皮质病变进行了检查。存活 7 天时，TBI 和联合损伤模型的海马 RNA 的差异显示、RT-PCR 和 Northern 印迹分析显示 COII mRNA 显着诱导。 COII 基因表达的长期升高得到 COII 免疫结合增加的支持。相比之下，受伤大脑组织切片内的细胞色素氧化酶组织化学活性表明，TBI 病例中复合物 IV 活性降低，但在遭受联合损伤的动物中却没有降低。使用大脑皮层和海马组织对复合物 IV 进行体外测定，支持了细胞色素 C 氧化酶活性的这些差异。我们目前的结果支持这样的假设：COH 选择性地容易受到 TBI 的影响，并且 COII 差异可能表明不同病理引起的代谢功能障碍的程度。总而言之，这些数据将更好地确定代谢功能在 TBI 后长期恢复中的作用。
Traumatic brain injury (TBI) is documented to have detrimental effects on CNS metabolism, including alterations in glucose utilization and the depression of mitochondrial oxidative phosphorylation. Studies on mitochondrial metabolism have also provided evidence for reduced activity of the cytochrome oxidase complex of the electron transport chain (complex IV) after TBI and an immediate (1hr) reduction in mitochondrial state 3 respiratory rate, which can persist for up to 14 days postinjury. Using differential display methods to screen for differences in gene expression, we have found that cytochrome c oxidase H (COII), a mitochondrial encoded subunit of complex IV, is upregulated following TBI. Since COH carries a binding site for cytochrome c in the respiratory chain, and since it is required for the passage of chain electrons to molecular oxygen, driving the production of ATP, we hypothesized that metabolic dysfunction resulting from TBI alters COII gene expression directly, perhaps influencing the synaptic plasticity that occurs during postinjury recovery processes. To test this hypothesis, we documented COII mRNA expression and complex IV (cytochrome c oxidase) functional activity at 7 days postinjury, focusing on the long-term postinjury period most closely associated with synaptic reorganization. Both central fluid percussion TBI and combined TBI and bilateral entorhinal cortical lesion were examined. At 7 days survival, differential display, RT-PCR, and Northern blot analysis of hippocampal RNA from both TBI and combined insult models showed a significant induction of COII mRNA. This long-term elevation in COII gene expression was supported by increases in COII immunobinding. By contrast, cytochrome oxidase histochemical activity within tissue sections from injured brains suggested a reduction of complex IV activity within the TBI cases, but not within animals subjected to the combined insult. These differences in cytochrome c oxidase activity were supported by in vitro assay of complex IV using cerebral cortical and hippocampal tissues. Our present results support the hypothesis that COH is selectively vulnerable to TBI and that COII differences may indicate the degree of metabolic dysfunction induced by different pathologies. Taken together, such data will better define the role of metabolic function in long-term recovery after TBI.