Mitochondrial Dysfunction After Repeated Mild Blast Traumatic Brain Injury Is Attenuated by a Mild Mitochondrial Uncoupling Prodrug.
Mitochondrial Dysfunction After Repeated Mild Blast Traumatic Brain Injury Is Attenuated by a Mild Mitochondrial Uncoupling Prodrug.
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轻度线粒体解偶联前药可减轻反复轻度冲击创伤性脑损伤后的线粒体功能障碍。
DOI：
10.1089/neu.2023.0102
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发表时间：
2023-11
影响因子：
4.2
通讯作者：
Sullivan, Patrick G
中科院分区：
文献类型：
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作者：
Hubbard, W Brad;Vekaria, Hemendra J;Velmurugan, Gopal V;Kalimon, Olivia J;Prajapati, Paresh;Brown, Emily;Geisler, John G;Sullivan, Patrick G
轻度创伤性脑损伤（mTBI）导致脑代谢受损，这是通过脑中的线粒体功能障碍传播的。线粒体功能障碍已被确定为一个病理生物学治疗靶点，以平息细胞内稳态失调。此外，靶向线粒体损伤的治疗方法，如轻度线粒体解偶联，已显示可减轻TBI后的行为改变。为了研究轻度线粒体解偶联如何在军事相关的mTBI模型中调节急性线粒体结果，我们利用11 psi峰值超压的重复冲击波超压来模拟大鼠的重复轻度冲击波创伤性脑损伤（rmbTBI），然后在rmbTBI后2天评估线粒体呼吸和脑相关的氧化损伤。给治疗组施用8或80 mg/kg MP201，MP201是2，4-二硝基苯酚（DNP）的前药，与其代谢形式相比，其显示出改善的药代动力学。使用线粒体磁分离技术分离突触和胶质细胞富集的线粒体。在实验组中，mbTBI后有一致的生理反应，心率降低。虽然没有损伤的影响，在线粒体呼吸的胶质细胞丰富的线粒体，有损伤的线粒体呼吸的突触线粒体分离的前额叶皮层（PFC）和杏仁核/内嗅/梨状皮质（AEP）区域。在rmbTBI后通过口服80 mg/kg MP201治疗来挽救突触线粒体呼吸的损伤，这可能通过复合物II和复合物IV活性的增加来促进。rmbTBI后PFC和海马中富含胶质细胞的线粒体中的线粒体氧化损伤增加。MP201治疗减轻rmbTBI后升高的富含胶质细胞的线粒体氧化损伤。然而，在突触线粒体中缺乏损伤相关的氧化损伤差异。总体而言，我们的报告表明，rmbTBI导致整个大脑弥漫性线粒体损伤，轻度线粒体解偶联可以恢复线粒体生物能量学和氧化平衡。
Mild traumatic brain injury (mTBI) results in impairment of brain metabolism, which is propagated by mitochondrial dysfunction in the brain. Mitochondrial dysfunction has been identified as a pathobiological therapeutic target to quell cellular dyshomeostasis. Further, therapeutic approaches targeting mitochondrial impairments, such as mild mitochondrial uncoupling, have been shown to alleviate behavioral alterations after TBI. To examine how mild mitochondrial uncoupling modulates acute mitochondrial outcomes in a military-relevant model of mTBI, we utilized repeated blast overpressure of 11 psi peak overpressure to model repeated mild blast traumatic brain injury (rmbTBI) in rats followed by assessment of mitochondrial respiration and mitochondrial-related oxidative damage at 2 days post-rmbTBI. Treatment groups were administered 8 or 80 mg/kg MP201, a prodrug of 2,4 dinitrophenol (DNP) that displays improved pharmacokinetics compared with its metabolized form. Synaptic and glia-enriched mitochondria were isolated using fractionated a mitochondrial magnetic separation technique. There was a consistent physiological response, decreased heart rate, following mbTBI among experimental groups. Although there was a lack of injury effect in mitochondrial respiration of glia-enriched mitochondria, there were impairments in mitochondrial respiration in synaptic mitochondria isolated from the prefrontal cortex (PFC) and the amygdala/entorhinal/piriform cortex (AEP) region. Impairments in synaptic mitochondrial respiration were rescued by oral 80 mg/kg MP201 treatment after rmbTBI, which may be facilitated by increases in complex II and complex IV activity. Mitochondrial oxidative damage in glia-enriched mitochondria was increased in the PFC and hippocampus after rmbTBI. MP201 treatment alleviated elevated glia-enriched mitochondrial oxidative damage following rmbTBI. However, there was a lack of injury-associated differences in oxidative damage in synaptic mitochondria. Overall, our report demonstrates that rmbTBI results in mitochondrial impairment diffusely throughout the brain and mild mitochondrial uncoupling can restore mitochondrial bioenergetics and oxidative balance.