LRP1 Deficiency Promotes Mitostasis in Response to Oxidative Stress: Implications for Mitochondrial Targeting after Traumatic Brain Injury.
LRP1 Deficiency Promotes Mitostasis in Response to Oxidative Stress: Implications for Mitochondrial Targeting after Traumatic Brain Injury.
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LRP1缺乏促进氧化应激反应中的有丝分裂：对创伤性脑损伤后线粒体靶向的影响
DOI：
10.3390/cells12101445
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发表时间：
2023-05-22
期刊：
影响因子：
6
通讯作者：
Sullivan, Patrick G.
中科院分区：
文献类型：
--
作者：
Velmurugan, Gopal V.;Hubbard, W. Brad;Prajapati, Paresh;Vekaria, Hemendra J.;Patel, Samir P.;Rabchevsky, Alexander G.;Sullivan, Patrick G.
关键词：
在遭受诸如创伤性脑损伤（TBI）、缺血再灌注和中风等生理损伤后，大脑会经历氧化应激和线粒体功能障碍。针对线粒体以对抗氧化应激的药物疗法（线粒体药物）包括抗氧化剂、温和的解偶联剂以及线粒体生物发生增强剂，这些已被证明可改善创伤性脑损伤后的病理生理结果。然而，到目前为止，创伤性脑损伤尚无有效的治疗方法。研究表明，在成年神经元或神经胶质细胞中缺失低密度脂蛋白受体相关蛋白1（LRP1）可能是有益的，并能促进神经元健康。在本研究中，我们使用野生型（WT）和LRP1基因敲除（LKO）小鼠胚胎成纤维细胞来检测外源性氧化应激后的线粒体结果。此外，我们开发了一种新技术，利用转基因线粒体报告小鼠mtD2g（线粒体特异性Dendra2绿色）在创伤性脑损伤模型中测量线粒体形态动力学。我们发现，氧化应激增加了创伤性脑损伤后同侧皮质损伤核心中碎片化和球形线粒体的数量，而在相应的对侧皮质中则观察到杆状伸长的线粒体。关键的是，LRP1缺乏显著减少了线粒体碎片化，在外源性氧化应激后保留了线粒体功能和细胞生长。总之，我们的结果表明，靶向LRP1以改善线粒体功能是一种针对创伤性脑损伤和其他神经退行性疾病中氧化损伤的潜在药物治疗策略。
The brain undergoes oxidative stress and mitochondrial dysfunction following physiological insults such as Traumatic brain injury (TBI), ischemia-reperfusion, and stroke. Pharmacotherapeutics targeting mitochondria (mitoceuticals) against oxidative stress include antioxidants, mild uncouplers, and enhancers of mitochondrial biogenesis, which have been shown to improve pathophysiological outcomes after TBI. However, to date, there is no effective treatment for TBI. Studies have suggested that the deletion of LDL receptor-related protein 1 (LRP1) in adult neurons or glial cells could be beneficial and promote neuronal health. In this study, we used WT and LRP1 knockout (LKO) mouse embryonic fibroblast cells to examine mitochondrial outcomes following exogenous oxidative stress. Furthermore, we developed a novel technique to measure mitochondrial morphometric dynamics using transgenic mitochondrial reporter mice mtD2g (mitochondrial-specific Dendra2 green) in a TBI model. We found that oxidative stress increased the quantity of fragmented and spherical-shaped mitochondria in the injury core of the ipsilateral cortex following TBI, whereas rod-like elongated mitochondria were seen in the corresponding contralateral cortex. Critically, LRP1 deficiency significantly decreased mitochondrial fragmentation, preserving mitochondrial function and cell growth following exogenous oxidative stress. Collectively, our results show that targeting LRP1 to improve mitochondrial function is a potential pharmacotherapeutic strategy against oxidative damage in TBI and other neurodegenerative diseases.
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影响因子：
3.7
作者：
Boucher, Philippe;Li, Wei-Ping;Matz, Rachel L.;Takayama, Yoshiharu;Auwerx, Johan;Anderson, Richard G. W.;Herz, Joachim
通讯作者：
Herz, Joachim
影响因子：
15.9
作者：
Gaultier, Alban;Arandjelovic, Sanja;Campana, W. Marie
通讯作者：
Campana, W. Marie
DOI：
10.1124/jpet.112.192138
发表时间：
2012-09-01
影响因子：
3.5
作者：
Johri, Ashu;Beal, M. Flint
通讯作者：
Beal, M. Flint
融合或裂变：线粒体在不同严重性的脑外伤中的命运。
影响因子：
4.6
作者：
Di Pietro V;Lazzarino G;Amorini AM;Signoretti S;Hill LJ;Porto E;Tavazzi B;Lazzarino G;Belli A
通讯作者：
Belli A
影响因子：
3.7
作者：
Fuentealba RA;Liu Q;Zhang J;Kanekiyo T;Hu X;Lee JM;LaDu MJ;Bu G
通讯作者：
Bu G