Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI 48201, USA.
Exp Neurol. 2010 Jun;223(2):523-8. doi: 10.1016/j.expneurol.2010.01.020. Epub 2010 Feb 8.
The importance of mitochondria in spinal cord injury has mainly been attributed to their participation in apoptosis at the site of injury. But another aspect of mitochondrial function is the generation of more than 90% of cellular energy in the form of ATP, mediated by the oxidative phosphorylation (OxPhos) process. Cytochrome c oxidase (CcO) is a central OxPhos component and changes in its activity reflect changes in energy demand. A recent study suggests that respiratory muscle function in chronic obstructive pulmonary disease (COPD) patients is compromised via alterations in mitochondrial function. In an animal model of cervical spinal cord hemisection (C2HS) respiratory dysfunction, we have shown that theophylline improves respiratory function. In the present study, we tested the hypothesis that theophylline improves respiratory function at the cellular level via improved mitochondrial function in the C2HS model. We demonstrate that CcO activity was significantly (33%) increased in the spinal cord adjacent to the site of injury (C3-C5), and that administration of theophylline (20mg/kg 3x daily orally) after C2HS leads to an even more pronounced increase in CcO activity of 62% compared to sham-operated animals. These results are paralleled by a significant increase in cellular ATP levels (51% in the hemidiaphragm ipsilateral to the hemisection). We conclude that C2HS increases energy demand and activates mitochondrial respiration, and that theophylline treatment improves energy levels through activation of the mitochondrial OxPhos process to provide energy for tissue repair and functional recovery after paralysis in the C2HS model.
线粒体在脊髓损伤中的重要性主要归因于它们在损伤部位参与细胞凋亡。但是，线粒体功能的另一个方面是通过氧化磷酸化（OxPhos）过程以 ATP 的形式产生超过 90%的细胞能量。细胞色素 c 氧化酶（CcO）是 OxPhos 的核心组成部分，其活性的变化反映了能量需求的变化。最近的一项研究表明，慢性阻塞性肺疾病（COPD）患者的呼吸肌功能受损是通过线粒体功能的改变引起的。在颈脊髓半切（C2HS）动物模型中，我们已经证明茶碱可改善呼吸功能。在本研究中，我们假设茶碱通过改善 C2HS 模型中的线粒体功能来提高细胞水平的呼吸功能。我们证明，与假手术动物相比，损伤部位相邻的脊髓（C3-C5）中 CcO 活性显著增加了 33%，而 C2HS 后给予茶碱（20mg/kg，每日 3 次口服）可使 CcO 活性进一步显著增加 62%。这些结果与细胞 ATP 水平的显著增加（半横切同侧膈肌增加 51%）相平行。我们得出结论，C2HS 增加了能量需求并激活了线粒体呼吸，而茶碱治疗通过激活线粒体 OxPhos 过程来提高能量水平，为瘫痪后的组织修复和功能恢复提供能量。
