Harmon Jennifer L, Gibbs Whitney S, Whitaker Ryan M, Schnellmann Rick G, Adkins DeAnna L
1 Department of Drug Discovery and Biomedical Sciences, Medical University of South Carolina , Charleston, South Carolina.
2 Ralph H. Johnson Veterans Administration Medical Center , Charleston, South Carolina.
J Neurotrauma. 2017 Jan 15;34(2):487-494. doi: 10.1089/neu.2015.4395. Epub 2016 Aug 1.
Traumatic brain injury (TBI) results in oxidative stress and calcium dysregulation in mitochondria. However, little work has examined perturbations of mitochondrial homeostasis in peri-injury tissue. We examined mitochondrial homeostasis after a unilateral controlled cortical impact over the sensorimotor cortex in adult male rats. There was a significant reduction in peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) messenger RNA (mRNA) at post-injury days 3 and 6 and a transient reduction in mitochondrial DNA copy number at 3 days post-injury that recovered by 6 days in the ipsi-injury striatum. In ipsilateral cortex, PGC-1α mRNA was reduced only at 6 days post-injury. Additionally, expression of mitochondrial-encoded mRNAs, cytochrome c oxidase subunit 1 and NADH dehydrogenase subunit 1, was decreased at 3 and 6 days post-injury in ipsilesional striatum and at 6 days post-injury in ipsilesional cortex. There was no observable decrease in nuclear-encoded mRNAs mitochondrial transcription factor A or NADH dehydrogenase (ubiquinone) Fe-S protein 1. We detected an acute increase in superoxide dismutase 2 mRNA expression, as well as an induction of microRNA (miR)-21 and miR-155, which have been previously demonstrated to disrupt mitochondrial homeostasis. Behaviorally, rats with TBI exhibited marked error rates in contrainjury forelimb performance on the ladder test. These findings reveal that there may be differential susceptibilities of various peri-injury brain structures to mitochondrial dysfunction and associated behavioral deficits, and that molecular pathways demonstrated to interfere with mitochondrial homeostasis and function are activated subacutely post-TBI.
创伤性脑损伤（TBI）会导致线粒体中的氧化应激和钙调节异常。然而，很少有研究探讨损伤周围组织中线粒体稳态的扰动情况。我们在成年雄性大鼠的感觉运动皮层上进行单侧控制性皮质撞击后，检查了线粒体稳态。在损伤后第3天和第6天，过氧化物酶体增殖物激活受体γ共激活因子1α（PGC-1α）信使核糖核酸（mRNA）显著减少，损伤后3天线粒体DNA拷贝数短暂减少，在损伤同侧纹状体中到6天时恢复。在同侧皮质中，PGC-1α mRNA仅在损伤后6天减少。此外，线粒体编码的mRNA、细胞色素c氧化酶亚基1和烟酰胺腺嘌呤二核苷酸脱氢酶亚基1的表达在损伤后3天和6天在损伤同侧纹状体中降低，在损伤后6天在损伤同侧皮质中降低。核编码的mRNA线粒体转录因子A或烟酰胺腺嘌呤二核苷酸脱氢酶（泛醌）铁硫蛋白1没有明显减少。我们检测到超氧化物歧化酶2 mRNA表达急性增加，以及微小RNA（miR）-21和miR-155的诱导，先前已证明它们会破坏线粒体稳态。行为学上，TBI大鼠在阶梯试验中损伤对侧前肢表现出明显的错误率。这些发现表明，损伤周围的各种脑结构可能对线粒体功能障碍和相关行为缺陷有不同的易感性，并且已证明干扰线粒体稳态和功能的分子途径在TBI后亚急性被激活。
