Xing Guoqiang, Ren Ming, Watson William D, O'Neill J Timothy, Verma Ajay
Department of Psychiatry, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814-4799, United States.
Neurosci Lett. 2009 Apr 17;454(1):38-42. doi: 10.1016/j.neulet.2009.01.047. Epub 2009 Jan 23.
Dysregulated brain glucose metabolism and lactate accumulation are seen following traumatic brain injury (TBI). The underlying molecular mechanism is poorly understood. Pyruvate dehydrogenase (PDH), the rate-limiting enzyme coupling cytosolic glycolysis to mitochondrial citric acid cycle, plays a critical role in maintaining homeostasis of brain glucose metabolism. PDH activity is maintained by the expression of its E1alpha1 subunit 1 (PDHE1alpha1) and is inhibited by the phosphorylation of PDHE1alpha1 (p-PDHE1alpha1). We hypothesized that PDHE1alpha1 expression and phosphorylation was altered in rat brain following controlled cortical impact (CCI)-induced TBI. Compared to naïve controls (=100%), PDHE1alpha1 protein decreased significantly ipsilateral to CCI (62%, P<0.05; 75%, P<0.05; 57%, P<0.05; and 39%, P<0.01) and contralateral to CCI (77%, 78%, 78% and 36% P<0.01) at 4h, 24h, 3- and 7-day post-CCI, respectively. PDHE1alpha1 protein phosphorylation level also decreased significantly ipsilateral to CCI (31%, P<0.01; 102%, P>0.05; 64%, P<0.05; and 14%, P<0.01) and to contralateral CCI (35%, 74%, P<0.05; 60%, P<0.05; 20%, P<0.01) at 4h, 24h, 3- and 7-day post-CCI, respectively. Similar reduction in PDHE1alpha1 and p-PDHE1alpha1 protein was found in the craniotomy (sham CCI) group. TBI-induced change in PDHE1alpha1 expression and phosphorylation could alter brain PDH activity and glucose metabolism.
创伤性脑损伤（TBI）后可见脑葡萄糖代谢失调和乳酸堆积。其潜在分子机制尚不清楚。丙酮酸脱氢酶（PDH）是将胞质糖酵解与线粒体柠檬酸循环相偶联的限速酶，在维持脑葡萄糖代谢稳态中起关键作用。PDH活性由其E1α1亚基1（PDHE1α1）的表达维持，并受PDHE1α1磷酸化（p-PDHE1α1）抑制。我们假设在可控皮质撞击（CCI）诱导的TBI后，大鼠脑内PDHE1α1的表达和磷酸化会发生改变。与未受伤对照组（=100%）相比，在CCI后4小时、24小时、3天和7天，CCI同侧的PDHE1α1蛋白显著减少（分别为62%，P<0.05；75%，P<0.05；57%，P<0.05；39%，P<0.01），CCI对侧的PDHE1α1蛋白也显著减少（分别为77%、78%、78%和36%，P<0.01）。在CCI后4小时、24小时、3天和7天，CCI同侧的PDHE1α1蛋白磷酸化水平也显著降低（分别为31%，P<0.01；102%，P>0.05；64%，P<0.05；14%，P<0.01），CCI对侧的PDHE1α1蛋白磷酸化水平也显著降低（分别为35%、74%，P<0.05；60%，P<0.05；20%，P<0.01）。在开颅手术（假CCI）组中也发现了PDHE1α1和p-PDHE1α1蛋白的类似减少。TBI诱导的PDHE1α1表达和磷酸化变化可能会改变脑PDH活性和葡萄糖代谢。
