Traumatic brain injury-induced expression and phosphorylation of pyruvate dehydrogenase: a mechanism of dysregulated glucose metabolism.
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.
Department of Psychiatry, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814-4799, United States. gxing@usuhs.mil
Guoqiang
G
Xing
Ming
M
Ren
William D
WD
Watson
William A
WA
Watson
J Timothy
JT
O'Neill
J Timothy
JT
O'Neil
Ajay
A
Verma
D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism; D001930:Brain Injuries / Q000201:enzymology*; D005947:Glucose / Q000378:metabolism*; D007150:Immunohistochemistry; D008297:Male; D010766:Phosphorylation; D030481:Pyruvate Dehydrogenase (Lipoamide) / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction
D030481:Pyruvate Dehydrogenase (Lipoamide); C065640:pyruvate dehydrogenase E1alpha subunit; D005947:Glucose