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 E1α1 subunit 1 (PDHE1α1) and is inhibited by the phosphorylation of PDHE1α1 (p-PDHE1α1). We hypothesized that PDHE1α1 expression and phosphorylation was altered in rat brain following controlled cortical impact (CCI)-induced TBI. Compared to naïve controls (=100%), PDHE1α1 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 4 h, 24 h, 3- and 7-day post-CCI, respectively. PDHE1α1 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 4 h, 24 h, 3- and 7-day post-CCI, respectively. Similar reduction in PDHE1α1 and p-PDHE1α1 protein was found in the craniotomy (sham CCI) group. TBI-induced change in PDHE1α1 expression and phosphorylation could alter brain PDH activity and glucose metabolism.