title: Controlled cortical impact injury and craniotomy result in divergent alterations of pyruvate metabolizing enzymes in rat brain.
abstract: Dysregulated glucose metabolism and energy deficit is a characteristic of severe traumatic brain injury (TBI) but its mechanism remains to be fully elucidated. Phosphorylation of pyruvate dehydrogenase (PDH) is the rate-limiting mitochondria enzyme reaction coupling glycolysis to the tricarboxylic acid cycle. Phosphorylation of PDH E1α1 subunit catalyzed by PDH kinase (PDK) inhibits PDH activity, effectively decoupling aerobic glycolysis whereas dephosphorylation of phosphorylated PDHE1α1 by PDH phosphatase (PDP) restores PDH activity. We recently reported altered expression and phosphorylation of pyruvate dehydrogenase (PDH) following TBI. However, little is known about PDK and PDP involvement. We determined PDK (PDK1-4) and PDP isoenzyme (PDP1-2) mRNA and protein expression in rat brain using immunohistochemistry and in situ hybridization techniques. We also quantified PDK and PDP mRNA and protein levels in rat brain following TBI using quantitative real-time PCR and Western blot, respectively. Controlled cortical impact-induced TBI (CCI-TBI) and craniotomy significantly enhanced PDK1-2 isoenzyme mRNA expression level but significantly suppressed PDP1 and PDK4 mRNA expression after the injury (4h to 7days). CCI-TBI and craniotomy also significantly increased PDK1-4 isoenzyme protein expression but suppressed PDP1-2 protein expression in rat brain. In summary, the divergent changes between PDK and PDP expression indicate imbalance between PDK and PDP activities that would favor increased PDHE1α1 phosphorylation and enzyme inhibition contributing to impaired oxidative glucose metabolism in TBI as well as craniotomy.
authors.affiliation: Department of Neurology, Uniformed Services University of the Health Sciences, Bethesda, MD 20814-4799, USA. gxing99@yahoo.com
authors.forename: Guoqiang
authors.initials: G
authors.lastname: Xing
authors.forename: Ming
authors.initials: M
authors.lastname: Ren
authors.forename: J Timothy
authors.initials: JT
authors.lastname: O'Neill
authors.forename: Ajay
authors.initials: A
authors.lastname: Verma
authors.forename: William D
authors.initials: WD
authors.lastname: Watson
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001921:Brain / Q000201:enzymology*; D001930:Brain Injuries / Q000209:etiology / Q000473:pathology*; D002540:Cerebral Cortex / Q000473:pathology*; D003399:Craniotomy / Q000009:adverse effects; D007839:Functional Laterality; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D008297:Male; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011769:Pyruvate Dehydrogenase (Lipoamide)-Phosphatase / Q000235:genetics / Q000378:metabolism*; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D011773:Pyruvates; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
chemical_list: D007527:Isoenzymes; C000631434:Pdk1 protein, rat; C000631440:Pdk4 protein, rat; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D011773:Pyruvates; D012333:RNA, Messenger; D017346:Protein Serine-Threonine Kinases; D011769:Pyruvate Dehydrogenase (Lipoamide)-Phosphatase