Mkrtchyan 2018 Biochim Biophys Acta

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Mkrtchyan GV, Üçal M, Müllebner A, Dumitrescu S, Kames M, Moldzio R, Molcanyi M, Schaefer S, Weidinger A, Schaefer U, Hescheler J, Duvigneau JC, Redl H, Bunik VI, Kozlov AV (2018) Thiamine preserves mitochondrial function in a rat model of traumatic brain injury, preventing inactivation of the 2-oxoglutarate dehydrogenase complex. Biochim Biophys Acta 1859:925-31.

» PMID: 29777685

Mkrtchyan GV, Uecal M, Muellebner A, Dumitrescu S, Kames M, Moldzio R, Molcanyi M, Schaefer S, Weidinger A, Schaefer U, Hescheler J, Duvigneau JC, Redl H, Bunik VI, Kozlov AV (2018) Biochim Biophys Acta

Abstract: Based on the fact that traumatic brain injury is associated with mitochondrial dysfunction we aimed at localization of mitochondrial defect and attempted to correct it by thiamine.

Interventional controlled experimental animal study was used. Adult male Sprague-Dawley rats were subjected to lateral fluid percussion traumatic brain injury. Thiamine was administered 1 h prior to trauma; cortex was extracted for analysis 4 h and 3 d after trauma.

Increased expression of inducible nitric oxide synthase (iNOS) and tumor necrosis factor receptor 1 (TNF-R1) by 4 h was accompanied by a decrease in mitochondrial respiration with glutamate but neither with pyruvate nor succinate. Assays of TCA cycle flux-limiting 2-oxoglutarate dehydrogenase complex (OGDHC) and functionally linked enzymes (glutamate dehydrogenase, glutamine synthetase, pyruvate dehydrogenase, malate dehydrogenase and malic enzyme) indicated that only OGDHC activity was decreased. Application of the OGDHC coenzyme precursor thiamine rescued the activity of OGDHC and restored mitochondrial respiration. These effects were not mediated by changes in the expression of the OGDHC sub-units (E1k and E3), suggesting post-translational mechanism of thiamine effects. By the third day after TBI, thiamine treatment also decreased expression of TNF-R1. Specific markers of unfolded protein response did not change in response to thiamine.

Our data point to OGDHC as a major site of damage in mitochondria upon traumatic brain injury, which is associated with neuroinflammation and can be corrected by thiamine. Further studies are required to evaluate the pathological impact of these findings in clinical settings.

Copyright © 2018. Published by Elsevier B.V.

Keywords: 2-Oxoglutarate dehydrogenase complex, Mitochondria, Neuroinflammation, TCA cycle, Thiamine, Traumatic brain injury (TBI) Bioblast editor: Kandolf G O2k-Network Lab: AT Vienna Kozlov AV

Labels: MiParea: Respiration, mt-Medicine, Pharmacology;toxicology 

Organism: Rat  Tissue;cell: Nervous system  Preparation: Homogenate 

Coupling state: OXPHOS  Pathway: N, S  HRR: Oxygraph-2k 

Labels, 2018-07