Thiamine preserves mitochondrial function in a rat model of traumatic brain injury, preventing inactivation of the 2-oxoglutarate dehydrogenase complex

Garik V. Mkrtchyan; Muammer Üçal; Andrea Müllebner; Sergiu Dumitrescu; Martina Kames; Rudolf Moldzio; Marek Molcanyi; Samuel Schaefer; Adelheid Weidinger; Ute Schaefer; Juergen Hescheler; Johanna Catharina Duvigneau; Heinz Redl; Victoria I. Bunik; Andrey V. Kozlov

doi:10.1016/j.bbabio.2018.05.005

Thiamine preserves mitochondrial function in a rat model of traumatic brain injury, preventing inactivation of the 2-oxoglutarate dehydrogenase complex

Garik V. Mkrtchyan, Muammer Üçal, Andrea Müllebner, Sergiu Dumitrescu, Martina Kames, Rudolf Moldzio, Marek Molcanyi, Samuel Schaefer, Adelheid Weidinger, Ute Schaefer, Juergen Hescheler, Johanna Catharina Duvigneau, Heinz Redl, Victoria I. Bunik, Andrey V. Kozlov^*

^*Corresponding author af dette arbejde

9 Citationer (Scopus)

Abstract

Background and purpose: 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. Experimental approach: 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. Key results: 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. Conclusion and implications: 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.

Originalsprog	Engelsk
Tidsskrift	Biochimica et Biophysica Acta - Bioenergetics
Vol/bind	1859
Udgave nummer	9
Sider (fra-til)	925-931
Antal sider	7
ISSN	0005-2728
DOI	https://doi.org/10.1016/j.bbabio.2018.05.005
Status	Udgivet - 2018
Udgivet eksternt	Ja

Adgang til dokumentet

10.1016/j.bbabio.2018.05.005

Citationsformater

Mkrtchyan, G. V., Üçal, M., Müllebner, A., Dumitrescu, S., Kames, M., Moldzio, R., Molcanyi, M., Schaefer, S., Weidinger, A., Schaefer, U., Hescheler, J., Duvigneau, J. C., Redl, H., Bunik, V. I., & Kozlov, A. V. (2018). Thiamine preserves mitochondrial function in a rat model of traumatic brain injury, preventing inactivation of the 2-oxoglutarate dehydrogenase complex. Biochimica et Biophysica Acta - Bioenergetics, 1859(9), 925-931. https://doi.org/10.1016/j.bbabio.2018.05.005

Thiamine preserves mitochondrial function in a rat model of traumatic brain injury, preventing inactivation of the 2-oxoglutarate dehydrogenase complex. / Mkrtchyan, Garik V.; Üçal, Muammer; Müllebner, Andrea et al.
I: Biochimica et Biophysica Acta - Bioenergetics, Bind 1859, Nr. 9, 2018, s. 925-931.

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review

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', Biochimica et Biophysica Acta - Bioenergetics, bind 1859, nr. 9, s. 925-931. https://doi.org/10.1016/j.bbabio.2018.05.005

@article{c2e53325b03e4c7f9556a65b0d98133d,

title = "Thiamine preserves mitochondrial function in a rat model of traumatic brain injury, preventing inactivation of the 2-oxoglutarate dehydrogenase complex",

abstract = "Background and purpose: 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. Experimental approach: 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. Key results: 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. Conclusion and implications: 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.",

keywords = "2-Oxoglutarate dehydrogenase complex, Mitochondria, Neuroinflammation, TCA cycle, Thiamine, Traumatic brain injury (TBI)",

author = "Mkrtchyan, {Garik V.} and Muammer {\"U}{\c c}al and Andrea M{\"u}llebner and Sergiu Dumitrescu and Martina Kames and Rudolf Moldzio and Marek Molcanyi and Samuel Schaefer and Adelheid Weidinger and Ute Schaefer and Juergen Hescheler and Duvigneau, {Johanna Catharina} and Heinz Redl and Bunik, {Victoria I.} and Kozlov, {Andrey V.}",

year = "2018",

doi = "10.1016/j.bbabio.2018.05.005",

language = "English",

volume = "1859",

pages = "925--931",

journal = "Biochimica et Biophysica Acta - Bioenergetics",

issn = "0005-2728",

publisher = "Elsevier",

number = "9",

}

TY - JOUR

T1 - Thiamine preserves mitochondrial function in a rat model of traumatic brain injury, preventing inactivation of the 2-oxoglutarate dehydrogenase complex

AU - Mkrtchyan, Garik V.

AU - Üçal, Muammer

AU - Müllebner, Andrea

AU - Dumitrescu, Sergiu

AU - Kames, Martina

AU - Moldzio, Rudolf

AU - Molcanyi, Marek

AU - Schaefer, Samuel

AU - Weidinger, Adelheid

AU - Schaefer, Ute

AU - Hescheler, Juergen

AU - Duvigneau, Johanna Catharina

AU - Redl, Heinz

AU - Bunik, Victoria I.

AU - Kozlov, Andrey V.

PY - 2018

Y1 - 2018

N2 - Background and purpose: 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. Experimental approach: 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. Key results: 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. Conclusion and implications: 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.

AB - Background and purpose: 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. Experimental approach: 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. Key results: 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. Conclusion and implications: 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.

KW - 2-Oxoglutarate dehydrogenase complex

KW - Mitochondria

KW - Neuroinflammation

KW - TCA cycle

KW - Thiamine

KW - Traumatic brain injury (TBI)

U2 - 10.1016/j.bbabio.2018.05.005

DO - 10.1016/j.bbabio.2018.05.005

M3 - Journal article

C2 - 29777685

AN - SCOPUS:85048460718

SN - 0005-2728

VL - 1859

SP - 925

EP - 931

JO - Biochimica et Biophysica Acta - Bioenergetics

JF - Biochimica et Biophysica Acta - Bioenergetics

IS - 9

ER -

Thiamine preserves mitochondrial function in a rat model of traumatic brain injury, preventing inactivation of the 2-oxoglutarate dehydrogenase complex

Abstract

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