Pyruvate Dehydrogenase and Tricarboxylic Acid Cycle Enzymes Are Sensitive Targets of Traumatic Brain Injury Induced Metabolic Derangement

Abstract

Using a closed-head impact acceleration model of mild or severe traumatic brain injury (mTBI or sTBI, respectively) in rats, we evaluated the effects of graded head impacts on the gene and protein expressions of pyruvate dehydrogenase (PDH), as well as major enzymes of mitochondrial tricarboxylic acid cycle (TCA). TBI was induced in anaesthetized rats by dropping 450 g from 1 (mTBI) or 2 m height (sTBI). After 6 h, 12 h, 24 h, 48 h, and 120 h gene expressions of enzymes and subunits of PDH. PDH kinases and phosphatases (PDK1-4 and PDP1-2, respectively), citrate synthase (CS), isocitrate dehydrogenase (IDH), oxoglutarate dehydrogenase (OGDH), succinate dehydrogenase (SDH), succinyl-CoA synthase (SUCLG), and malate dehydrogenase (MDH) were determined in whole brain extracts (n = 6 rats at each time for both TBI levels). In the same samples, the high performance liquid chromatographic (HPLC) determination of acetyl-coenzyme A (acetyl-CoA) and free coenzyme A (CoA-SH) was performed. Sham-operated animals (n = 6) were used as controls. After mTBI, the results indicated a general transient decrease, followed by significant increases, in PDH and TCA gene expressions. Conversely, permanent PDH and TCA downregulation occurred following sTBI. The inhibitory conditions of PDH (caused by PDP1-2 downregulations and PDK1-4 overexpression) and SDH appeared to operate only after sTBI. This produced almost no change in acetyl-CoA and free CoA-SH following mTBI and a remarkable depletion of both compounds after sTBI. These results again demonstrated temporary or steady mitochondrial malfunctioning, causing minimal or profound modifications to energy-related metabolites, following mTBI or sTBI, respectively. Additionally, PDH and SDH appeared to be highly sensitive to traumatic insults and are deeply involved in mitochondrial-related energy metabolism imbalance.

Severe Spinal Cord Injury in Rats Induces Chronic Changes in the Spinal Cord and Cerebral Cortex Metabolism, Adjusted by Thiamine That Improves Locomotor Performance

“…Earlier works considered negative outcome of the neurotrauma-decreased enzymatic activities for the energy metabolism during a short-term period up to several days after the trauma ( Sharma et al, 2009 ; Mannino et al, 2018 ; Mkrtchyan et al, 2018b ; Lazzarino et al, 2019 ; Pandya et al, 2019 ). On the other hand, levels of free amino acids and related peptides, such as glutathione, are known to be of marker significance in different neuropathologies, including not only traumatic injuries of CNS, but also individual action of associated pathogenic factors, such as hypoxia and perturbed neurotransmitter metabolism ( Dash et al, 2016 ; Amorini et al, 2017 ; Griffin and Bradshaw, 2017 ; Graf et al, 2020 ; Rana et al, 2020 ).…”

Low Molecular Weight Dextran Sulfate (ILB®) Administration Restores Brain Energy Metabolism Following Severe Traumatic Brain Injury in the Rat

“…The raised NAA concentrations found in the post-injured brain of ILB ® -treated rats may have been due to acetyl-CoA, generated by the enhanced activity of the pyruvate dehydrogenase (PDH) complex, thereby regenerating NAA via the NAT8L-dependent biosynthetic reaction [48,49]. Recently, we found that, following sTBI, the genes controlling the sophisticated enzymatic mechanism regulating the PDH complex activity are expressed in an inhibitory mode causing an overall inhibition of the PDH complex and compromising restoration of energy metabolism of the post-injured brain [50]. Therefore, ILB ® treatment may disinhibit the PDH complex and potentiate acetyl-CoA production at an adequate rate to supply the TCA cycle, as well as to allow NAT8L-mediated condensation of acetyl-CoA with aspartate to form NAA.…”

Glutamine, Glutamate, and Aspartate Improves Morphology and Energy Production of Small Intestine in Piglets with Different Energy Levels Diets

“…PDH represents a cornerstone in cellular energy metabolism, linking glycolysis and Krebs' cycle and lipid metabolism [50]. In this study, PDH activity was failed to detected, whereas the decreased Pdk4 gene expression might suggest the in ux of acetyl-CoA from glycolysis into the Krebs' cycle increased in response to T2 treatment on d 5 post-weaning.…”