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

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Authors

  • Giacomo Lazzarino
  • Angela Maria Amorini
  • Stefano Signoretti
  • Giuseppe Musumeci
  • Giuseppe Lazzarino
  • Giuseppe Caruso
  • Francesco Saverio Pastore
  • Barbara Tavazzi

External organisations

  • UniCamillus-Saint Camillus International University of Health Sciences
  • Department of Surgery, University of Catania, Catania, Italy.
  • S. Eugenio Hospital
  • Investigative Medicine Program, Yale University School of Medicine
  • Oasi Research Institute - IRCCS
  • University of Rome Tor Vergata
  • Neurotrauma and Ophthalmology Research Group, Institute of Inflammation and Aging, University of Birmingham, Birmingham, UK.
  • School of Clinical and Experimental Medicine
  • Univ Birmingham Edgbaston
  • National Institute for Health Research Surgical Reconstruction and Microbiology Research Centre (NIHR-SRMRC)
  • Queen Elizabeth Hospital Birmingham, Queen Elizabeth Medical Centre
  • Catholic University of Rome

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.

Details

Original languageEnglish
JournalInternational Journal of Molecular Sciences
Volume20
Issue number22
Publication statusPublished - 16 Nov 2019

Keywords

  • Acetyl Coenzyme A/analysis, Animals, Brain Injuries, Traumatic/metabolism, Chromatography, High Pressure Liquid, Citric Acid Cycle/genetics, Coenzyme A/analysis, Down-Regulation, Energy Metabolism, Male, Mitochondria/metabolism, Protein Subunits/genetics, Pyruvate Dehydrogenase Complex/genetics, Rats, Rats, Wistar, Severity of Illness Index, Succinate Dehydrogenase/genetics, Up-Regulation