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In Vitro and In Vivo Pipeline for Validation of Disease-Modifying Effects of Systems Biology-Derived Network Treatments for Traumatic Brain Injury—Lessons Learned
Open AccessArticle

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

1
UniCamillus-Saint Camillus International University of Health Sciences, Via di Sant’Alessandro 8, 00131 Rome, Italy
2
Department of Biomedical and Biotechnological Sciences, Division of Medical Biochemistry, University of Catania, Viale A. Doria 6, 95125 Catania, Italy
3
Division of Emergency-Urgency, UOC of Neurosurgery, S. Eugenio Hospital, Via Filippo Meda 35, 00157 Rome, Italy
4
Department of Biomedical and Biotechnological Sciences, Human Anatomy and Histology Section, School of Medicine, Via S. Sofia 97, 95123 Catania, Italy
5
Oasi Research Institute–IRCCS, Via Conte Ruggero 73, 94018 Troina (EN), Italy
6
Department of System Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy
7
Neurotrauma and Ophthalmology Research Group, School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK
8
National Institute for Health Research Surgical Reconstruction and Microbiology Research Centre, Queen Elizabeth Hospital, Edgbaston, Birmingham B15 2TT, UK
9
Institute of Biochemistry and Clinical Biochemistry, Catholic University of Rome, Largo F. Vito 1, 00168 Rome, Italy
10
Fondazione Policlinico Universitario A. Gemelli IRCCS, Largo A. Gemelli 8, 00168 Rome, Italy
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
Int. J. Mol. Sci. 2019, 20(22), 5774; https://doi.org/10.3390/ijms20225774
Received: 13 September 2019 / Revised: 5 November 2019 / Accepted: 13 November 2019 / Published: 16 November 2019
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. View Full-Text
Keywords: traumatic brain injury; mitochondrial dysfunction; pyruvate dehydrogenase; tricarboxylic acid cycle; acetyl-CoA; concussion traumatic brain injury; mitochondrial dysfunction; pyruvate dehydrogenase; tricarboxylic acid cycle; acetyl-CoA; concussion
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Lazzarino, G.; Amorini, A.M.; Signoretti, S.; Musumeci, G.; Lazzarino, G.; Caruso, G.; Pastore, F.S.; Di Pietro, V.; Tavazzi, B.; Belli, A. Pyruvate Dehydrogenase and Tricarboxylic Acid Cycle Enzymes Are Sensitive Targets of Traumatic Brain Injury Induced Metabolic Derangement. Int. J. Mol. Sci. 2019, 20, 5774.

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