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Evidence to support mitochondrial neuroprotection, in severe traumatic brain injury

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Abstract

Traumatic brain injury (TBI) is still the leading cause of disability in young adults worldwide. The major mechanisms – diffuse axonal injury, cerebral contusion, ischemic neurological damage, and intracranial hematomas have all been shown to be associated with mitochondrial dysfunction in some form. Mitochondrial dysfunction in TBI patients is an active area of research, and attempts to manipulate neuronal/astrocytic metabolism to improve outcomes have been met with limited translational success. Previously, several preclinical and clinical studies on TBI induced mitochondrial dysfunction have focused on opening of the mitochondrial permeability transition pore (PTP), consequent neurodegeneration and attempts to mitigate this degeneration with cyclosporine A (CsA) or analogous drugs, and have been unsuccessful. Recent insights into normal mitochondrial dynamics and into diseases such as inherited mitochondrial neuropathies, sepsis and organ failure could provide novel opportunities to develop mitochondria-based neuroprotective treatments that could improve severe TBI outcomes. This review summarizes those aspects of mitochondrial dysfunction underlying TBI pathology with special attention to models of penetrating traumatic brain injury, an epidemic in modern American society.

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References

  • Adamczak SE, de Rivero Vaccari JP, Dale G, Brand FJ 3rd, Nonner D, Bullock MR et al (2014) Pyroptotic neuronal cell death mediated by the AIM2 inflammasome. J Cereb Blood Flow Metab 34(4):621–629. doi:10.1038/jcbfm.2013.236

    CAS  Google Scholar 

  • Alessandri B, Rice AC, Levasseur J, DeFord M, Hamm RJ, Bullock MR (2002) Cyclosporin a improves brain tissue oxygen consumption and learning/memory performance after lateral fluid percussion injury in rats. J Neurotrauma 19(7):829–841. doi:10.1089/08977150260190429

    Google Scholar 

  • Alessandri BGM, Levasseur JE, Bullock M (2009) Lactate and glucose as energy substrates and their role in traumatic brain injury and therapy. [Review]. Future Neurol 4(2):209–228. doi:10.2217/14796708.4.2.209

    CAS  Google Scholar 

  • Aminmansour B, Fard SA, Habibabadi MR, Moein P, Norouzi R, Naderan M (2014) The efficacy of cyclosporine-a on diffuse axonal injury after traumatic brain injury. Adv Biomed Res 3:35. doi:10.4103/2277-9175.125031

    Google Scholar 

  • Amo T, Sato S, Saiki S, Wolf AM, Toyomizu M, Gautier CA et al (2011) Mitochondrial membrane potential decrease caused by loss of PINK1 is not due to proton leak, but to respiratory chain defects. Neurobiol Dis 41(1):111–118. doi:10.1016/j.nbd.2010.08.027

    CAS  Google Scholar 

  • Arun P, Ariyannur PS, Moffett JR, Xing G, Hamilton K, Grunberg NE et al (2010) Metabolic acetate therapy for the treatment of traumatic brain injury. J Neurotrauma 27(1):293–298. doi:10.1089/neu.2009.0994

    Google Scholar 

  • Balan IS, Saladino AJ, Aarabi B, Castellani RJ, Wade C, Stein DM et al (2013) Cellular alterations in human traumatic brain injury: changes in mitochondrial morphology reflect regional levels of injury severity. J Neurotrauma 30(5):367–381. doi:10.1089/neu.2012.2339

    Google Scholar 

  • Barrientos A, Fontanesi F, Diaz F (2009) Evaluation of the mitochondrial respiratory chain and oxidative phosphorylation system using polarography and spectrophotometric enzyme assays. Curr Protoc Hum Genet, Chapter 19, Unit19 13, doi:10.1002/0471142905.hg1903s63

  • Baskaya MK, Dogan A, Temiz C, Dempsey RJ (2000) Application of 2,3,5-triphenyltetrazolium chloride staining to evaluate injury volume after controlled cortical impact brain injury: role of brain edema in evolution of injury volume. J Neurotrauma 17(1):93–99

    CAS  Google Scholar 

  • Bhatt DP, Houdek HM, Watt JA, Rosenberger TA (2013) Acetate supplementation increases brain phosphocreatine and reduces AMP levels with no effect on mitochondrial biogenesis. Neurochem Int 62(3):296–305. doi:10.1016/j.neuint.2013.01.004

    CAS  Google Scholar 

  • Binder S, Corrigan JD, Langlois JA (2005) The public health approach to traumatic brain injury: an overview of CDC’s research and programs. J Head Trauma Rehabil 20(3):189–195

    Google Scholar 

  • Blaya MO, Bramlett HM, Naidoo J, Pieper AA, Dietrich WD (2014) Neuroprotective efficacy of a proneurogenic compound after traumatic brain injury. J Neurotrauma 31(5):476–486. doi:10.1089/neu.2013.3135

    Google Scholar 

  • Bough KJ, Wetherington J, Hassel B, Pare JF, Gawryluk JW, Greene JG et al (2006) Mitochondrial biogenesis in the anticonvulsant mechanism of the ketogenic diet. Ann Neurol 60(2):223–235. doi:10.1002/ana.20899

    CAS  Google Scholar 

  • Bouzat P, Sala N, Suys T, Zerlauth JB, Marques-Vidal P, Feihl F et al (2014) Cerebral metabolic effects of exogenous lactate supplementation on the injured human brain. Intensive Care Med 40(3):412–421. doi:10.1007/s00134-013-3203-6

    CAS  Google Scholar 

  • Brealey D, Karyampudi S, Jacques TS, Novelli M, Stidwill R, Taylor V et al (2004) Mitochondrial dysfunction in a long-term rodent model of sepsis and organ failure. Am J Physiol Regul Integr Comp Physiol 286(3):R491–R497. doi:10.1152/ajpregu.00432.2003

    CAS  Google Scholar 

  • Brophy GM, Mazzeo AT, Brar S, Alves OL, Bunnell K, Gilman C et al (2013) Exposure of cyclosporin a in whole blood, cerebral spinal fluid, and brain extracellular fluid dialysate in adults with traumatic brain injury. J Neurotrauma 30(17):1484–1489. doi:10.1089/neu.2012.2524

    Google Scholar 

  • Bullock R, Maxwell WL, Graham DI, Teasdale GM, Adams JH (1991) Glial swelling following human cerebral contusion: an ultrastructural study. J Neurol Neurosurg Psychiatry 54(5):427–434

    CAS  Google Scholar 

  • Carpenter KL, Jalloh I, Gallagher CN, Grice P, Howe DJ, Mason A et al (2014) (13)C-labelled microdialysis studies of cerebral metabolism in TBI patients. Eur J Pharm Sci 57:87–97. doi:10.1016/j.ejps.2013.12.012

    CAS  Google Scholar 

  • Carre JE, Singer M (2008) Cellular energetic metabolism in sepsis: the need for a systems approach. Biochim Biophys Acta 1777(7–8):763–771. doi:10.1016/j.bbabio.2008.04.024

    CAS  Google Scholar 

  • Carre JE, Orban JC, Re L, Felsmann K, Iffert W, Bauer M et al (2010) Survival in critical illness is associated with early activation of mitochondrial biogenesis. Am J Respir Crit Care Med 182(6):745–751. doi:10.1164/rccm.201003-0326OC

    Google Scholar 

  • Cartagena CM, Phillips KL, Tortella FC, Dave JR, Schmid KE (2014) Temporal alterations in aquaporin and transcription factor HIF1alpha expression following penetrating ballistic-like brain injury (PBBI). Mol Cell Neurosci 60:81–87. doi:10.1016/j.mcn.2014.04.005

    CAS  Google Scholar 

  • Chan NC, Salazar AM, Pham AH, Sweredoski MJ, Kolawa NJ, Graham RL et al (2011) Broad activation of the ubiquitin-proteasome system by parkin is critical for mitophagy. Hum Mol Genet 20(9):1726–1737. doi:10.1093/hmg/ddr048

    CAS  Google Scholar 

  • Chen T, Qian YZ, Di X, Rice A, Zhu JP, Bullock R (2000) Lactate/glucose dynamics after rat fluid percussion brain injury. J Neurotrauma 17(2):135–142

    CAS  Google Scholar 

  • Cherian L, Goodman JC, Robertson CS (1997) Hyperglycemia increases brain injury caused by secondary ischemia after cortical impact injury in rats. Crit Care Med 25(8):1378–1383

    CAS  Google Scholar 

  • Choi J, Levey AI, Weintraub ST, Rees HD, Gearing M, Chin LS et al (2004) Oxidative modifications and down-regulation of ubiquitin carboxyl-terminal hydrolase L1 associated with idiopathic Parkinson’s and Alzheimer’s diseases. J Biol Chem 279(13):13256–13264. doi:10.1074/jbc.M314124200

    CAS  Google Scholar 

  • Clark JF, Doepke A, Filosa JA, Wardle RL, Lu A, Meeker TJ et al (2006) N-acetylaspartate as a reservoir for glutamate. Med Hypotheses 67(3):506–512. doi:10.1016/j.mehy.2006.02.047

    CAS  Google Scholar 

  • Clausen T, Bullock R (2001) Medical treatment and neuroprotection in traumatic brain injury. Curr Pharm Des 7(15):1517–1532

    CAS  Google Scholar 

  • Clifton GL, Valadka A, Zygun D, Coffey CS, Drever P, Fourwinds S et al (2011) Very early hypothermia induction in patients with severe brain injury (the national acute brain injury study: hypothermia II): a randomised trial. Lancet Neurol 10(2):131–139. doi:10.1016/S1474-4422(10)70300-8

    Google Scholar 

  • Conley YP, Okonkwo DO, Deslouches S, Alexander S, Puccio AM, Beers SR et al (2014) Mitochondrial polymorphisms impact outcomes after severe traumatic brain injury. J Neurotrauma 31(1):34–41. doi:10.1089/neu.2013.2855

    Google Scholar 

  • Coulombe J, Gamage P, Gray MT, Zhang M, Tang MY, Woulfe J et al (2014) Loss of UCHL1 promotes age-related degenerative changes in the enteric nervous system. Front Aging Neurosci 6:129. doi:10.3389/fnagi.2014.00129

    Google Scholar 

  • Dare AJ, Phillips AR, Hickey AJ, Mittal A, Loveday B, Thompson N et al (2009) A systematic review of experimental treatments for mitochondrial dysfunction in sepsis and multiple organ dysfunction syndrome. Free Radic Biol Med 47(11):1517–1525. doi:10.1016/j.freeradbiomed.2009.08.019

    CAS  Google Scholar 

  • Daugherty WP, Levasseur JE, Sun D, Spiess BD, Bullock MR (2004) Perfluorocarbon emulsion improves cerebral oxygenation and mitochondrial function after fluid percussion brain injury in rats. Neurosurgery 54(5):1223–1230, discussion 1230

    Google Scholar 

  • Davis CH, Kim KY, Bushong EA, Mills EA, Boassa D, Shih T et al (2014) Transcellular degradation of axonal mitochondria. Proc Natl Acad Sci U S A 111(26):9633–9638. doi:10.1073/pnas.1404651111

    CAS  Google Scholar 

  • De Fazio M, Rammo R, O’Phelan K, Bullock MR (2011) Alterations in cerebral oxidative metabolism following traumatic brain injury. Neurocrit Care 14(1):91–96. doi:10.1007/s12028-010-9494-3

    CAS  Google Scholar 

  • De Vos KJ, Grierson AJ, Ackerley S, Miller CC (2008) Role of axonal transport in neurodegenerative diseases. Annu Rev Neurosci 31:151–173. doi:10.1146/annurev.neuro.31.061307.090711

    Google Scholar 

  • DeBerardinis RJ, Thompson CB (2012) Cellular metabolism and disease: what do metabolic outliers teach us? Cell 148(6):1132–1144. doi:10.1016/j.cell.2012.02.032

    CAS  Google Scholar 

  • Duncan JE, Goldstein LS (2006) The genetics of axonal transport and axonal transport disorders. PLoS Genet 2(9):e124. doi:10.1371/journal.pgen.0020124

    Google Scholar 

  • Ehses S, Raschke I, Mancuso G, Bernacchia A, Geimer S, Tondera D et al (2009) Regulation of OPA1 processing and mitochondrial fusion by m-AAA protease isoenzymes and OMA1. J Cell Biol 187(7):1023–1036. doi:10.1083/jcb.200906084

    CAS  Google Scholar 

  • Faithfull NS (1992) Oxygen delivery from fluorocarbon emulsions–aspects of convective and diffusive transport. Biomater Artif Cells Immobilization Biotechnol 20(2–4):797–804

    CAS  Google Scholar 

  • Fu ES, Tummala RP (2005) Neuroprotection in brain and spinal cord trauma. Curr Opin Anaesthesiol 18(2):181–187. doi:10.1097/01.aco.0000162838.56344.88

    Google Scholar 

  • Gaetz M (2004) The neurophysiology of brain injury. Clin Neurophysiol 115(1):4–18

    CAS  Google Scholar 

  • Gajavelli Shyam AB, Spurlock M, Diaz D, Burks S, Bomberger C, Bidot CJ, Yokobori S, Diaz J, Sanchez-Chavez J, Bullock R (Ed.) (2012) Immunohistochemical correlation of novel biomarkers with neurodegeneration in rat models of brain injury (Applications of Immunocytochemistry)

  • Galley HF (2011) Oxidative stress and mitochondrial dysfunction in sepsis. Br J Anaesth 107(1):57–64. doi:10.1093/bja/aer093

    CAS  Google Scholar 

  • Gantner D, Moore EM, Cooper DJ (2014) Intravenous fluids in traumatic brain injury: what’s the solution? Curr Opin Crit Care 20(4):385–389. doi:10.1097/MCC.0000000000000114

    Google Scholar 

  • Gilmer LK, Roberts KN, Joy K, Sullivan PG, Scheff SW (2009) Early mitochondrial dysfunction after cortical contusion injury. J Neurotrauma 26(8):1271–1280. doi:10.1089/neu.2008.0857

    Google Scholar 

  • Gilmer LK, Ansari MA, Roberts KN, Scheff SW (2010) Age-related mitochondrial changes after traumatic brain injury. J Neurotrauma 27(5):939–950. doi:10.1089/neu.2009.1181

    Google Scholar 

  • Gomez LA, Monette JS, Chavez JD, Maier CS, Hagen TM (2009) Supercomplexes of the mitochondrial electron transport chain decline in the aging rat heart. Arch Biochem Biophys 490(1):30–35. doi:10.1016/j.abb.2009.08.002

    CAS  Google Scholar 

  • Gordon GR, Choi HB, Rungta RL, Ellis-Davies GC, MacVicar BA (2008) Brain metabolism dictates the polarity of astrocyte control over arterioles. Nature 456(7223):745–749. doi:10.1038/nature07525

    CAS  Google Scholar 

  • Gurevich B, Talmor D, Artru AA, Katcko L, Geva D, Gurman G et al (1997) Brain edema, hemorrhagic necrosis volume, and neurological status with rapid infusion of 0.45 % saline or 5 % dextrose in 0.9 % saline after closed head trauma in rats. Anesth Analg 84(3):554–559

    CAS  Google Scholar 

  • Halestrap AP (2013) The SLC16 gene family - structure, role and regulation in health and disease. Mol Aspects Med 34(2–3):337–349. doi:10.1016/j.mam.2012.05.003

    CAS  Google Scholar 

  • Hanafy KA, Selim MH (2012) Antioxidant strategies in neurocritical care. Neurotherapeutics 9(1):44–55. doi:10.1007/s13311-011-0085-6

    CAS  Google Scholar 

  • Harbauer AB, Zahedi RP, Sickmann A, Pfanner N, Meisinger C (2014) The protein import machinery of mitochondria-a regulatory hub in metabolism, stress, and disease. Cell Metab 19(3):357–372. doi:10.1016/j.cmet.2014.01.010

    CAS  Google Scholar 

  • Hatton J, Rosbolt B, Empey P, Kryscio R, Young B (2008) Dosing and safety of cyclosporine in patients with severe brain injury. J Neurosurg 109(4):699–707. doi:10.3171/jns/2008/109/10/0699

    CAS  Google Scholar 

  • Haut ER, Kalish BT, Cotton BA, Efron DT, Haider AH, Stevens KA et al (2011) Prehospital intravenous fluid administration is associated with higher mortality in trauma patients: a national trauma data bank analysis. Ann Surg 253(2):371–377. doi:10.1097/SLA.0b013e318207c24f

    Google Scholar 

  • Henry B, Emilie C, Bertrand P, Erwan D (2012) Cerebral microdialysis and PtiO2 to decide unilateral decompressive craniectomy after brain gunshot. J Emerg Trauma Shock 5(1):103–105. doi:10.4103/0974-2700.93101

    Google Scholar 

  • Hertz L (2006) Glutamate, a neurotransmitter–and so much more. A synopsis of Wierzba III. Neurochem Int 48(6–7):416–425. doi:10.1016/j.neuint.2005.12.021

    CAS  Google Scholar 

  • Hertz NT, Berthet A, Sos ML, Thorn KS, Burlingame AL, Nakamura K et al (2013) A neo-substrate that amplifies catalytic activity of parkinson’s-disease-related kinase PINK1. Cell 154(4):737–747. doi:10.1016/j.cell.2013.07.030

    CAS  Google Scholar 

  • Hoane MR, Swan AA, Heck SE (2011) The effects of a high-fat sucrose diet on functional outcome following cortical contusion injury in the rat. Behav Brain Res 223(1):119–124. doi:10.1016/j.bbr.2011.04.028

    CAS  Google Scholar 

  • Hughes SD, Kanabus M, Anderson G, Hargreaves IP, Rutherford T, O’Donnell M et al (2014) The ketogenic diet component decanoic acid increases mitochondrial citrate synthase and complex I activity in neuronal cells. J Neurochem 129(3):426–433. doi:10.1111/jnc.12646

    CAS  Google Scholar 

  • Ichai C, Armando G, Orban JC, Berthier F, Rami L, Samat-Long C et al (2009) Sodium lactate versus mannitol in the treatment of intracranial hypertensive episodes in severe traumatic brain-injured patients. Intensive Care Med 35(3):471–479. doi:10.1007/s00134-008-1283-5

    CAS  Google Scholar 

  • Investigators, S. S., Australian, New Zealand Intensive Care Society Clinical Trials, G., Australian Red Cross Blood, S., George Institute for International, H, Myburgh J et al (2007) Saline or albumin for fluid resuscitation in patients with traumatic brain injury. N Engl J Med 357(9):874–884. doi:10.1056/NEJMoa067514

    Google Scholar 

  • Ji J, Tyurina YY, Tang M, Feng W, Stolz DB, Clark RS et al (2012) Mitochondrial injury after mechanical stretch of cortical neurons in vitro: biomarkers of apoptosis and selective peroxidation of anionic phospholipids. J Neurotrauma 29(5):776–788. doi:10.1089/neu.2010.1602

    Google Scholar 

  • Jin SM, Youle RJ (2012) PINK1- and parkin-mediated mitophagy at a glance. J Cell Sci 125(Pt 4):795–799. doi:10.1242/jcs.093849

    CAS  Google Scholar 

  • Kilbaugh TJ, Bhandare S, Lorom DH, Saraswati M, Robertson CL, Margulies SS (2011) Cyclosporin a preserves mitochondrial function after traumatic brain injury in the immature rat and piglet. J Neurotrauma 28(5):763–774. doi:10.1089/neu.2010.1635

    Google Scholar 

  • Kim I, Rodriguez-Enriquez S, Lemasters JJ (2007) Selective degradation of mitochondria by mitophagy. Arch Biochem Biophys 462(2):245–253. doi:10.1016/j.abb.2007.03.034

    CAS  Google Scholar 

  • Kirkinezos IG, Moraes CT (2001) Reactive oxygen species and mitochondrial diseases. Semin Cell Dev Biol 12(6):449–457. doi:10.1006/scdb.2001.0282

    CAS  Google Scholar 

  • Koizumi J, Shiraishi H (1970) Fine structural changes of mitochondria in cerebral edema and dehydration. Arch Histol Jpn 32(3):241–249

    CAS  Google Scholar 

  • Kollmann TR, Levy O, Montgomery RR, Goriely S (2012) Innate immune function by toll-like receptors: distinct responses in newborns and the elderly. Immunity 37(5):771–783. doi:10.1016/j.immuni.2012.10.014

    CAS  Google Scholar 

  • Korde AS, Sullivan PG, Maragos WF (2005) The uncoupling agent 2,4-dinitrophenol improves mitochondrial homeostasis following Striatal quinolinic acid injections. J Neurotrauma 22(10):1142–1149. doi:10.1089/neu.2005.22.1142

    Google Scholar 

  • Kortbeek JB, Al Turki SA, Ali J, Antoine JA, Bouillon B, Brasel K et al (2008) Advanced trauma life support, 8th edition, the evidence for change. J Trauma 64(6):1638–1650. doi:10.1097/TA.0b013e3181744b03

    Google Scholar 

  • Kozlov AV, Bahrami S, Calzia E, Dungel P, Gille L, Kuznetsov AV et al (2011) Mitochondrial dysfunction and biogenesis: do ICU patients die from mitochondrial failure? Ann Intensive Care 1(1):41. doi:10.1186/2110-5820-1-41

    Google Scholar 

  • Kristal BS, Stavrovskaya IG, Narayanan MV, Krasnikov BF, Brown AM, Beal MF et al (2004) The mitochondrial permeability transition as a target for neuroprotection. J Bioenerg Biomembr 36(4):309–312. doi:10.1023/b:jobb.0000041759.35731.70

    CAS  Google Scholar 

  • Kwon TH, Sun D, Daugherty WP, Spiess BD, Bullock MR (2005) Effect of perfluorocarbons on brain oxygenation and ischemic damage in an acute subdural hematoma model in rats. J Neurosurg 103(4):724–730. doi:10.3171/jns.2005.103.4.0724

    CAS  Google Scholar 

  • Langlois JA, Marr A, Mitchko J, Johnson RL (2005) Tracking the silent epidemic and educating the public: CDC’s traumatic brain injury-associated activities under the TBI Act of 1996 and the Children’s health Act of 2000. J Head Trauma Rehabil 20(3):196–204

    Google Scholar 

  • Lanza IR, Nair KS (2010) Mitochondrial metabolic function assessed in vivo and in vitro. Curr Opin Clin Nutr Metab Care 13(5):511–517. doi:10.1097/MCO.0b013e32833cc93d

    Google Scholar 

  • Lifshitz J, Sullivan PG, Hovda DA, Wieloch T, McIntosh TK (2004) Mitochondrial damage and dysfunction in traumatic brain injury. Mitochondrion 4(5–6):705–713. doi:10.1016/j.mito.2004.07.021

    CAS  Google Scholar 

  • Liu X, Weaver D, Shirihai O, Hajnoczky G (2009) Mitochondrial ‘kiss-and-run’: interplay between mitochondrial motility and fusion-fission dynamics. EMBO J 28(20):3074–3089. doi:10.1038/emboj.2009.255

    CAS  Google Scholar 

  • Liu S, Sawada T, Lee S, Yu W, Silverio G, Alapatt P et al (2012) Parkinson’s disease-associated kinase PINK1 regulates Miro protein level and axonal transport of mitochondria. PLoS Genet 8(3):e1002537. doi:10.1371/journal.pgen.1002537

    CAS  Google Scholar 

  • Matsuda N, Sato S, Shiba K, Okatsu K, Saisho K, Gautier CA et al (2010) PINK1 stabilized by mitochondrial depolarization recruits Parkin to damaged mitochondria and activates latent Parkin for mitophagy. J Cell Biol 189(2):211–221. doi:10.1083/jcb.200910140

    CAS  Google Scholar 

  • Mazzeo AT, Kunene NK, Gilman CB, Hamm RJ, Hafez N, Bullock MR (2006) Severe human traumatic brain injury, but not cyclosporin a treatment, depresses activated T lymphocytes early after injury. J Neurotrauma 23(6):962–975. doi:10.1089/neu.2006.23.962

    Google Scholar 

  • Mazzeo AT, Alves OL, Gilman CB, Hayes RL, Tolias C, Niki Kunene K et al (2008) Brain metabolic and hemodynamic effects of cyclosporin A after human severe traumatic brain injury: a microdialysis study. Acta Neurochir (Wien) 150(10):1019–1031. doi:10.1007/s00701-008-0021-7, discussion 1031

    Google Scholar 

  • Mazzeo AT, Beat A, Singh A, Bullock MR (2009a) The role of mitochondrial transition pore, and its modulation, in traumatic brain injury and delayed neurodegeneration after TBI. Exp Neurol 218(2):363–370. doi:10.1016/j.expneurol.2009.05.026

    CAS  Google Scholar 

  • Mazzeo AT, Brophy GM, Gilman CB, Alves OL, Robles JR, Hayes RL et al (2009b) Safety and tolerability of cyclosporin a in severe traumatic brain injury patients: results from a prospective randomized trial. J Neurotrauma 26(12):2195–2206. doi:10.1089/neu.2009.1012

    Google Scholar 

  • Miller DM, Singh IN, Wang JA, Hall ED (2013) Administration of the Nrf2-ARE activators sulforaphane and carnosic acid attenuates 4-hydroxy-2-nonenal-induced mitochondrial dysfunction ex vivo. Free Radic Biol Med 57:1–9. doi:10.1016/j.freeradbiomed.2012.12.011

    CAS  Google Scholar 

  • Misko A, Jiang S, Wegorzewska I, Milbrandt J, Baloh RH (2010) Mitofusin 2 is necessary for transport of axonal mitochondria and interacts with the Miro/Milton complex. J Neurosci 30(12):4232–4240. doi:10.1523/JNEUROSCI. 6248-09.2010

    CAS  Google Scholar 

  • Moraes CT (2014) A magic bullet to specifically eliminate mutated mitochondrial genomes from patients’ cells. EMBO Mol Med 6(4):434–435. doi:10.1002/emmm.201303769

    CAS  Google Scholar 

  • Morawetz RB, DeGirolami U, Ojemann RG, Marcoux FW, Crowell RM (1978) Cerebral blood flow determined by hydrogen clearance during middle cerebral artery occlusion in unanesthetized monkeys. Stroke 9(2):143–149

    CAS  Google Scholar 

  • Moro N, Sutton RL (2010) Beneficial effects of sodium or ethyl pyruvate after traumatic brain injury in the rat. Exp Neurol 225(2):391–401. doi:10.1016/j.expneurol.2010.07.013

    CAS  Google Scholar 

  • Moro N, Ghavim SS, Hovda DA, Sutton RL (2011) Delayed sodium pyruvate treatment improves working memory following experimental traumatic brain injury. Neurosci Lett 491(2):158–162. doi:10.1016/j.neulet.2011.01.029

    CAS  Google Scholar 

  • Moro N, Ghavim S, Harris NG, Hovda DA, Sutton RL (2013) Glucose administration after traumatic brain injury improves cerebral metabolism and reduces secondary neuronal injury. Brain Res 1535:124–136. doi:10.1016/j.brainres.2013.08.044

    CAS  Google Scholar 

  • Murakami Y, Wei G, Yang X, Lu XC, Leung LY, Shear DA et al (2012) Brain oxygen tension monitoring following penetrating ballistic-like brain injury in rats. [Research Support, U.S. Gov’t, Non-P.H.S.]. J Neurosci Methods 203(1):115–121. doi:10.1016/j.jneumeth.2011.09.025

    Google Scholar 

  • Myburgh JA, Finfer S (2009) Albumin is a blood product too - is it safe for all patients? Crit Care Resusc 11(1):67–70

    Google Scholar 

  • Narayan RK, Michel ME, Ansell B, Baethmann A, Biegon A, Bracken MB et al (2002) Clinical trials in head injury. J Neurotrauma 19(5):503–557. doi:10.1089/089771502753754037

    Google Scholar 

  • Nguyen JV, Soto I, Kim KY, Bushong EA, Oglesby E, Valiente-Soriano FJ et al (2011) Myelination transition zone astrocytes are constitutively phagocytic and have synuclein dependent reactivity in glaucoma. Proc Natl Acad Sci U S A 108(3):1176–1181. doi:10.1073/pnas.1013965108

    CAS  Google Scholar 

  • Nordstrom CH, Nielsen TH (2014) Exogenous lactate supplementation to the injured brain: misleading conclusions with clinical implications. Intensive Care Med 40(6):919. doi:10.1007/s00134-014-3297-5

    Google Scholar 

  • Nordstrom CH, Nielsen TH, Jacobsen A (2013) Techniques and strategies in neurocritical care originating from southern Scandinavia. J Rehabil Med 45(8):710–717. doi:10.2340/16501977-1157

    Google Scholar 

  • Nunnari J, Suomalainen A (2012) Mitochondria: in sickness and in health. Cell 148(6):1145–1159. doi:10.1016/j.cell.2012.02.035

    CAS  Google Scholar 

  • Oehmichen M, Walter T, Meissner C, Friedrich HJ (2003) Time course of cortical hemorrhages after closed traumatic brain injury: statistical analysis of posttraumatic histomorphological alterations. J Neurotrauma 20(1):87–103. doi:10.1089/08977150360517218

    Google Scholar 

  • Oka T, Hikoso S, Yamaguchi O, Taneike M, Takeda T, Tamai T et al (2012) Mitochondrial DNA that escapes from autophagy causes inflammation and heart failure. Nature 485(7397):251–255. doi:10.1038/nature10992

    CAS  Google Scholar 

  • Okonkwo DO, Buki A, Siman R, Povlishock JT (1999) Cyclosporin a limits calcium-induced axonal damage following traumatic brain injury. Neuroreport 10(2):353–358

    CAS  Google Scholar 

  • Owen OE, Kalhan SC, Hanson RW (2002) The key role of anaplerosis and cataplerosis for citric acid cycle function. J Biol Chem 277(34):30409–30412. doi:10.1074/jbc.R200006200

    CAS  Google Scholar 

  • Palikaras K, Tavernarakis N (2014) Mitochondrial homeostasis: the interplay between mitophagy and mitochondrial biogenesis. Exp Gerontol 56:182–188. doi:10.1016/j.exger.2014.01.021

    CAS  Google Scholar 

  • Palmer CS, Osellame LD, Stojanovski D, Ryan MT (2011) The regulation of mitochondrial morphology: intricate mechanisms and dynamic machinery. Cell Signal 23(10):1534–1545. doi:10.1016/j.cellsig.2011.05.021

    CAS  Google Scholar 

  • Pandya JD, Nukala VN, Sullivan PG (2013) Concentration dependent effect of calcium on brain mitochondrial bioenergetics and oxidative stress parameters. Front Neuroenergetics 5:10. doi:10.3389/fnene.2013.00010

    Google Scholar 

  • Parra V, Verdejo HE, Iglewski M, Del Campo A, Troncoso R, Jones D et al (2014) Insulin stimulates mitochondrial fusion and function in cardiomyocytes via the Akt-mTOR-NFkappaB-Opa-1 signaling pathway. Diabetes 63(1):75–88. doi:10.2337/db13-0340

    CAS  Google Scholar 

  • Perez-Pinzon MA, Stetler RA, Fiskum G (2012) Novel mitochondrial targets for neuroprotection. J Cereb Blood Flow Metab 32(7):1362–1376. doi:10.1038/jcbfm.2012.32

    CAS  Google Scholar 

  • Perri BR, Smith DH, Murai H, Sinson G, Saatman KE, Raghupathi R et al (1997) Metabolic quantification of lesion volume following experimental traumatic brain injury in the rat. J Neurotrauma 14(1):15–22

    CAS  Google Scholar 

  • Piantadosi CA, Suliman HB (2012) Redox regulation of mitochondrial biogenesis. Free Radic Biol Med 53(11):2043–2053. doi:10.1016/j.freeradbiomed.2012.09.014

    CAS  Google Scholar 

  • Piot C, Croisille P, Staat P, Thibault H, Rioufol G, Mewton N et al (2008) Effect of cyclosporine on reperfusion injury in acute myocardial infarction. N Engl J Med 359(5):473–481. doi:10.1056/NEJMoa071142

    CAS  Google Scholar 

  • Prins M, Matsumoto J (2014) The collective therapeutic potential of cerebral ketone metabolism in traumatic brain injury. J Lipid Res. doi:10.1194/jlr.R046706

    Google Scholar 

  • Prins M, Greco T, Alexander D, Giza CC (2013) The pathophysiology of traumatic brain injury at a glance. Dis Model Mech 6(6):1307–1315. doi:10.1242/dmm.011585

    CAS  Google Scholar 

  • Procaccio V, Bris C, Chao de la Barca JM, Oca F, Chevrollier A, Amati-Bonneau P et al (2014) Perspectives of drug-based neuroprotection targeting mitochondria. Rev Neurol (Paris) 170(5):390–400. doi:10.1016/j.neurol.2014.03.005

    CAS  Google Scholar 

  • Ren C, Zoltewicz S, Guingab-Cagmat J, Anagli J, Gao M, Hafeez A et al (2013) Different expression of ubiquitin C-terminal hydrolase-L1 and alphaII-spectrin in ischemic and hemorrhagic stroke: potential biomarkers in diagnosis. Brain Res 1540:84–91. doi:10.1016/j.brainres.2013.09.051

    CAS  Google Scholar 

  • Rho JM, Sankar R (2008) The ketogenic diet in a pill: is this possible? Epilepsia 49(Suppl 8):127–133. doi:10.1111/j.1528-1167.2008.01857.x

    Google Scholar 

  • Rockswold SB, Rockswold GL, Zaun DA, Liu J (2013) A prospective, randomized Phase II clinical trial to evaluate the effect of combined hyperbaric and normobaric hyperoxia on cerebral metabolism, intracranial pressure, oxygen toxicity, and clinical outcome in severe traumatic brain injury. J Neurosurg 118(6):1317–1328. doi:10.3171/2013.2.JNS121468

    CAS  Google Scholar 

  • Russo GJ, Louie K, Wellington A, Macleod GT, Hu F, Panchumarthi S et al (2009) Drosophila Miro is required for both anterograde and retrograde axonal mitochondrial transport. J Neurosci 29(17):5443–5455. doi:10.1523/JNEUROSCI. 5417-08.2009

    CAS  Google Scholar 

  • Sauerbeck A, Gao J, Readnower R, Liu M, Pauly JR, Bing G et al (2011) Pioglitazone attenuates mitochondrial dysfunction, cognitive impairment, cortical tissue loss, and inflammation following traumatic brain injury. Exp Neurol 227(1):128–135. doi:10.1016/j.expneurol.2010.10.003

    CAS  Google Scholar 

  • Schell JC, Rutter J (2013) The long and winding road to the mitochondrial pyruvate carrier. Cancer Metab 1(1):6. doi:10.1186/2049-3002-1-6

    Google Scholar 

  • Segel R, Anikster Y, Zevin S, Steinberg A, Gahl WA, Fisher D et al (2011) A safety trial of high dose glyceryl triacetate for Canavan disease. Mol Genet Metab 103(3):203–206. doi:10.1016/j.ymgme.2011.03.012

    CAS  Google Scholar 

  • Signoretti S, Marmarou A, Tavazzi B, Dunbar J, Amorini AM, Lazzarino G et al (2004) The protective effect of cyclosporin a upon N-acetylaspartate and mitochondrial dysfunction following experimental diffuse traumatic brain injury. J Neurotrauma 21(9):1154–1167. doi:10.1089/neu.2004.21.1154

    Google Scholar 

  • Signoretti S, Marmarou A, Aygok GA, Fatouros PP, Portella G, Bullock RM (2008) Assessment of mitochondrial impairment in traumatic brain injury using high-resolution proton magnetic resonance spectroscopy. J Neurosurg 108(1):42–52. doi:10.3171/jns/2008/108/01/0042

    CAS  Google Scholar 

  • Simmons ML, Frondoza CG, Coyle JT (1991) Immunocytochemical localization of N-acetyl-aspartate with monoclonal antibodies. Neuroscience 45(1):37–45

    CAS  Google Scholar 

  • Singer M (2007) Mitochondrial function in sepsis: acute phase versus multiple organ failure. Crit Care Med 35(9 Suppl):S441–S448. doi:10.1097/01.CCM.0000278049.48333.78

    CAS  Google Scholar 

  • Singh IN, Sullivan PG, Deng Y, Mbye LH, Hall ED (2006) Time course of post-traumatic mitochondrial oxidative damage and dysfunction in a mouse model of focal traumatic brain injury: implications for neuroprotective therapy. J Cereb Blood Flow Metab 26(11):1407–1418. doi:10.1038/sj.jcbfm.9600297

    CAS  Google Scholar 

  • Soane L, Kahraman S, Kristian T, Fiskum G (2007) Mechanisms of impaired mitochondrial energy metabolism in acute and chronic neurodegenerative disorders. J Neurosci Res 85(15):3407–3415. doi:10.1002/jnr.21498

    CAS  Google Scholar 

  • Soustiel JF, Larisch S (2010) Mitochondrial damage: a target for new therapeutic horizons. Neurotherapeutics 7(1):13–21. doi:10.1016/j.nurt.2009.11.001

    CAS  Google Scholar 

  • Soustiel JF, Sviri GE (2007) Monitoring of cerebral metabolism: non-ischemic impairment of oxidative metabolism following severe traumatic brain injury. Neurol Res 29(7):654–660. doi:10.1179/016164107x240017

    CAS  Google Scholar 

  • Suliman HB, Piantadosi CA (2014) Mitochondrial Biogenesis: Regulation By Endogenous Gases during Inflammation and Organ Stress. Curr Pharm Des

  • Sullivan PG, Thompson MB, Scheff SW (1999) Cyclosporin a attenuates acute mitochondrial dysfunction following traumatic brain injury. Exp Neurol 160(1):226–234. doi:10.1006/exnr.1999.7197

    CAS  Google Scholar 

  • Sullivan PG, Thompson M, Scheff SW (2000) Continuous infusion of cyclosporin a postinjury significantly ameliorates cortical damage following traumatic brain injury. Exp Neurol 161(2):631–637. doi:10.1006/exnr.1999.7282

    CAS  Google Scholar 

  • Traeger EC, Rapin I (1998) The clinical course of Canavan disease. Pediatr Neurol 18(3):207–212

    CAS  Google Scholar 

  • Tsukada H, Ohba H, Nishiyama S, Kanazawa M, Kakiuchi T, Harada N (2014) PET imaging of ischemia-induced impairment of mitochondrial complex I function in monkey brain. J Cereb Blood Flow Metab 34(4):708–714. doi:10.1038/jcbfm.2014.5

    CAS  Google Scholar 

  • Twig G, Hyde B, Shirihai OS (2008) Mitochondrial fusion, fission and autophagy as a quality control axis: the bioenergetic view. Biochim Biophys Acta 1777(9):1092–1097. doi:10.1016/j.bbabio.2008.05.001

    CAS  Google Scholar 

  • Uchino H, Elmer E, Uchino K, Lindvall O, Siesjo BK (1995) Cyclosporin a dramatically ameliorates CA1 hippocampal damage following transient forebrain ischaemia in the rat. Acta Physiol Scand 155(4):469–471

    CAS  Google Scholar 

  • Valadka AB, Gopinath SP, Contant CF, Uzura M, Robertson CS (1998) Relationship of brain tissue PO2 to outcome after severe head injury. Crit Care Med 26(9):1576–1581

    CAS  Google Scholar 

  • van den Brink WA, van Santbrink H, Avezaat CJ, Hogesteeger C, Jansen W, Kloos LM et al (1998) Monitoring brain oxygen tension in severe head injury: the Rotterdam experience. Acta Neurochir Suppl 71:190–194

    Google Scholar 

  • Vaz R, Sarmento A, Borges N, Cruz C, Azevedo I (1997) Ultrastructural study of brain microvessels in patients with traumatic cerebral contusions. Acta Neurochir (Wien) 139(3):215–220

    CAS  Google Scholar 

  • Verweij BH, Muizelaar JP, Vinas FC, Peterson PL, Xiong Y, Lee CP (2000) Impaired cerebral mitochondrial function after traumatic brain injury in humans. J Neurosurg 93(5):815–820. doi:10.3171/jns.2000.93.5.0815

    CAS  Google Scholar 

  • Vespa PM, McArthur D, O’Phelan K, Glenn T, Etchepare M, Kelly D et al (2003) Persistently low extracellular glucose correlates with poor outcome 6 months after human traumatic brain injury despite a lack of increased lactate: a microdialysis study. J Cereb Blood Flow Metab 23(7):865–877. doi:10.1097/01.WCB.0000076701.45782.EF

    CAS  Google Scholar 

  • Vespa P, Bergsneider M, Hattori N, Wu HM, Huang SC, Martin NA et al (2005) Metabolic crisis without brain ischemia is common after traumatic brain injury: a combined microdialysis and positron emission tomography study. J Cereb Blood Flow Metab 25(6):763–774. doi:10.1038/sj.jcbfm.9600073

    CAS  Google Scholar 

  • Vink R, Nimmo AJ (2009) Multifunctional drugs for head injury. Neurotherapeutics 6(1):28–42. doi:10.1016/j.nurt.2008.10.036

    CAS  Google Scholar 

  • Vink R, Golding EM, Williams JP, McIntosh TK (1997) Blood glucose concentration does not affect outcome in brain trauma: A 31P MRS study. J Cereb Blood Flow Metab 17(1):50–53. doi:10.1097/00004647-199701000-00007

    CAS  Google Scholar 

  • Waldmeier PC, Zimmermann K, Qian T, Tintelnot-Blomley M, Lemasters JJ (2003) Cyclophilin D as a drug target. Curr Med Chem 10(16):1485–1506

    CAS  Google Scholar 

  • Wallace DC (1999) Mitochondrial diseases in man and mouse. Science 283(5407):1482–1488

    CAS  Google Scholar 

  • Wang N, Gray M, Lu XH, Cantle JP, Holley SM, Greiner E et al (2014) Neuronal targets for reducing mutant huntingtin expression to ameliorate disease in a mouse model of Huntington’s disease. Nat Med 20(5):536–541. doi:10.1038/nm.3514

    CAS  Google Scholar 

  • Westermann B (2010) Mitochondrial fusion and fission in cell life and death. Nat Rev Mol Cell Biol 11(12):872–884. doi:10.1038/nrm3013

    CAS  Google Scholar 

  • Williams AJ, Wei HH, Dave JR, Tortella FC (2007) Acute and delayed neuroinflammatory response following experimental penetrating ballistic brain injury in the rat. J Neuroinflammation 4:17. doi:10.1186/1742-2094-4-17

    Google Scholar 

  • Xiong Y, Gu Q, Peterson PL, Muizelaar JP, Lee CP (1997) Mitochondrial dysfunction and calcium perturbation induced by traumatic brain injury. J Neurotrauma 14(1):23–34

    CAS  Google Scholar 

  • Yao C, Williams AJ, Ottens AK, Lu XC, Liu MC, Hayes RL et al (2009) P43/pro-EMAPII: a potential biomarker for discriminating traumatic versus ischemic brain injury. J Neurotrauma 26(8):1295–1305. doi:10.1089/neu. 2008-0811

    Google Scholar 

  • Yao C, Wei G, Lu XC, Yang W, Tortella FC, Dave JR (2011) Selective brain cooling in rats ameliorates intracerebral hemorrhage and edema caused by penetrating brain injury: possible involvement of heme oxygenase-1 expression. J Neurotrauma 28(7):1237–1245. doi:10.1089/neu.2010.1678

    Google Scholar 

  • Yokobori S, Gajavelli S, Mondello S, Mo-Seaney J, Bramlett HM, Dietrich WD et al (2013a) Neuroprotective effect of preoperatively induced mild hypothermia as determined by biomarkers and histopathological estimation in a rat subdural hematoma decompression model. J Neurosurg 118(2):370–380. doi:10.3171/2012.10.JNS12725

    CAS  Google Scholar 

  • Yokobori S, Mazzeo AT, Gajavelli S, Bullock MR (2013) Mitochondrial Neuroprotection in Traumatic Brain Injury: Rationale and Therapeutic Strategies. CNS Neurol Disord Drug Targets

  • Yoshino A, Hovda DA, Kawamata T, Katayama Y, Becker DP (1991) Dynamic changes in local cerebral glucose utilization following cerebral conclusion in rats: evidence of a hyper- and subsequent hypometabolic state. Brain Res 561(1):106–119

    CAS  Google Scholar 

  • Yun J, Finkel T (2014) Mitohormesis. Cell Metab 19(5):757–766. doi:10.1016/j.cmet.2014.01.011

    CAS  Google Scholar 

  • Zamzami N, Kroemer G (2001) The mitochondrion in apoptosis: how Pandora’s box opens. Nat Rev Mol Cell Biol 2(1):67–71. doi:10.1038/35048073

    CAS  Google Scholar 

  • Zhang Q, Raoof M, Chen Y, Sumi Y, Sursal T, Junger W et al (2010) Circulating mitochondrial DAMPs cause inflammatory responses to injury. Nature 464(7285):104–107. doi:10.1038/nature08780

    CAS  Google Scholar 

  • Zhang M, Li, W, Niu G, Leak RK, Chen J, Zhang F (2013) ATP induces mild hypothermia in rats but has a strikingly detrimental impact on focal cerebral ischemia. J Cereb Blood Flow Metab, 33(1), doi:10.1038/jcbfm.2012.146

  • Zhou Z, Sun D, Levasseur JE, Merenda A, Hamm RJ, Zhu J et al (2008) Perfluorocarbon emulsions improve cognitive recovery after lateral fluid percussion brain injury in rats. Neurosurgery 63(4):799–806. doi:10.1227/01.NEU.0000325493.51900.53, discussion 806–797

    Google Scholar 

  • Zoltewicz JS, Mondello S, Yang B, Newsom KJ, Kobeissy F, Yao C et al (2013) Biomarkers track damage after graded injury severity in a rat model of penetrating brain injury. J Neurotrauma 30(13):1161–1169. doi:10.1089/neu.2012.2762

    Google Scholar 

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Acknowledgments

This work was supported by Department of Defense Grant # #PT074521W81XWH-08-1-0419 to RB. The authors acknowledge Daniela Bruce and Joseph Prieto for illustrations

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Authors and Affiliations

  1. Department of Neurosurgery, Miller School of Medicine, University of Miami, Lois Pope LIFE Center, Room 3-20, 1095 NW 14th Terrace, Miami, FL, 33136, USA

    Shyam Gajavelli, Vishal K. Sinha, Markus S. Spurlock, Stephanie W. Lee, Aminul I. Ahmed & Ross M. Bullock

  2. Department of Emergency and Critical Care Medicine, Nippon Medical School, Tokyo, Japan

    Shoji Yokobori

  3. Department of Anesthesia and Intensive Care, University of Turin, Turin, Italy

    Anna T. Mazzeo

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  1. Shyam Gajavelli
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  2. Vishal K. Sinha
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  5. Stephanie W. Lee
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Correspondence to Ross M. Bullock.

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Gajavelli, S., Sinha, V.K., Mazzeo, A.T. et al. Evidence to support mitochondrial neuroprotection, in severe traumatic brain injury. J Bioenerg Biomembr 47, 133–148 (2015). https://doi.org/10.1007/s10863-014-9589-1

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