Mitochondrial Damage in Traumatic CNS Injury

  • Laurie M. Davis
  • Patrick G. Sullivan


With over 1.5 million injuries every year, traumatic brain injury (TBI) has become an almost ubiquitous phenomenon in our country. As this disorder can be present without any outward sign of physical damage and the victims are usually cognitively impaired (i.e., not vocal), it has become a largely “silent epidemic” (Jennett 1998; Thurman et al. 1999; Jager et al. 2000; CDC 2003; Langlois et al. 2006). Current advancements in medicine have allowed patients who would have previously succumbed to their wounds, to survive long after their initial injury. Also, there is a growing population of individuals who sustain a mild to moderate TBI who do not seek treatment (∼25%), and often develop prolonged and chronic neurological symptoms (CDC 2003). The growing injured population has presented our society with an enormous economic and social burden, as these patients are commonly unable to properly reintegrate in to their previous professional and social networks. They become exceedingly dependent on family and social outreach programs to live their daily lives which cause their health care costs to total tens of billion dollars per year (Langlois et al. 2006). Although there are limited treatment options designed to allow people to survive their injuries, consisting of minimizing acute brain edema, decreasing intracranial pressure, and the prevention of peripheral complications, there is no current treatment to attenuate or recover the loss of neural tissue (Hatton 2001).


Traumatic Brain Injury Electron Transport Chain Central Nervous System Injury Electrochemical Proton Gradient Excitotoxic Insult 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. Brookes PS, Yoon Y, Robotham JL, Anders MW, Sheu SS (2004) Calcium, ATP, and ROS: a mitochondrial love-hate triangle. Am J Physiol Cell Physiol 287:C817–C833PubMedCrossRefGoogle Scholar
  2. CDC (2003) Report to Congress on Mild Traumatic Brain Injury in the United States: Steps to Prevent a Serious Public Health Problem. Centers for Disease Control and Prevention, Atlanta, GAGoogle Scholar
  3. Davis LM, Pauly JR, Readnower RD, Rho JM, Sullivan PG (2008) Fasting is neuroprotective following traumatic brain injury. J Neurosci Res 86(8):1812–1822PubMedCrossRefGoogle Scholar
  4. Faden AI, Demediuk P, Panter SS, Vink R (1989) The role of excitatory amino acids and NMDA receptors in traumatic brain injury. Science 244:798–800PubMedCrossRefGoogle Scholar
  5. Garcia M, Bondada V, Geddes JW (2005) Mitochondrial localization of mu-calpain. Biochem Biophys Res Commun 338:1241–1247PubMedCrossRefGoogle Scholar
  6. Gunter TE, Yule DI, Gunter KK, Eliseev RA, Salter JD (2004) Calcium and mitochondria. FEBS Lett 567:96–102PubMedCrossRefGoogle Scholar
  7. Hall ED, Sullivan PG (2005) Preserving function in acute nervous system injury. In: From Neuroscience to Neurology: Neuroscience, Molecular Medicine, and the Theraputic Translation of Neurology. Waxman, S (ed) Elsevier/Academic Press, pp. 35–39Google Scholar
  8. Hatton J (2001) Pharmacological treatment of traumatic brain injury: a review of agents in development. CNS Drugs 15:553–581PubMedCrossRefGoogle Scholar
  9. Hoge CW, Castro CA, Messer SC, McGurk D, Cotting DI, Koffman RL (2004) Combat duty in Iraq and Afghanistan, mental health problems, and barriers to care. N Engl J Med 351:13–22PubMedCrossRefGoogle Scholar
  10. Hoge CW, McGurk D, Thomas JL, Cox AL, Engel CC, Castro CA (2008) Mild traumatic brain injury in U.S. Soldiers returning from Iraq. N Engl J Med 358:453–463PubMedCrossRefGoogle Scholar
  11. Hovda DA, Becker DP, Katayama Y (1992) Secondary injury and acidosis. J Neurotrauma 9(Suppl 1):S47–S60PubMedGoogle Scholar
  12. Jager TE, Weiss HB, Coben JH, Pepe PE (2000) Traumatic brain injuries evaluated in U.S. emergency departments, 1992–1994. Acad Emerg Med 7:134–140PubMedCrossRefGoogle Scholar
  13. Jennett B (1998) Epidemiology of head injury. Arch Dis Child 78:403–406PubMedCrossRefGoogle Scholar
  14. Jones E, Fear NT, Wessely S (2007) Shell shock and mild traumatic brain injury: a historical review. Am J Psychiatry 164:1641–1645PubMedCrossRefGoogle Scholar
  15. Lane N (2006) Power, sex, suicide : mitochondria and the meaning of life. Oxford University Press, Oxford, New YorkGoogle Scholar
  16. Langlois JA, Rutland-Brown W, Wald MM (2006) The epidemiology and impact of traumatic brain injury: a brief overview. J Head Trauma Rehabil 21:375–378PubMedCrossRefGoogle Scholar
  17. Lifshitz J, Sullivan PG, Hovda DA, Wieloch T, McIntosh TK (2004) Mitochondrial damage and dysfunction in traumatic brain injury. Mitochondria 1:705–713CrossRefGoogle Scholar
  18. Maalouf M, Sullivan PG, Davis L, Kim DY, Rho JM (2007) Ketones inhibit mitochondrial production of reactive oxygen species production following glutamate excitotoxicity by increasing NADH oxidation. Neuroscience 145:256–264PubMedCrossRefGoogle Scholar
  19. Nasr P, Gursahani HI, Pang Z, Bondada V, Lee J, Hadley RW, Geddes JW (2003) Influence of cytosolic and mitochondrial Ca2+, ATP, mitochondrial membrane potential, and calpain activity on the mechanism of neuron death induced by 3-nitropropionic acid. Neurochem Int 43:89–99PubMedCrossRefGoogle Scholar
  20. Nicholls DG, Budd SL (2000) Mitochondria and neuronal survival. Physiol Rev 80:315–360PubMedGoogle Scholar
  21. Nicholls DG, Budd SL, Castilho RF, Ward MW (1999) Glutamate excitotoxicity and neuronal energy metabolism. Ann N Y Acad Sci 893:1–12PubMedCrossRefGoogle Scholar
  22. Nicholls DG, Ferguson SJ (2002) Bioenergetics3. Academic Press, LondonGoogle Scholar
  23. Obrenovitch TP (2008) Molecular physiology of preconditioning-induced brain tolerance to ischemia. Physiol Rev 88:211–247PubMedCrossRefGoogle Scholar
  24. Pandya JD, Pauly JR, Nukala VN, Sebastian AH, Day KM, Korde AS, Maragos WF, Hall ED, Sullivan PG (2007) Post-injury administration of mitochondrial uncouplers increases tissue sparing and improves behavioral outcome following traumatic brain injury in rodents. J Neurotrauma 24:798–811PubMedCrossRefGoogle Scholar
  25. Pellock JM, Dodson WE, Bourgeois BFD (2001) Pediatric epilepsy: diagnosis and therapy. DEMOS, New YorkGoogle Scholar
  26. Prins ML (2008) Cerebral metabolic adaptation and ketone metabolism after brain injury. J Cereb Blood Flow Metab 28:1–16PubMedCrossRefGoogle Scholar
  27. Rapoport MJ, Kiss A, Feinstein A (2006) The impact of major depression on outcome following mild-to-moderate traumatic brain injury in older adults. J Affect Disord 92:273–276PubMedCrossRefGoogle Scholar
  28. Robertson CS, Goodman JC, Narayan RK, Contant CF, Grossman RG (1991) The effect of glucose administration on carbohydrate metabolism after head injury. J Neurosurg 74:43–50PubMedCrossRefGoogle Scholar
  29. Rutland-Brown W, Langlois JA, Thomas KE, Xi YL (2006) Incidence of traumatic brain injury in the United States, 2003. J Head Trauma Rehabil 21:544–548PubMedCrossRefGoogle Scholar
  30. Scheff SW, Sullivan PG (1999) Cyclosporin A significantly ameliorates cortical damage following experimental traumatic brain injury in rodents. J Neurotrauma 16:783–792PubMedCrossRefGoogle Scholar
  31. Schurr A (2002) Energy metabolism, stress hormones and neural recovery from cerebral ischemia/hypoxia. Neurochem Int 41:1–8PubMedCrossRefGoogle Scholar
  32. Setnik L, Bazarian JJ (2007) The characteristics of patients who do not seek medical treatment for traumatic brain injury. Brain Inj 21:1–9PubMedCrossRefGoogle Scholar
  33. 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 26:1407–1418PubMedCrossRefGoogle Scholar
  34. Sleven H, Gibbs JE, Heales S, Thom M, Cock HR (2006) Depletion of reduced glutathione precedes inactivation of mitochondrial enzymes following limbic status epilepticus in the rat hippocampus. Neurochem Int 48:75–82PubMedCrossRefGoogle Scholar
  35. Sullivan PG (2005) Interventions with neuroprotective agents: novel targets and opportunities. Epilepsy Behav 7(Suppl 3):S12–S17PubMedCrossRefGoogle Scholar
  36. Sullivan PG, Keller JN, Bussen WL, Scheff SW (2002) Cytochrome c release and caspase activation after traumatic brain injury. Brain Res 949:88–96PubMedCrossRefGoogle Scholar
  37. Sullivan PG, Keller JN, Mattson MP, Scheff SW (1998) Traumatic brain injury alters synaptic homeostasis: implications for impaired mitochondrial and transport function. J Neurotrauma 15:789–798PubMedCrossRefGoogle Scholar
  38. Sullivan PG, Rabchevsky AG, Keller JN, Lovell M, Sodhi A, Hart RP, Scheff SW (2004a) Intrinsic differences in brain and spinal cord mitochondria: implication for therapeutic interventions. J Comp Neurol 474:524–534PubMedCrossRefGoogle Scholar
  39. Sullivan PG, Rabchevsky AG, Waldmeier PC, Springer JE (2005) Mitochondrial permeability transition in CNS trauma: cause or effect of neuronal cell death? J Neurosci Res 79:231–239PubMedCrossRefGoogle Scholar
  40. Sullivan PG, Springer JE, Hall ED, Scheff SW (2004b) Mitochondrial uncoupling as a therapeutic target following neuronal injury. J Bioenerg Biomembr 36:353–356PubMedCrossRefGoogle Scholar
  41. Sullivan PG, Thompson M, Scheff SW (2000) Continuous infusion of cyclosporin A postinjury significantly ameliorates cortical damage following traumatic brain injury. Exp Neurol 161:631–637PubMedCrossRefGoogle Scholar
  42. Thurman DJ, Alverson C, Dunn KA, Guerrero J, Sniezek JE (1999) Traumatic brain injury in the United States: a public health perspective. J Head Trauma Rehabil 14:602–615PubMedCrossRefGoogle Scholar
  43. Tieu K, Perier C, Caspersen C, Teismann P, Wu DC, Yan SD, Naini A, Vila M, Jackson-Lewis V, Ramasamy R, Przedborski S (2003) D-beta-hydroxybutyrate rescues mitochondrial respiration and mitigates features of Parkinson disease. J Clin Invest 112:892–901PubMedGoogle Scholar
  44. Woodruff L, Woodruff B (2007) In an instant: a family’s journey of love and healing. Random House, New YorkGoogle Scholar
  45. Yang J, Phillips G, Xiang H, Allareddy V, Heiden E, Peek-Asa C (2008) Hospitalizations for sport-related concussions in US children aged 5 to 18 years during 2000–2004. Br J Sports Med 42(8):664–669PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Laurie M. Davis
    • 1
  • Patrick G. Sullivan
    • 1
  1. 1.The Spinal Cord & Brain Injury Research CenterThe University of Kentucky Chandler College of MedicineLexingtonUSA

Personalised recommendations