title: The emerging neuroprotective role of mitochondrial uncoupling protein-2 in traumatic brain injury.
abstract: Traumatic brain injury (TBI) is a multifaceted disease with intrinsically complex heterogeneity and remains a significant clinical challenge to manage. TBI model systems have demonstrated many mechanisms that contribute to brain parenchymal cell death, including glutamate and calcium toxicity, oxidative stress, inflammation, and mitochondrial dysfunction. Mitochondria are critically regulated by uncoupling proteins (UCP), which allow protons to leak back into the matrix and thus reduce the mitochondrial membrane potential by dissipating the proton motive force. This uncoupling of oxidative phosphorylation from adenosine triphosphate (ATP) synthesis is potentially critical for protection against cellular injury as a result of TBI and stroke. A greater understanding of the underlying mechanism or mechanisms by which uncoupling protein-2 (UCP2) functions to maintain or optimize mitochondrial function, and the conditions which precipitate the failure of these mechanisms, would inform future research and treatment strategies. We posit that UCP2-mediated function underlies the physiological response to neuronal stress associated with traumatic and ischemic injury and that clinical development of UCP2-targeted treatment would significantly impact these patient populations. With a focus on clinical relevance in TBI, we synthesize current knowledge concerning UCP2 and its potential neuroprotective role and apply this body of knowledge to current and potential treatment modalities.
authors.affiliation: Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, IL, USA; College of Medicine, University of Illinois at Urbana-Champaign, Urbana, IL, USA; Department of Child Neurology, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: Kieran P
authors.initials: KP
authors.lastname: Normoyle
authors.affiliation: College of Medicine, University of Illinois at Urbana-Champaign, Urbana, IL, USA; Department of Cell and Developmental Biology, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
authors.forename: Miri
authors.initials: M
authors.lastname: Kim
authors.affiliation: Department of Neurosurgery, Carle Foundation Hospital, Urbana, IL, USA.
authors.forename: Arash
authors.initials: A
authors.lastname: Farahvar
authors.affiliation: Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, IL, USA; Department of Neurology, Carle Foundation Hospital, Urbana, IL, USA; The Beckman Institute, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Llano
authors.affiliation: The Beckman Institute, University of Illinois at Urbana-Champaign, Urbana, IL, USA; Thermal Neuroscience Laboratory (TNL), Beckman Institute, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Jackson
authors.affiliation: Department of Neurology, Carle Foundation Hospital, Urbana, IL, USA; Thermal Neuroscience Laboratory (TNL), Beckman Institute, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
authors.forename: Huan
authors.initials: H
authors.lastname: Wang
keywords: Ischemia; Mitochondria; Neuronal cell death; Neuronal injury; Traumatic brain injury