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The Emerging Neuroprotective Role of Mitochondrial Uncoupling Protein

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The Emerging Neuroprotective Role of Mitochondrial Uncoupling Protein Review Article • DOI: 10.1515/tnsci-2015-0019 • Translational Neuroscience • 6 • 2015 • 179-186 Translational Neuroscience THE EMERGING NEUROPROTECTIVE ROLE Kieran P. Normoyle1,2,3, OF MITOCHONDRIAL Miri Kim2,4, Arash Farahvar5, UNCOUPLING PROTEIN-2 Daniel Llano1,6,7, Kevin Jackson7,8, IN TRAUMATIC BRAIN INJURY Huan Wang6,8* Abstract 1Department of Molecular and Integrative Traumatic brain injury (TBI) is a multifaceted disease with intrinsically complex heterogeneity and remains a Physiology, University of Illinois at Urbana- Champaign, Urbana, IL, USA significant clinical challenge to manage. TBI model systems have demonstrated many mechanisms that contribute 2College of Medicine, University of Illinois at to brain parenchymal cell death, including glutamate and calcium toxicity, oxidative stress, inflammation, and Urbana-Champaign, Urbana, IL, USA mitochondrial dysfunction. Mitochondria are critically regulated by uncoupling proteins (UCP), which allow 3Department of Child Neurology, Massachusetts protons to leak back into the matrix and thus reduce the mitochondrial membrane potential by dissipating the General Hospital, Boston, MA, USA 4Department of Cell and Developmental Biology, proton motive force. This uncoupling of oxidative phosphorylation from adenosine triphosphate (ATP) synthesis University of Illinois at Urbana-Champaign, is potentially critical for protection against cellular injury as a result of TBI and stroke. A greater understanding Urbana, IL, USA of the underlying mechanism or mechanisms by which uncoupling protein-2 (UCP2) functions to maintain 5Department of Neurosurgery, Carle Foundation or optimize mitochondrial function, and the conditions which precipitate the failure of these mechanisms, Hospital, Urbana, IL, USA 6Department of Neurology, Carle Foundation would inform future research and treatment strategies. We posit that UCP2-mediated function underlies Hospital, Urbana, IL, USA the physiological response to neuronal stress associated with traumatic and ischemic injury and that clinical 7The Beckman Institute, University of Illinois at development of UCP2-targeted treatment would significantly impact these patient populations. With a focus on Urbana-Champaign, Urbana, IL, USA clinical relevance in TBI, we synthesize current knowledge concerning UCP2 and its potential neuroprotective 8Thermal Neuroscience Laboratory (TNL), Beckman Institute, University of Illinois at Urbana- role and apply this body of knowledge to current and potential treatment modalities. Champaign, Urbana, IL, USA Keywords Received 29 June 2015 • Neuronal injury • Mitochondria • Traumatic brain injury • Ischemia • Neuronal cell death accepted 20 July 2015 Introduction oxidative phosphorylation from adenosine allowing hydrogen ions to move down their triphosphate (ATP) synthesis [3]. Of the five energy gradient through ATP synthase, but is Traumatic brain injury (TBI) is a global public UCP thus far discovered, emerging evidence also the source of potentially dangerous reactive health epidemic resulting in over 2.8 million identifies uncoupling protein-2 (UCP2) as oxygen species (ROS) [13, 14]. In the instance hospitalizations of Americans each year, with potentially critical for protection against of TBI and stroke, ΔΨm is too great, resulting in more than 500,000 deaths. Because of the cellular injury from TBI and stroke [4-8]. With calcium flows into mitochondria with concurrent composite and destructive effects of both the a focus on clinical relevance in TBI, this review production of ROS and subsequent cellular initial mechanical insult and the secondary article will synthesize the state of our present damage, thus initiating the process of cell death. injury arising from a variety of biochemical knowledge concerning UCP2 and its potential This process occurs through the direct result of cascades, TBI is a multifaceted disease with neuroprotective role. the ΔΨm increase triggering the mitochondrial intrinsically complex heterogeneity and remains pore transition protein (mPTP) complex [15-18]. a significant clinical challenge to manage. Mitochondria An alternative pathway capable of dissipating Experimental TBI models have demonstrated ΔΨm to reduce mitochondrial calcium load and many mechanisms that contribute to neuronal Mitochondrial ATP synthase completes the mPTP activation without increasing oxidative and glial cell death, including glutamate and enzymatic process of oxidative phosphorylation, damage is through the function of uncoupling calcium toxicity, oxidative stress, inflammation, converting nutrient energy to reduced cofactors proteins such as UCP2, which account for 95% and mitochondrial dysfunction. Mitochondria (nicotinamide adenine dinucleotide, NADH, of all proton movement that bypasses the ATP have been recently established as the principal and flavin adenine dinucleotide, FADH2) synthase [19]. These proteins are ubiquitous mediators of cell death, orchestrating the through electron shuttling and a proton motive enough to account for 25% of the standard necrotic, apoptotic, and autophagic cellular force (PMF) across the inner mitochondrial metabolic rate [20]. death pathways [1, 2]. These pathways are membrane. These gradient forces consist of critically regulated by uncoupling proteins a chemical potential and, more critically, an UCP2 (UCP), which reduce the mitochondrial electrical potential (ΔΨm), which accounts for membrane potential by causing a proton leak 90% of the PMF [9-12]. This ΔΨm is the potential UCP1, or thermogenin, was discovered in back into the matrix. This process dissipates energy source that drives phosphorylation brown adipose tissue where its diversion of the proton motive force and uncouples of adenosine diphosphate (ADP) to ATP by metabolic energy to non-shivering thermal * E-mail: [email protected] © 2015 Kieran P. Normoyle et al., licensee De Gruyter Open. This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivs 3.0 License. 179 Translational Neuroscience energy is recognized for its importance in futile cycle, but under conditions in which ATP Reactive oxygen species (ROS) thermoregulation of newborns as well as production is limited due to lack of necessary Reactive oxygen species (ROS), both radicals and in cold-blooded, hibernating, and overfed substrates, including oxygen, the dissipation of non-radicals (hydrogen peroxide), are highly members of the animal kingdom [21-23]. ΔΨm through other means would be necessary reactive byproducts of oxidative respiration Discovered in 1997, UCP2 [24] is the best- to protect against ROS damage and initiation present in all cells that function as signaling studied of the non-adipose UCP. UPC2 was of apoptosis [19, 40, 41]. Experimental data elements at physiological concentrations [19, well characterized in secondary and tertiary suggest that UCP2 contributes to neuronal 53]. Mitochondrial ROS production is highly structure in comparison to a bovine ADP/ stress tolerance in acute settings, which over sensitive to slight changes in ΔΨm [54-56]. UCP2 ATP carrier, adenine nucleotide translocase-1 time triggers mitochondrial proliferation and lowers ΔΨm with the subsequent decrease of (ANT1), which also permits dissipation of the increased ATP/ADP production [32, 42]. As ROS production [38, 42, 57, 58]; conversely, in mitochondrial proton gradient. These two ΔΨm is intimately linked to ATP production, a UCP2 knockout animals, an increase in ΔΨm is proteins were found to have similar molecular disruption of delivery or ability to effectively observed, which promotes ROS production [42, structure despite having only 20% sequence utilize substrates for oxidative phosphorylation 59]. Interestingly, UCP2 also serves as a cellular homology [24, 25]. Interestingly, UCP2 appears would lead to ΔΨm increasing to dangerous target of ROS signals such as superoxide, to have an unusually short half-life of 30 min, levels with subsequent ROS production, which activates UCP2 to reduce ΔΨm and compared to its homologue UCP1, which has a calcium influx into mitochondria and eventually lower ROS generation [60]. Recent evidence half-life of 30 h [26]. This short half-life permits cell death [39, 40, 43-45]. Recent evidence further supports the notion that rising levels rapid variability of activity at both the mRNA further indicates that the principle function of of ROS induce mitochondrial uncoupling and protein levels [20], suggesting a role in rapid UCP2 is to dissipate ΔΨm in vivo [46], which may through UCP2 activation, a process which also physiological stress responses. UCP2 exists in underlie the emerging neuroprotective role of liberates glutathione [27], indicating that under a glutathione-bound inactive state such that UCP2 in TBI. physiological conditions UCP2 is part of an UCP2 activation to reduce ROS production in adaptive response to maintain proper redox a stressed cell also liberates a stoichiometric Calcium regulation and apoptosis homeostasis through bidirectional regulation. amount of glutathione to mitigate existing Mitochondria represent a point of integration ROS moieties [27]. In the central nervous for cell death signaling in vertebrates through Physiological compensation system, mammalian UCP2 mRNA and protein the activation of mitochondrial membrane The physiological role of UCP2 is thus one expression is highest in areas that could be permeabilization [1, 40, 44, 47, 48], releasing of compensations to decrease ΔΨm in the described as high-risk for stress. High risk myriad cell death factors
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