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Mitochondrial Uncoupling Proteins in the Central Nervous System Jeong Sook Kim-Han Washington University School of Medicine in St

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Mitochondrial Uncoupling Proteins in the Central Nervous System Jeong Sook Kim-Han Washington University School of Medicine in St Washington University School of Medicine Digital Commons@Becker Open Access Publications 2005 Mitochondrial uncoupling proteins in the central nervous system Jeong Sook Kim-Han Washington University School of Medicine in St. Louis Laura L. Dugan Washington University School of Medicine in St. Louis Follow this and additional works at: https://digitalcommons.wustl.edu/open_access_pubs Recommended Citation Kim-Han, Jeong Sook and Dugan, Laura L., ,"Mitochondrial uncoupling proteins in the central nervous system." Antioxidants & Redox Signaling.7,9-10. 1173-1181. (2005). https://digitalcommons.wustl.edu/open_access_pubs/3159 This Open Access Publication is brought to you for free and open access by Digital Commons@Becker. It has been accepted for inclusion in Open Access Publications by an authorized administrator of Digital Commons@Becker. For more information, please contact [email protected]. 14024C09.pgs 8/11/05 10:32 AM Page 1173 ANTIOXIDANTS & REDOX SIGNALING Volume 7, Numbers 9 & 10, 2005 © Mary Ann Liebert, Inc. Forum Review Mitochondrial Uncoupling Proteins in the Central Nervous System JEONG SOOK KIM-HAN1 and LAURA L. DUGAN1,2,3 ABSTRACT Mitochondrial uncoupling proteins (UCPs), a subfamily of the mitochondrial transporter family, are related by sequence homology to UCP1. This protein, which is located in the inner mitochondrial membrane, dissi- pates the proton gradient between the intermembrane space and the mitochondrial matrix to uncouple elec- tron transport from ATP synthesis. UCP1 (thermogenin) was first discovered in brown adipose tissue and is responsible for non-shivering thermogenesis. Expression of mRNA for three other UCP isoforms, UCP2, UCP4, and BMCP1/UCP5, has been found at high levels in brain. However, the physiological function(s) of UCPs in the brain have not been determined, although it has recently been postulated that UCPs regulate free radical flux from mitochondria by physiologically modulating mitochondrial membrane potential. In the CNS, this hypothesis has been studied primarily for UCP2. UCP2 message has been shown to be up-regulated in the CNS by stress signals such as kainate administration or ischemia, and overexpression of UCP2 has been reported to be neuroprotective against oxidative stress in vivo and in vitro, although the exact mechanism has not been fully established. In this review, studies on UCPs in the nervous system will be reviewed, and the po- tential roles of these intriguing proteins in acute and chronic diseases of the nervous system will be discussed. Antioxid. Redox Signal. 7, 1173–1181. GENERAL INTRODUCTION TO it acts as the non-shivering heat generator to maintain the UNCOUPLING PROTEINS body temperature in newborns and hibernating mammals (9, 47, 64). HE ELECTROCHEMICAL PROTON GRADIENT (the proton mo- A number of other protein members of the SLC25 sub- Ttive force, ⌬p = ⌬␺ + ⌬pH) between the intermembrane family of the mitochondrial transporter superfamily (for re- space and the matrix of mitochondria is produced by the elec- view, see 67) have been designated as “uncoupling proteins” tron transport chain residing in the mitochondrial inner mem- (UCPs) based initially on their sequence homology with brane (Fig. 1). As first proposed by Mitchell (61), this gradi- UCP1 and evidence that they had many of the same func- ent is now known to be the driving force for ATP synthesis, tional motifs. Of those studied to date, all appear to be lo- called “coupling.” Many proteins, including members of the cated in the inner mitochondrial membrane and to uncouple mitochondrial carrier family, harness ⌬p for their function, the proton gradient. More than 45 genes encoding UCP iso- some using its electrical component (ADP/ATP carrier and forms have been described in single-cell organisms, plants, glutamate/aspartate carrier) and others using the ⌬pH gradi- and animals, including humans (54). In addition to UCP1, ent (phosphate carrier and other carriers using substrate-H+ many of these additional UCP isoforms have been cloned symport). Any process using ⌬p without ATP synthesis has from plants and mammals, and their physiological roles have been termed “uncoupling.” Uncoupling protein 1 (UCP1; ther- begun to be investigated (8). UCPs are expressed in a tissue- mogenin) was first recognized as the protein-mediated un- specific manner, suggesting distinct roles and regulation of coupling activity in brown adipose tissues (BAT), in which their function in different locations. UCP2 has broad tissue 1Department of Neurology and 2Department of Medicine, Washington University School of Medicine, St. Louis, MO. 3Department of Medicine, University of California San Diego, San Diego, CA. 1173 14024C09.pgs 8/11/05 10:32 AM Page 1174 1174 KIM-HAN AND DUGAN FIG. 1. Effect of UCP on the production of ROS. (A) Under normal conditions, the proton gradient established by the elec- tron transport chain (ETC) is coupled to ATP synthesis through F1F0-ATPase. When the membrane is highly polarized, electron transfer from the ETC to oxygen is enhanced, increasing levels of ROS (superoxide, H2O2). In the presence of purine nucleotides (GDP), UCP activity is inhibited and elevated membrane potential and ROS production are maintained. (B) When overexpression of UCP or activation of the protein occurs, e.g., by binding of free fatty acids (FFA) or coenzyme Q10, the proton gradient is brought below the critical point for ROS production, and mitochondrial ROS formation decreases. expression, whereas UCP1 is almost exclusively expressed described, and the physiological and pathological roles of in BAT, and UCP3 is found mainly in BAT and skeletal mus- UCPs in the nervous system will be discussed. cle. UCP2 and UCP3 have the highest degree of homology to UCP1. Although they have significantly lower degrees of homology to UCP1, UCP4 and BMCP1/UCP5 have been added as putative members of the UCP family because UCP EXPRESSION: TRANSCRIPTIONALAND they show most of the functional motifs of UCP1. Another POSTTRANSCRIPTIONAL REGULATION isoform, SLC25A30, was recently reported by the RIKEN cDNA library to have a high degree of sequence homology to Although regulation of UCP gene expression at the BMCP1/UCP5, but has not yet been studied. In BAT, UCP1 mRNA level has been demonstrated in response to a diverse is highly expressed as one of the major mitochondrial pro- range of stimuli, including exposure to cold, high fat and ke- teins and, when activated, results in sufficient heat genera- togenic diets, starvation, leptin, insulin, inflammatory cyto- tion to maintain body temperature in newborns. Evidence kines, and endotoxin (for review, see 14), regulation of pro- suggests that UCP2 is not important for thermogenesis, how- tein is rarely reported. In part, this reflects problems with ever (2, 87). All UCPs are expressed at significantly lower currently available UCP antibodies, including both custom- levels in their respective tissues compared with UCP1 in prepared and commercially available antibodies. Most are not BAT, suggesting that the function of these UCP isoforms exclusively specific to each isoform (69), and we have found may not be thermogenesis. The observation that the newer that several antibodies detect 32–36-kDa bands in various UCPs are expressed at such low levels prompted introduc- knockout mice (Dugan and Kim-Han, unpublished observa- tion of the concept of “mild uncoupling” (76)—in which tions), suggesting that specific, well characterized antibodies functional regulation of mitochondrial reactive oxygen would be extremely useful reagents for future studies on the species (ROS) production occurs through modest decreases UCPs. ⌿ in m—for the non-UCP1 family members (Fig. 1). Mito- Regulation of UCP mRNA has not, in many cases, been chondria are considered to be one of the main sources for in- followed by changes in UCP protein expression (43, 75), tracellular ROS, and the mitochondrial membrane potential suggesting posttranscriptional regulation of UCP expression is the driving force for ROS generation as well as ATP produc- (23, 69). Recently, message for UCP2 has been found with- ⌿ tion. A small decrease in m can dramatically reduce pro- out concomitant protein expression (84). This disconnect duction of ROS, specifically hydrogen peroxide (H2O2) (49). between mRNA and protein expression results from an up- In addition, this mild uncoupling activity has been proposed stream AUG stop codon and alternative open reading frames to be one of the key modulators of cellular metabolism and (ORFs) in the 5Ј-untranslated region as a key determinant of signal transduction through regulation of mitochondrial ROS posttranscriptional regulation (69). One or three upstream production (11, 32), because many critical signaling path- ORFs have been identified in UCP2/3 and BMCP1/UCP5, re- ways have redox-sensitive components (30, 31). As the in- spectively, and these result in dramatically reduced efficiency volvement of mitochondrial ROS dysregulation in neurode- of translation (Fig. 2). In addition, more than six mRNA generative diseases has been a focus of research for many splicing variants have been detected for BMCP1/UCP5 decades, and altered production or decomposition of ROS mRNA (Dugan and Kim-Han, unpublished observations). has been observed in many experimental models of CNS in- We have also experienced inhibition of UCP expression after jury and neurodegenerative diseases, the possibility that UCPs, in vitro transfection in mammalian cells, although mRNA by regulating mitochondrial ROS levels, could be important was clearly present (Dugan and Kim-Han, unpublished obser- modifiers of CNS damage has recently emerged. In this review, vations). Other posttranscriptional mechanisms, including the involvement of UCPs in regulation of ROS will be changes in mRNA stability, need to be studied for these pro- 14024C09.pgs 8/11/05 10:32 AM Page 1175 UNCOUPLING PROTEINS IN THE NERVOUS SYSTEM 1175 FIG. 2. The putative ORFs at the upstream of the starting codon in mouse UCP mRNAs. Among UCPs, UCP1 does not have any putative ORF. UCP2 and UCP5/BMCP1 have three ATG codons at the upstream of the starting codon with one and three ORFs, respectively. Rat UCP4 mRNA has an ORF found in the 5Ј-untranslated region.
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