**9.2. Mitochondrial uncoupling proteins**

caused by complete loss of transport and uniport activity of the protein [182–184]. Clinical manifestations are similar to epileptic spasms and focal seizures associated with suppression bursts beginning in the first days of life, microcephaly, hypotonia, abnormal retinogram

Glutamate can also enter mitochondria through aspartate/glutamate carrier (AGC1 and 2 isoforms, known as aralar and citrin) combining the input of glutamate to the release of aspartate [185]. The export of aspartate is favored in energized mitochondria. Moreover, in increased cytosolic calcium concentration, respiration is strongly increased associated with the reduction of mitochondrial membrane potential [185]. A decrease in ROS production could be expected given the opposite relationship between the mitochondrial membrane potential and ROS production [186]. Another attribute contributing to this effect is glutamate entry through AGC1 (SLC25A12) in cotransport with proton. The loss of membrane potential is compensated by the extrusion of four protons by the respiratory chain when one molecule of glutamate is processed through the citric acid cycle generating two molecules of NADH [187]. AGC together with the OGC plays a crucial role in the transport of NADH from cytosol to the mitochondria as a part of malate-aspartate shuttle [188]. Therefore, AGC1 and AGC2 (SLC25A13) are expressed in tissues differently according to their demands for maintenance of the redox balance between anaerobic and aerobic glycolysis. An interesting finding is that expression of AGC1 and AGC2 is almost completely restricted to neurons and photoreceptor cells [180, 189], in contrast to GC1 expressed in astrocytes. Cytosolic Ca2+ has a direct role in the regulation of *AGC1* gene expression via cAMP response element-binding protein in neuronal cells, underlining the key role of AGC1 in the central nervous system by upregulation in neuronal differentiation and downregulation in neuroinflammation [190]. AGC1 is also highly expressed in skeletal and heart muscle [191]. Upregulation of both isoforms was found

in several cancers, which is also related to the change in glycolytic metabolism [187].

Translocation of the ornithine and related substrates is mediated by mitochondrial ornithine carrier (ORC). The physiological importance of this carrier reclines on urea production, delivery-rate control of arginine, and interferential formation of NO, agmatine, creatine, glutamine, glutamate polyamines, and proline [192]. The human isoforms ORC1 (SLC25A15), ORC2 (SLC25A2), and ORC3 (SLC25A29) [193, 194] provide transport by exchange or by exchange

 but differ in substrate transport rates, substrate specificity, and tissue expression. They all facilitate passage of L-ornithine, L-lysine, and L-arginine. The ORC1 prefers transport of amino acid substrates with shorter and noncyclized side chains. It does not enable transport of L-homoarginine, D-ornithine, D-histidine, and D-arginine. The ORC2 transports all substrates with the same efficiency (L,D-forms of ornithine, lysine, histidine, arginine, and L-citrulline, L-homoarginine). The ORC3 enables transport of L-forms with longer side chains across MIM, e.g., lysine, arginine, and histidine [192]. The isoform expresses lower affinity to

recording, and psychomotor retardation [183].

**9. Aspartate/glutamate carrier**

268 Mitochondrial Diseases

**9.1. Ornithine carriers**

ornithine and does not transport citrulline [194].

for H+

Uncoupling proteins (UCP) sharing the same tripartite structure belongs to the family of the mitochondrial anion carriers. Six families of UCP members encoding by 45 genes have been described [199]. In mammals, UCPs consist of five homologs: UCP1 (SLC25A7), UCP2 (SLC25A8), UCP3 (SLC25A9), UCP4 (SLC25A27), and UCP5 (SLC25A14, BMCP1). *UCP1* genes are localized on human chromosome 4. The human and mouse *UCP2* genes are located 7–20 kb downstream of the *UCP3* stop codon, as the result of a duplication; the *UCP3-UCP2* locus is located on human chromosome 11q13 (between the genetic markers D11S916 and D11S911). The UCP5 homolog *Bmcp1* is located on Xq25–26 chromosome (between the markers DXS1206 and DXS1047), and *UCP4* on 6p11.2-q12 (close to the genetic marker SHGC-34952) [200].

UCPs are ubiquitous, except for UCP2 [201], however, exhibiting tissue-specific expression pattern. As reviewed in Gutérrez-Aquilar and Baines [202], UCP1 is unique to brown adipose tissue, UCP3 to heart and skeletal muscle, and UCP4 and 5 are typical to the brain. The general designation of this carrier family is derived from observed function of the first member, UCP1 in brown fat tissue—the heat production in the nonshivering thermogenesis [199]. According to Mitchell's theory, any proton leak not coupled with ATP synthesis would provoke uncoupling of respiration and thermogenesis. The discharge of proton gradient formed in respiratory chain causes dissipation of energy of oxidation as heat. Besides adaptive thermogenesis, uncoupling of respiration allows continuous reoxidation of coenzymes that are essential to metabolic pathways [203], prevents inhibition of mitochondrial respiration from excessive ATP production, and decreases ROS formation [204].

cytokines, concentration of metabolites, and individual nutrition components, which can alter their amount and activity. Most metabolites or their precursors can be mutually transported by different transport systems to provide the desired concentrations on both sides of the mitochondrial membranes. The specificity of transport and regulation of compounds in different organs and tissues provide various isoforms encoded by different nuclear genes. More detailed knowledge of transport mechanisms can contribute to better diagnosis and treatment

Nuclear Encoded Mitochondrial Proteins in Metabolite Transport and Oxidation Pathway…

http://dx.doi.org/10.5772/intechopen.72937

271

This work was supported by Slovak Grant Agency for Science VEGA 1/0782/15.

and Ladislav Vaško1

1 Department of Medical and Clinical Biochemistry, Faculty of Medicine, Pavol Jozef Šafárik

2 1st Clinic of Anaesthesiology and Instensive Medicine, Faculty of Medicine, Louis Pasteur University Hospital, Pavol Jozef Šafárik University in Košice, Košice, Slovak Republic

[1] Wohlrab H. Transport proteins (carriers) of mitochondria. IUBMB Life. 2009;**61**(1):40-46.

[2] Dudek J, Rehling P, van der Laan M. Mitochondrial protein import: Common principles and physiological networks. Biochimica et Biophysica Acta. 2013;**1833**(22):274-285. DOI:

[3] Schell JC, Rutter J. The long and winding road to the mitochondrial pyruvate carrier.

[4] Lemeshko VV.VDAC electronics: 1. VDAC-hexo(gluco)kinase generator of the mitochondrial outer membrane potential. Biochimica et Biophysica Acta. 2014;**1838**(5):1362-1371.

[5] Colombini M. VDAC structure, selectivity, and dynamics. Biochimica et Biophysica

[6] Colombini M, Mannella CA. VDAC, the early days. Biochimica et Biophysica Acta.

Cancer & Metabolism. 2013;**1**(1):6. DOI: 10.1186/2049-3002-1-6

Acta. 2012;**1818**(6):1457-1465. DOI: 10.1016/j.bbamem.2011.12.026

2012;**1818**(6):1438-1443. DOI: 10.1016/j.bbamem.2011.11.014

of metabolic disorders.

**Acknowledgements**

\*, Jozef Firment2

University in Košice, Košice, Slovak Republic

\*Address all correspondence to: janka.vaskova@upjs.sk

**Author details**

Janka Vašková1

**References**

DOI: 10.1002/iub.139

10.1016/j.bbamcr.2012.05.028

DOI: 10.1016/j.bbamem.2014.01.001

The activity of UCPs requires ubiquinone as a cofactor [205] and is regulated by two ligands. UCP1 is activated by fatty acids and inhibited by purine nucleoside di- and triphosphates. UCP2 and 3 can be activated by fatty acid and are less sensitive to purine inhibition. There are not many findings about UCP4 and 5 regulation; however, they were reported to be GDPsensitive [206]. The mechanism of proton transport is still controversial. The UCP is referred to act as a pure proton transporter activated by fatty acids, while by other mechanism, UCP facilitates protonated fatty acid transbilayer movements, flip-flop, to the matrix where they release the proton and are then transported back to the IMS by UCP [199, 206]. Consistently with transport of fatty acid anion, UCP1 was shown to transport a variety of ions, suggesting that UCP1 is a hydroxyl anion transporter rather than a proton carrier [207].

As has already been mentioned, the physiological function of UCP1 is the production of heat in brown adipocytes. The UCP1 induction is influenced by thyroid hormones and sympathetic nerves and therefore also by drugs activating adrenoceptors [203]. Capsaicin was found to increase levels of all UCPs [206]. A mutation in gene encoding UCP1 is associated to diabetic retinopathy [208].

Although, UCP2 and 3 are not involved in thermogenesis, polymorphisms in the coding region of the *UCP*2 gene are associated with the level of energy expenditure during sleep [209]. These two members reduce ROS formation by mild uncoupling [208] and related to function to decrease mitochondrial oxidative stress load and transport fatty acid peroxides to MOM [210]. Cytokines and thyroid hormone upregulate UCP2 and UCP3 [211]. Thus, physiological response of macrophages is lowering the UCP levels and enhancing the ROS production. Moreover, UCP2 was proposed to act as carrier for the superoxide anion [205]. The expression of UCP2 is induced under starvation when there are elevated levels of fatty acid in the circulation. The expression of UCP3 increases during fasting [212]. In leptin-induced lipolysis, fatty acids are not exported to the liver but are oxidized in adipocytes, where UCP2 initiates fat oxidation that is not associated with energy-requiring processes [213]. Pharmacological inhibition and genetic mutations in UCP2 and UCP3 have been shown to reverse damaging consequences of obesity and diabetes-induced pancreatic β-cell dysfunction [214, 215].

UCP4 and 5 have been shown to be upregulated by oxidative stress, while insulin downregulates their levels [216]. Mutations in *UCP*4 gene have been linked to schizophrenia [217]. For all UCPs, a continuity of upregulation of the expression and incidence of tumor diseases has been described [202].
