The human uncoupling proteins 5 and 6 (UCP5/SLC25A14 and UCP6/SLC25A30) transport sulfur oxyanions, phosphate and dicarboxylates

Gorgoglione, Ruggiero; Porcelli, Vito; Santoro, Antonella; Daddabbo, Lucia; Vozza, Angelo; Monné, Magnus; Noia, Maria Antonietta Di; Palmieri, Luigi; Fiermonte, Giuseppe; Palmieri, Ferdinando

doi:10.1016/j.bbabio.2019.07.010

Cited by 40 publications

(49 citation statements)

References 70 publications

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“…Isolated cardiac mitochondria from SLC25A3 knockout mice displayed a reduced ATP synthesis rate, although phosphate transport capacity was not completely abolished, as seen by measuring the uptake of radioactive phosphate. The latter observation may be explained by the fact that there are other MCs capable of transporting phosphate, such as the ATP-Mg 2+ /phosphate carriers (APCs), dicarboxylate carrier (DIC), and various uncoupling proteins (UCP2, UCP5, and UCP6) [19,[64][65][66][67][68][69][70]. Furthermore, in SLC25A3 deficiency patients who have mutations only in PiC isoform A, also PiC isoform B may partly compensate for the defective phosphate transport.…”

Section: Slc25a3 (Phosphate Carrier Pic) Deficiencymentioning

confidence: 99%

“…Oxidative damage may lead to the loss of mitochondrial DNA and, subsequently, to the symptoms observed. It might be that, in some tissues, other MCs that transport certain DIC substrates partly compensate for the lack of SLC25A10 activity: PiC and APCs transport phosphate [19,58,85]; the oxoglutarate carrier transports malate and succinate [86][87][88][89]; UCP2 transports malate, phosphate, and sulfate [69]; and UCP5 and UCP6 transport malate, succinate, phosphate, sulfate, and thiosulfate [70].…”

Section: Slc25a10 (Dicarboxylate Carrier Dic) Deficiencymentioning

confidence: 99%

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Diseases Caused by Mutations in Mitochondrial Carrier Genes SLC25: A Review

2020

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In the 1980s, after the mitochondrial DNA (mtDNA) had been sequenced, several diseases resulting from mtDNA mutations emerged. Later, numerous disorders caused by mutations in the nuclear genes encoding mitochondrial proteins were found. A group of these diseases are due to defects of mitochondrial carriers, a family of proteins named solute carrier family 25 (SLC25), that transport a variety of solutes such as the reagents of ATP synthase (ATP, ADP, and phosphate), tricarboxylic acid cycle intermediates, cofactors, amino acids, and carnitine esters of fatty acids. The disease-causing mutations disclosed in mitochondrial carriers range from point mutations, which are often localized in the substrate translocation pore of the carrier, to large deletions and insertions. The biochemical consequences of deficient transport are the compartmentalized accumulation of the substrates and dysfunctional mitochondrial and cellular metabolism, which frequently develop into various forms of myopathy, encephalopathy, or neuropathy. Examples of diseases, due to mitochondrial carrier mutations are: combined D-2- and L-2-hydroxyglutaric aciduria, carnitine-acylcarnitine carrier deficiency, hyperornithinemia-hyperammonemia-homocitrillinuria (HHH) syndrome, early infantile epileptic encephalopathy type 3, Amish microcephaly, aspartate/glutamate isoform 1 deficiency, congenital sideroblastic anemia, Fontaine progeroid syndrome, and citrullinemia type II. Here, we review all the mitochondrial carrier-related diseases known until now, focusing on the connections between the molecular basis, altered metabolism, and phenotypes of these inherited disorders.

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Section: Slc25a3 (Phosphate Carrier Pic) Deficiencymentioning

confidence: 99%

Section: Slc25a10 (Dicarboxylate Carrier Dic) Deficiencymentioning

confidence: 99%

Diseases Caused by Mutations in Mitochondrial Carrier Genes SLC25: A Review

2020

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“…Mitochondrial uncoupling proteins (UCPs) constitute a subfamily of the SLC25 family allowing the leakage of protons into the mitochondrial matrix, thus dissipating the proton gradient created by the respiratory electron transport chain and uncoupling respiration from ADP phosphorylation [ 83 ]. To date, six human isoforms (hUCP1–6) have been identified, encoded by different genes, i.e., SLC25A7 - 9 , SLC25A27, SLC25A14 and SLC25A30 [ 84 ]. All the UCPs share amino acid sequences located in the first, second and fourth helices, as well as in the second matrix loop, and named “uncoupling protein (UCP) signatures”; furthermore, the purine nucleotide binding domain (PNBD) is highly homologous [ 85 , 86 ].…”

Section: Drosophila Melanogaster Vs Human Mitomentioning

confidence: 99%

“…According to a recent phylogenetic analysis of human UCPs and their closest relatives from other species, three different branches have been detected, including relatives of UCP4–6, UCP1–3 and DIC/OGC proteins. On the first principal branch, UCP5 and UCP6 proteins constitute two close clusters, while UCP4 relatives compose a different cluster [ 84 ].…”

Section: Drosophila Melanogaster Vs Human Mitomentioning

confidence: 99%

“…The uncoupling abilities of UCP2–5 appear to be moderate; their mild mitochondrial uncoupling could avoid excessive mitochondrial reactive oxygen species (ROS) production, thus reducing cellular oxidative damage [ 86 , 89 ], as recently proved for UCP2 and UCP3 in stroke and ischemia/reperfusion [ 90 ]. On the other hand, UCP6 is not able to transport protons but mainly sulfur compounds [ 84 ], while UCP2 can catalyze the transport of a dicarboxylate against phosphate plus a proton [ 91 ].…”

Section: Drosophila Melanogaster Vs Human Mitomentioning

confidence: 99%

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Drosophila melanogaster Mitochondrial Carriers: Similarities and Differences with the Human Carriers

Curcio

Lunetti

Zara

et al. 2020

IJMS

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Mitochondrial carriers are a family of structurally related proteins responsible for the exchange of metabolites, cofactors and nucleotides between the cytoplasm and mitochondrial matrix. The in silico analysis of the Drosophila melanogaster genome has highlighted the presence of 48 genes encoding putative mitochondrial carriers, but only 20 have been functionally characterized. Despite most Drosophila mitochondrial carrier genes having human homologs and sharing with them 50% or higher sequence identity, D. melanogaster genes display peculiar differences from their human counterparts: (1) in the fruit fly, many genes encode more transcript isoforms or are duplicated, resulting in the presence of numerous subfamilies in the genome; (2) the expression of the energy-producing genes in D. melanogaster is coordinated from a motif known as Nuclear Respiratory Gene (NRG), a palindromic 8-bp sequence; (3) fruit-fly duplicated genes encoding mitochondrial carriers show a testis-biased expression pattern, probably in order to keep a duplicate copy in the genome. Here, we review the main features, biological activities and role in the metabolism of the D. melanogaster mitochondrial carriers characterized to date, highlighting similarities and differences with their human counterparts. Such knowledge is very important for obtaining an integrated view of mitochondrial function in D. melanogaster metabolism.

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Human mitochondrial uncoupling protein 3 functions as a metabolite transporter

De Leonardis,

Ahmed,

Vozza

et al. 2023

FEBS Letters

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Since its discovery, a major debate about mitochondrial uncoupling protein 3 (UCP3) has been whether its metabolic actions result primarily from mitochondrial inner membrane proton transport, a process that decreases respiratory efficiency and ATP synthesis. However, UCP3 expression and activity are induced by conditions that would seem at odds with inefficient ‘uncoupled’ respiration, including fasting and exercise. Here, we demonstrate that the bacterially expressed human UCP3, reconstituted into liposomes, catalyses a strict exchange of aspartate, malate, sulphate and phosphate. The R282Q mutation abolishes the transport activity of the protein. Although the substrate specificity and inhibitor sensitivity of UCP3 display similarity with that of its close homolog UCP2, the two proteins significantly differ in their transport mode and kinetic constants.

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The human uncoupling proteins 5 and 6 (UCP5/SLC25A14 and UCP6/SLC25A30) transport sulfur oxyanions, phosphate and dicarboxylates

Cited by 40 publications

References 70 publications

Diseases Caused by Mutations in Mitochondrial Carrier Genes SLC25: A Review

Diseases Caused by Mutations in Mitochondrial Carrier Genes SLC25: A Review

Drosophila melanogaster Mitochondrial Carriers: Similarities and Differences with the Human Carriers

Human mitochondrial uncoupling protein 3 functions as a metabolite transporter

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