Solute Carrier Transporters as Potential Targets for the Treatment of Metabolic Disease

Schumann, Tina; König, Jörg; Henke, Christine; Willmes, Diana M.; Bornstein, Stefan R.; Jordan, Jens; Fromm, Martin F.; Birkenfeld, Andreas L.

doi:10.1124/pr.118.015735

Cited by 113 publications

(92 citation statements)

References 381 publications

(539 reference statements)

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“…Furthermore, UCP2 is required in the aspartate–argininosuccinate shunt of the tricarboxylic acid/urea cycle, since this carrier can exchange the cytosolic malate synthesized by cytosolic fumarase from fumarate [ 98 ], for intramitochondrial aspartate, which is then utilized in the cytosolic reactions of the urea cycle [ 99 ]. The activation of UCP2 can negatively modulate insulin secretion, impairing beta-cell functions [ 97 , 100 , 101 , 102 ]. On the other hand, mutations found in hUCP2 are responsible for human congenital hyperinsulinism [ 103 , 104 ].…”

Section: Drosophila Melanogaster Vs Human Mitomentioning

confidence: 99%

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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Section: Drosophila Melanogaster Vs Human Mitomentioning

confidence: 99%

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

Curcio

Lunetti

Zara

et al. 2020

IJMS

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“…On the other hand, we found altered an elevated number of genes from the solute carrier (SLC) group of membrane transport proteins. SLC transporters show high expression levels in metabolically active organs such as the kidney, liver or brain [38], and the kidney has been identified as one of the target organs for most high expression of SLCs-mediated diseases [39]. For instance, we found up-regulated the type I sodium-dependent phosphate transporters SLC17A1 (NPT1) and SLC17A3 (NPT4), which are the two most up-regulated genes in this condition, and also SLC27A2 (Fatty Acid Transporter FATP2), SLC16A4 (Monocarboxylate Transporter 4 MCT4) and SLC4A4 (Sodium Bicarbonate Cotransporter NBC1), all of them being involved in renal diseases [39].…”

Section: Clc-5 Silencing and Mutations V523del E527d And I524k Impaimentioning

confidence: 99%

Global gene-expression analysis reveals the molecular processes underlying ClC-5 loss-of-function in novel Dent Disease 1 cellular models

Durán

Burballa

Cantero-Recasens

et al. 2020

Preprint

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Dent disease 1 (DD1) is a rare X-linked renal proximal tubulopathy characterized by low molecular weight proteinuria (LMWP) and variable degree of hypercalciuria, nephrocalcinosis and/or nephrolithiasis with progression to chronic kidney disease (CKD). Although loss-of-function mutations in the geneCLCN5encoding the electrogenic Cl−/H+antiporter ClC-5, which impair endocytic uptake in proximal tubule cells, cause the disease, there is poor genotype-phenotype correlation and their contribution to proximal tubule dysfunction remains unclear. Here, in order to discover the mechanisms leading to proximal tubule dysfunction due to ClC-5 loss-of-function, we have generated and characterized new human cellular models of DD1 by silencingCLCN5and introducing the ClC-5 pathogenic mutants V523del, E527D and I524K into the human proximal tubule-derived cell line RPTEC/TERT1. Depletion ofCLCN5or expression of mutant ClC-5 impairs albumin endocytosis, increases substrate adhesion and decreases collective migration, which correlates with a less differentiated epithelial phenotype. Interestingly, although all conditions compromised the endocytic capacity in a similar way, their impact on gene expression profiles was different. Our DNA microarray studies show that ClC-5 silencing or mutant re-introduction alter pathways related to nephron development, anion homeostasis, organic acid transport, extracellular matrix organization and cell migration, compared to control cells. Cells carrying the V523del ClC-5 mutation show the largest differences in gene expression vs WT cells, which is in agreement with the more aggressive clinical phenotype observed in some DD1 patients. Overall, this work emphasizes the use of human proximal tubule derived cell models to identify the molecular processes underlying ClC-5 deficiency.

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“…nutrients, metabolites) across the plasma membrane and membranes of subcellular organelles (e.g. mitochondria, lysosomes) [ 1 , 2 ]. Although expressed throughout the body, transport proteins are particularly expressed at higher density and in a broader spectrum in the liver, intestine, kidney, and placenta where several nutrients and metabolites are secreted or absorbed/reabsorbed [ 1 , 2 ].…”

Section: Introductionmentioning

confidence: 99%

“…mitochondria, lysosomes) [ 1 , 2 ]. Although expressed throughout the body, transport proteins are particularly expressed at higher density and in a broader spectrum in the liver, intestine, kidney, and placenta where several nutrients and metabolites are secreted or absorbed/reabsorbed [ 1 , 2 ]. Transporters are divided into two major groups: ATP-binding cassette (ABC) proteins and the solute carrier (SLC) proteins [ 1 ].…”

Section: Introductionmentioning

confidence: 99%

Consequences of NaCT/SLC13A5/mINDY deficiency: good versus evil, separated only by the blood–brain barrier

Kopel

Bhutia

Sivaprakasam

et al. 2021

Biochemical Journal

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NaCT/SLC13A5 is a Na+-coupled transporter for citrate in hepatocytes, neurons, and testes. It is also called mINDY (mammalian ortholog of ‘I'm Not Dead Yet’ in Drosophila). Deletion of Slc13a5 in mice leads to an advantageous phenotype, protecting against diet-induced obesity, and diabetes. In contrast, loss-of-function mutations in SLC13A5 in humans cause a severe disease, EIEE25/DEE25 (early infantile epileptic encephalopathy-25/developmental epileptic encephalopathy-25). The difference between mice and humans in the consequences of the transporter deficiency is intriguing but probably explainable by the species-specific differences in the functional features of the transporter. Mouse Slc13a5 is a low-capacity transporter, whereas human SLC13A5 is a high-capacity transporter, thus leading to quantitative differences in citrate entry into cells via the transporter. These findings raise doubts as to the utility of mouse models to evaluate NaCT biology in humans. NaCT-mediated citrate entry in the liver impacts fatty acid and cholesterol synthesis, fatty acid oxidation, glycolysis, and gluconeogenesis; in neurons, this process is essential for the synthesis of the neurotransmitters glutamate, GABA, and acetylcholine. Thus, SLC13A5 deficiency protects against obesity and diabetes based on what the transporter does in hepatocytes, but leads to severe brain deficits based on what the transporter does in neurons. These beneficial versus detrimental effects of SLC13A5 deficiency are separable only by the blood-brain barrier. Can we harness the beneficial effects of SLC13A5 deficiency without the detrimental effects? In theory, this should be feasible with selective inhibitors of NaCT, which work only in the liver and do not get across the blood-brain barrier.

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Solute Carrier Transporters as Potential Targets for the Treatment of Metabolic Disease

Cited by 113 publications

References 381 publications

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

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

Global gene-expression analysis reveals the molecular processes underlying ClC-5 loss-of-function in novel Dent Disease 1 cellular models

Consequences of NaCT/SLC13A5/mINDY deficiency: good versus evil, separated only by the blood–brain barrier

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