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I'm Not Dead Yet in Metabolic Regulation
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I'm Not Dead Yet in Metabolic Regulation

A special issue of Metabolites (ISSN 2218-1989). This special issue belongs to the section "Cell Metabolism".

Deadline for manuscript submissions: closed (31 December 2022) | Viewed by 35172

Special Issue Editors

Prof. Andreas Birkenfeld

E-Mail Website
Guest Editor
1. Department of Internal Medicine IV – Endocrinology, Diabetology, and Nephrology, University Hospital Tübingen and Institute of Diabetes Research and Metabolic Diseases (IDM) of the Helmholtz Zentrum München, Tübingen, Germany
2. King’s College Transcampus of Diabetology, Diabetes and Nutritional Sciences, Rayne Institute, King’s College London, UK
Interests: type 2 diabetes; insulin resistance; lipid and glucose metabolism; obesity; ageing
Dr. Grit Zahn

E-Mail Website
Guest Editor
Head of Research at Eternygen GmbH, Berlin, Germany
Interests: citrate transporter; citrate metabolism; hepatic energy metabolism; drug development

Special Issue Information

Dear Colleagues,

Since 2000, when the INDY gene (SLC13A5/NaCT) was originally discovered as a longevity gene in Drosophila, a broad variety of functional roles of the INDY protein have been described, in particular in energy metabolism. The regulation of metabolic processes by the INDY gene was revealed through studies in lower organisms such as Drosophila and C. elegans, as well as mammalian species, up to monkeys and humans. Reducing the expression of INDY in lower species extends their life span by a mechanism resembling caloric restriction. Although, in humans, INDY is mainly found in the liver, it is also expressed in other tissues such as the brain, testes, and the adrenal gland. In all animal species tested so far, a reduced INDY function shows a vast majority of beneficial effects on energy metabolism, such as protection from dietary and age-related metabolic diseases. In contrast, a very rare loss of function mutation in human causes severe epileptic disease. Based on loss-of-function data in mouse and humans, as well as pharmacological intervention by anti-sense and small molecule inhibitors, the fundamental role of INDY in metabolic regulation in the liver; neuronal function; and, most recently, blood pressure regulation will be discussed in this Special Issue. Furthermore, its potential as a therapeutic target for finding new human medicines will be debated.

Prof. Andreas Birkenfeld
Dr. Grit Zahn
Guest Editors

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Keywords

  • Hepatic energy metabolism
  • Neuronal metabolism
  • INDY as therapeutic target
  • Metabolomics
  • Longevity
  • Caloric restriction
  • Structure–function relationship
  • Epilepsy
  • Citrate metabolism
  • Transcriptional regulation
  • Hepatocellular cancer

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Published Papers (11 papers)

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Research

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15 pages, 1925 KiB  
Article
Targeting Longevity Gene SLC13A5: A Novel Approach to Prevent Age-Related Bone Fragility and Osteoporosis
by Grit Zahn, Hannes A. Baukmann, Jasmine Wu, Jens Jordan, Andreas L. Birkenfeld, Naomi Dirckx and Marco F. Schmidt
Metabolites 2023, 13(12), 1186; https://doi.org/10.3390/metabo13121186 - 6 Dec 2023
Cited by 1 | Viewed by 2540
Abstract
Reduced expression of the plasma membrane citrate transporter SLC13A5, also known as INDY, has been linked to increased longevity and mitigated age-related cardiovascular and metabolic diseases. Citrate, a vital component of the tricarboxylic acid cycle, constitutes 1–5% of bone weight, binding to [...] Read more.
Reduced expression of the plasma membrane citrate transporter SLC13A5, also known as INDY, has been linked to increased longevity and mitigated age-related cardiovascular and metabolic diseases. Citrate, a vital component of the tricarboxylic acid cycle, constitutes 1–5% of bone weight, binding to mineral apatite surfaces. Our previous research highlighted osteoblasts’ specialized metabolic pathway facilitated by SLC13A5 regulating citrate uptake, production, and deposition within bones. Disrupting this pathway impairs bone mineralization in young mice. New Mendelian randomization analysis using UK Biobank data indicated that SNPs linked to reduced SLC13A5 function lowered osteoporosis risk. Comparative studies of young (10 weeks) and middle-aged (52 weeks) osteocalcin-cre-driven osteoblast-specific Slc13a5 knockout mice (Slc13a5cKO) showed a sexual dimorphism: while middle-aged females exhibited improved elasticity, middle-aged males demonstrated enhanced bone strength due to reduced SLC13A5 function. These findings suggest reduced SLC13A5 function could attenuate age-related bone fragility, advocating for SLC13A5 inhibition as a potential osteoporosis treatment. Full article
(This article belongs to the Special Issue I'm Not Dead Yet in Metabolic Regulation)
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16 pages, 1708 KiB  
Article
A Novel and Cross-Species Active Mammalian INDY (NaCT) Inhibitor Ameliorates Hepatic Steatosis in Mice with Diet-Induced Obesity
by Grit Zahn, Diana M. Willmes, Nermeen N. El-Agroudy, Christopher Yarnold, Richard Jarjes-Pike, Sabine Schaertl, Kay Schreiter, Wiebke Gehrmann, Andrea Kuan Cie Wong, Tommaso Zordan, Jörg König, Jens Jordan and Andreas L. Birkenfeld
Metabolites 2022, 12(8), 732; https://doi.org/10.3390/metabo12080732 - 8 Aug 2022
Cited by 7 | Viewed by 2675
Abstract
Mammalian INDY (mINDY, NaCT, gene symbol SLC13A5) is a potential target for the treatment of metabolically associated fatty liver disease (MAFLD). This study evaluated the effects of a selective, cross-species active, non-competitive, non-substrate-like inhibitor of NaCT. First, the small molecule inhibitor ETG-5773 [...] Read more.
Mammalian INDY (mINDY, NaCT, gene symbol SLC13A5) is a potential target for the treatment of metabolically associated fatty liver disease (MAFLD). This study evaluated the effects of a selective, cross-species active, non-competitive, non-substrate-like inhibitor of NaCT. First, the small molecule inhibitor ETG-5773 was evaluated for citrate and succinate uptake and fatty acid synthesis in cell lines expressing both human NaCT and mouse Nact. Once its suitability was established, the inhibitor was evaluated in a diet-induced obesity (DIO) mouse model. DIO mice treated with 15 mg/kg compound ETG-5773 twice daily for 28 days had reduced body weight, fasting blood glucose, and insulin, and improved glucose tolerance. Liver triglycerides were significantly reduced, and body composition was improved by reducing fat mass, supported by a significant reduction in the expression of genes for lipogenesis such as SREBF1 and SCD1. Most of these effects were also evident after a seven-day treatment with the same dose. Further mechanistic investigation in the seven-day study showed increased plasma β-hydroxybutyrate and activated hepatic adenosine monophosphate-activated protein kinase (AMPK), reflecting findings from Indy (−/−) knockout mice. These results suggest that the inhibitor ETG-5773 blocked citrate uptake mediated by mouse and human NaCT to reduce liver steatosis and body fat and improve glucose regulation, proving the concept of NaCT inhibition as a future liver treatment for MAFLD. Full article
(This article belongs to the Special Issue I'm Not Dead Yet in Metabolic Regulation)
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18 pages, 1765 KiB  
Article
Untargeted Metabolomics of Slc13a5 Deficiency Reveal Critical Liver–Brain Axis for Lipid Homeostasis
by Sofia Milosavljevic, Kevin E. Glinton, Xiqi Li, Cláudia Medeiros, Patrick Gillespie, John R. Seavitt, Brett H. Graham and Sarah H. Elsea
Metabolites 2022, 12(4), 351; https://doi.org/10.3390/metabo12040351 - 14 Apr 2022
Cited by 8 | Viewed by 3541
Abstract
Though biallelic variants in SLC13A5 are known to cause severe encephalopathy, the mechanism of this disease is poorly understood. SLC13A5 protein deficiency reduces citrate transport into the cell. Downstream abnormalities in fatty acid synthesis and energy generation have been described, though biochemical signs [...] Read more.
Though biallelic variants in SLC13A5 are known to cause severe encephalopathy, the mechanism of this disease is poorly understood. SLC13A5 protein deficiency reduces citrate transport into the cell. Downstream abnormalities in fatty acid synthesis and energy generation have been described, though biochemical signs of these perturbations are inconsistent across SLC13A5 deficiency patients. To investigate SLC13A5-related disorders, we performed untargeted metabolic analyses on the liver, brain, and serum from a Slc13a5-deficient mouse model. Metabolomic data were analyzed using the connect-the-dots (CTD) methodology and were compared to plasma and CSF metabolomics from SLC13A5-deficient patients. Mice homozygous for the Slc13a5tm1b/tm1b null allele had perturbations in fatty acids, bile acids, and energy metabolites in all tissues examined. Further analyses demonstrated that for several of these molecules, the ratio of their relative tissue concentrations differed widely in the knockout mouse, suggesting that deficiency of Slc13a5 impacts the biosynthesis and flux of metabolites between tissues. Similar findings were observed in patient biofluids, indicating altered transport and/or flux of molecules involved in energy, fatty acid, nucleotide, and bile acid metabolism. Deficiency of SLC13A5 likely causes a broader state of metabolic dysregulation than previously recognized, particularly regarding lipid synthesis, storage, and metabolism, supporting SLC13A5 deficiency as a lipid disorder. Full article
(This article belongs to the Special Issue I'm Not Dead Yet in Metabolic Regulation)
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14 pages, 2425 KiB  
Article
L-Arginine and Cardioactive Arginine Derivatives as Substrates and Inhibitors of Human and Mouse NaCT/Nact
by Daniela B. Surrer, Martin F. Fromm, Renke Maas and Jörg König
Metabolites 2022, 12(4), 273; https://doi.org/10.3390/metabo12040273 - 22 Mar 2022
Cited by 4 | Viewed by 2178
Abstract
The uptake transporter NaCT (gene symbol SLC13A5) is expressed in liver and brain and important for energy metabolism and brain development. Substrates include tricarboxylic acid cycle intermediates, e.g., citrate and succinate. To gain insights into the substrate spectrum of NaCT, we tested [...] Read more.
The uptake transporter NaCT (gene symbol SLC13A5) is expressed in liver and brain and important for energy metabolism and brain development. Substrates include tricarboxylic acid cycle intermediates, e.g., citrate and succinate. To gain insights into the substrate spectrum of NaCT, we tested whether arginine and the cardioactive L-arginine metabolites asymmetric dimethylarginine (ADMA) and L-homoarginine are also transported by human and mouse NaCT/Nact. Using HEK293 cells overexpressing human or mouse NaCT/Nact we characterized these substances as substrates. Furthermore, inhibition studies were performed using the arginine derivative symmetric dimethylarginine (SDMA), the NaCT transport inhibitor BI01383298, and the prototypic substrate citrate. Arginine and the derivatives ADMA and L-homoarginine were identified as substrates of human and mouse NaCT. Transport of arginine and derivatives mediated by human and mouse NaCT were dose-dependently inhibited by SDMA. Whereas BI01383298 inhibited only human NaCT-mediated citrate uptake, it inhibits the uptake of arginine and derivatives mediated by both human NaCT and mouse Nact. In contrast, the prototypic substrate citrate inhibited the transport of arginine and derivatives mediated only by human NaCT. These results demonstrate a so far unknown link between NaCT/Nact and L-arginine and its cardiovascular important derivatives. Full article
(This article belongs to the Special Issue I'm Not Dead Yet in Metabolic Regulation)
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11 pages, 1786 KiB  
Article
Growth and Overall Health of Patients with SLC13A5 Citrate Transporter Disorder
by Tanya L. Brown, Kimberly L. Nye and Brenda E. Porter
Metabolites 2021, 11(11), 746; https://doi.org/10.3390/metabo11110746 - 29 Oct 2021
Cited by 14 | Viewed by 3078
Abstract
We were interested in elucidating the non-neurologic health of patients with autosomal recessive SLC13A5 Citrate Transporter (NaCT) Disorder. Multiple variants have been reported that cause a loss of transporter activity, resulting in significant neurologic impairment, including seizures, as well as motor and cognitive [...] Read more.
We were interested in elucidating the non-neurologic health of patients with autosomal recessive SLC13A5 Citrate Transporter (NaCT) Disorder. Multiple variants have been reported that cause a loss of transporter activity, resulting in significant neurologic impairment, including seizures, as well as motor and cognitive dysfunction. Additionally, most patients lack tooth enamel (amelogenesis imperfecta). However, patients have not had their overall health and growth described in detail. Here we characterized the non-neurologic health of 15 patients with medical records uploaded to Ciitizen, a cloud-based patient medical records portal. Ciitizen used a query method for data extraction. Overall, the patients’ records suggested a moderate number of gastrointestinal issues related to feeding, reflux, vomiting and weight gain and a diverse number of respiratory complaints. Other organ systems had single or no abnormal diagnoses, including liver, renal and cardiac. Growth parameters were mostly in the normal range during early life, with a trend toward slower growth in the few adolescent patients with data available. The gastrointestinal and pulmonary issues may at least partially be explained by the severity of the neurologic disorder. More data are needed to clarify if growth is impacted during adolescence and if adult patients develop or are protected from non-neurologic disorders. Full article
(This article belongs to the Special Issue I'm Not Dead Yet in Metabolic Regulation)
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Review

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25 pages, 2779 KiB  
Review
Novel Approaches to Studying SLC13A5 Disease
by Adriana S. Beltran
Metabolites 2024, 14(2), 84; https://doi.org/10.3390/metabo14020084 - 24 Jan 2024
Cited by 1 | Viewed by 2630
Abstract
The role of the sodium citrate transporter (NaCT) SLC13A5 is multifaceted and context-dependent. While aberrant dysfunction leads to neonatal epilepsy, its therapeutic inhibition protects against metabolic disease. Notably, insights regarding the cellular and molecular mechanisms underlying these phenomena are limited due to the [...] Read more.
The role of the sodium citrate transporter (NaCT) SLC13A5 is multifaceted and context-dependent. While aberrant dysfunction leads to neonatal epilepsy, its therapeutic inhibition protects against metabolic disease. Notably, insights regarding the cellular and molecular mechanisms underlying these phenomena are limited due to the intricacy and complexity of the latent human physiology, which is poorly captured by existing animal models. This review explores innovative technologies aimed at bridging such a knowledge gap. First, I provide an overview of SLC13A5 variants in the context of human disease and the specific cell types where the expression of the transporter has been observed. Next, I discuss current technologies for generating patient-specific induced pluripotent stem cells (iPSCs) and their inherent advantages and limitations, followed by a summary of the methods for differentiating iPSCs into neurons, hepatocytes, and organoids. Finally, I explore the relevance of these cellular models as platforms for delving into the intricate molecular and cellular mechanisms underlying SLC13A5-related disorders. Full article
(This article belongs to the Special Issue I'm Not Dead Yet in Metabolic Regulation)
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15 pages, 2500 KiB  
Review
Mapping the Metabolic Niche of Citrate Metabolism and SLC13A5
by Fangfang Chen, Hanna Friederike Willenbockel and Thekla Cordes
Metabolites 2023, 13(3), 331; https://doi.org/10.3390/metabo13030331 - 23 Feb 2023
Cited by 1 | Viewed by 3164
Abstract
The small molecule citrate is a key molecule that is synthesized de novo and involved in diverse biochemical pathways influencing cell metabolism and function. Citrate is highly abundant in the circulation, and cells take up extracellular citrate via the sodium-dependent plasma membrane transporter [...] Read more.
The small molecule citrate is a key molecule that is synthesized de novo and involved in diverse biochemical pathways influencing cell metabolism and function. Citrate is highly abundant in the circulation, and cells take up extracellular citrate via the sodium-dependent plasma membrane transporter NaCT encoded by the SLC13A5 gene. Citrate is critical to maintaining metabolic homeostasis and impaired NaCT activity is implicated in metabolic disorders. Though citrate is one of the best known and most studied metabolites in humans, little is known about the consequences of altered citrate uptake and metabolism. Here, we review recent findings on SLC13A5, NaCT, and citrate metabolism and discuss the effects on metabolic homeostasis and SLC13A5-dependent phenotypes. We discuss the “multiple-hit theory” and how stress factors induce metabolic reprogramming that may synergize with impaired NaCT activity to alter cell fate and function. Furthermore, we underline how citrate metabolism and compartmentalization can be quantified by combining mass spectrometry and tracing approaches. We also discuss species-specific differences and potential therapeutic implications of SLC13A5 and NaCT. Understanding the synergistic impact of multiple stress factors on citrate metabolism may help to decipher the disease mechanisms associated with SLC13A5 citrate transport disorders. Full article
(This article belongs to the Special Issue I'm Not Dead Yet in Metabolic Regulation)
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10 pages, 800 KiB  
Review
INDY as a Therapeutic Target for Cardio-Metabolic Disease
by Dominik Pesta and Jens Jordan
Metabolites 2022, 12(3), 244; https://doi.org/10.3390/metabo12030244 - 14 Mar 2022
Cited by 1 | Viewed by 2767
Abstract
Decreased expression of the plasma membrane citrate transporter INDY (acronym I’m Not Dead, Yet) promotes longevity and protects from high-fat diet- and aging-induced metabolic derangements. Preventing citrate import into hepatocytes by different strategies can reduce hepatic triglyceride accumulation and improve hepatic insulin sensitivity, [...] Read more.
Decreased expression of the plasma membrane citrate transporter INDY (acronym I’m Not Dead, Yet) promotes longevity and protects from high-fat diet- and aging-induced metabolic derangements. Preventing citrate import into hepatocytes by different strategies can reduce hepatic triglyceride accumulation and improve hepatic insulin sensitivity, even in the absence of effects on body composition. These beneficial effects likely derive from decreased hepatic de novo fatty acid biosynthesis as a result of reduced cytoplasmic citrate levels. While in vivo and in vitro studies show that inhibition of INDY prevents intracellular lipid accumulation, body weight is not affected by organ-specific INDY inhibition. Besides these beneficial metabolic effects, INDY inhibition may also improve blood pressure control through sympathetic nervous system inhibition, partly via reduced peripheral catecholamine synthesis. These effects make INDY a promising candidate with bidirectional benefits for improving both metabolic disease and blood pressure control. Full article
(This article belongs to the Special Issue I'm Not Dead Yet in Metabolic Regulation)
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14 pages, 1810 KiB  
Review
Molecular Mechanisms of the SLC13A5 Gene Transcription
by Zhihui Li and Hongbing Wang
Metabolites 2021, 11(10), 706; https://doi.org/10.3390/metabo11100706 - 15 Oct 2021
Cited by 8 | Viewed by 3583
Abstract
Citrate is a crucial energy sensor that plays a central role in cellular metabolic homeostasis. The solute carrier family 13 member 5 (SLC13A5), a sodium-coupled citrate transporter highly expressed in the mammalian liver with relatively low levels in the testis and brain, imports [...] Read more.
Citrate is a crucial energy sensor that plays a central role in cellular metabolic homeostasis. The solute carrier family 13 member 5 (SLC13A5), a sodium-coupled citrate transporter highly expressed in the mammalian liver with relatively low levels in the testis and brain, imports citrate from extracellular spaces into the cells. The perturbation of SLC13A5 expression and/or activity is associated with non-alcoholic fatty liver disease, obesity, insulin resistance, cell proliferation, and early infantile epileptic encephalopathy. SLC13A5 has been proposed as a promising therapeutic target for the treatment of these metabolic disorders. In the liver, the inductive expression of SLC13A5 has been linked to several xenobiotic receptors such as the pregnane X receptor and the aryl hydrocarbon receptor as well as certain hormonal and nutritional stimuli. Nevertheless, in comparison to the heightened interest in understanding the biological function and clinical relevance of SLC13A5, studies focusing on the regulatory mechanisms of SLC13A5 expression are relatively limited. In this review, we discuss the current advances in our understanding of the molecular mechanisms by which the expression of SLC13A5 is regulated. We expect this review will provide greater insights into the regulation of the SLC13A5 gene transcription and the signaling pathways involved therein. Full article
(This article belongs to the Special Issue I'm Not Dead Yet in Metabolic Regulation)
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14 pages, 1166 KiB  
Review
The Role of Citrate Transporter INDY in Metabolism and Stem Cell Homeostasis
by Kavitha Kannan and Blanka Rogina
Metabolites 2021, 11(10), 705; https://doi.org/10.3390/metabo11100705 - 15 Oct 2021
Cited by 8 | Viewed by 3501
Abstract
I’m Not Dead Yet (Indy) is a fly gene that encodes a homologue of mammalian SLC13A5 plasma membrane citrate transporter. Reducing expression of Indy gene in flies, and its homologues in worms, extends longevity. Indy reduction in flies, worms, mice and [...] Read more.
I’m Not Dead Yet (Indy) is a fly gene that encodes a homologue of mammalian SLC13A5 plasma membrane citrate transporter. Reducing expression of Indy gene in flies, and its homologues in worms, extends longevity. Indy reduction in flies, worms, mice and rats affects metabolism by regulating the levels of cytoplasmic citrate, inducing a state similar to calorie restriction. Changes include lower lipid levels, increased insulin sensitivity, increased mitochondrial biogenesis, and prevention of weight gain, among others. The INDY protein is predominantly expressed in fly metabolic tissues: the midgut, fat body and oenocytes. Changes in fly midgut metabolism associated with reduced Indy gene activity lead to preserved mitochondrial function and reduced production of reactive oxygen species. All these changes lead to preserved intestinal stem cell homeostasis, which has a key role in maintaining intestinal epithelium function and enhancing fly healthspan and lifespan. Indy gene expression levels change in response to caloric content of the diet, inflammation and aging, suggesting that INDY regulates metabolic adaptation to nutrition or energetic requirements by controlling citrate levels. Full article
(This article belongs to the Special Issue I'm Not Dead Yet in Metabolic Regulation)
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14 pages, 3168 KiB  
Review
Drosophila INDY and Mammalian INDY: Major Differences in Transport Mechanism and Structural Features despite Mostly Similar Biological Functions
by Valeria Jaramillo-Martinez, Sathish Sivaprakasam, Vadivel Ganapathy and Ina L. Urbatsch
Metabolites 2021, 11(10), 669; https://doi.org/10.3390/metabo11100669 - 29 Sep 2021
Cited by 5 | Viewed by 2634
Abstract
INDY (I’m Not Dead Yet) is a plasma membrane transporter for citrate, first identified in Drosophila. Partial deficiency of INDY extends lifespan in this organism in a manner similar to that of caloric restriction. The mammalian counterpart (NaCT/SLC13A5) also transports citrate. In [...] Read more.
INDY (I’m Not Dead Yet) is a plasma membrane transporter for citrate, first identified in Drosophila. Partial deficiency of INDY extends lifespan in this organism in a manner similar to that of caloric restriction. The mammalian counterpart (NaCT/SLC13A5) also transports citrate. In mice, it is the total, not partial, absence of the transporter that leads to a metabolic phenotype similar to that caloric restriction; however, there is evidence for subtle neurological dysfunction. Loss-of-function mutations in SLC13A5 (solute carrier gene family 13, member A5) occur in humans, causing a recessive disease, with severe clinical symptoms manifested by neonatal seizures and marked disruption in neurological development. Though both Drosophila INDY and mammalian INDY transport citrate, the translocation mechanism differs, the former being a dicarboxylate exchanger for the influx of citrate2− in exchange for other dicarboxylates, and the latter being a Na+-coupled uniporter for citrate2−. Their structures also differ as evident from only ~35% identity in amino acid sequence and from theoretically modeled 3D structures. The varied biological consequences of INDY deficiency across species, with the beneficial effects predominating in lower organisms and detrimental effects overwhelming in higher organisms, are probably reflective of species-specific differences in tissue expression and also in relative contribution of extracellular citrate to metabolic pathways in different tissues Full article
(This article belongs to the Special Issue I'm Not Dead Yet in Metabolic Regulation)
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