NaCT (<i>SLC13A5</i>) facilitates citrate import and metabolism under nutrient-limited conditions

Kumar, Avi; Cordes, Thekla; Thalacker‐Mercer, Anna; Pajor, Ana M.; Murphy, Anne N.; Metallo, Christian M.

doi:10.1101/2021.04.08.439058

Cited by 3 publications

(4 citation statements)

References 64 publications

(71 reference statements)

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“…In contrast, maximum respiratory capacity and reserve capacity were upregulated by 28.2% and 351.2%, respectively (5a -/-;5b -/-), whereas proton leaks were unchanged (Fig. S5A-C), consistent with other reports whereby the loss of citrate uptake by cells due to SLC13A5 mutations causes changes in cellular metabolism (42)(43)(44)(45).…”

Section: Resultssupporting

confidence: 90%

Epileptic phenotypes inslc13a5loss-of-function zebrafish are rescued by blocking NMDA receptor signaling

Dogra,

Phan,

Gavrilovici

et al. 2024

Preprint

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SLC13A5 encodes a citrate transporter highly expressed in the brain important for regulating intra- and extracellular citrate levels. Mutations in this gene cause a rare infantile epilepsy characterized by lifelong seizures, developmental delays, behavioral deficits, poor motor progression, and language impairments. SLC13A5 individuals respond poorly to treatment options; yet drug discovery programs are limited due to a paucity of animal models that phenocopy human symptoms. Here, we used CRISPR/Cas9 to create loss-of-function mutations in slc13a5a and slc13a5b, the zebrafish paralogs to human SLC13A5. slc13a5 mutant larvae showed cognitive dysfunction and sleep disturbances, consistent with SLC13A5 individuals. These mutants also exhibited fewer neurons and a concomitant increase in apoptosis across the optic tectum, a region important for sensory processing. slc13a5 mutants displayed hallmark features of epilepsy, including an imbalance in glutamatergic and GABAergic excitatory-inhibitory gene expression, disrupted neurometabolism, and neuronal hyperexcitation as measured in vivo by extracellular field recordings and live calcium imaging. Mechanistically, we tested the involvement of NMDA signaling in slc13a5 mutant epilepsy-like phenotypes. Slc13a5 protein co-localizes with excitatory NMDA receptors in wild-type zebrafish and blocking NMDA receptors in slc13a5 mutant larvae rescued bioenergetics, hyperexcitable calcium events, and behavioral defects. These data provide empirical evidence in support of the hypothesis that excess extracellular citrate over-chelates the ions needed to regulate NMDA receptor function, leading to sustained channel opening and an exaggerated excitatory response that manifests as seizures. These data show the utility of slc13a5 mutant zebrafish for studying SLC13A5 epilepsy and open new avenues for drug discovery.

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Section: Resultssupporting

confidence: 90%

Epileptic phenotypes inslc13a5loss-of-function zebrafish are rescued by blocking NMDA receptor signaling

Dogra,

Phan,

Gavrilovici

et al. 2024

Preprint

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“…This adds to the body of data on five patients with elevated citrate levels previously published ( Bainbridge et al, 2017 ). Interestingly, SLC13A5−/− rodent models and in vitro models harboring patient mutations in the SLC13A5 gene all lacked citrate transport and reported elevated citrate levels ( Hardies et al, 2015 ; Klotz et al, 2016 ; Pajor et al, 2016 ; Selch et al, 2018 ; Henke et al, 2020 ; Kumar et al, 2021 ; Sauer et al, 2021 ; Dirckx et al, 2022 ). The data highlight that serum citrate level elevation might be used as a biomarker for the disorder in both mice and humans.…”

Section: Discussionmentioning

confidence: 99%

“…The SLC13A5 gene encodes a sodium-dependent citrate transporter protein, NaCT, that is highly expressed in the liver, brain, bone, teeth, and reproductive organs, and in other organs at much lower levels ( Pajor et al, 2001 ; Inoue, et al, 2002 ; Gopal et al, 2007 ; Kumar et al, 2021 ). Pathogenic variants in NaCT confer an autosomal recessive risk for epilepsy, developmental disability, and a constellation of other phenotypic abnormalities.…”

Section: Introductionmentioning

confidence: 99%

Characterizing a rare neurogenetic disease, SLC13A5 citrate transporter disorder, utilizing clinical data in a cloud-based medical record collection system

Spelbrink

Brown²,

Brimble

et al. 2023

Front. Genet.

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Introduction: SLC13A5 citrate transporter disorder is a rare autosomal recessive genetic disease that has a constellation of neurologic symptoms. To better characterize the neurologic and clinical laboratory phenotype, we utilized patient medical records collected by Ciitizen, an Invitae company, with support from the TESS Research Foundation.Methods: Medical records for 15 patients with a suspected genetic and clinical diagnosis of SLC13A5 citrate transporter disorder were collected by Ciitizen, an Invitae company. Genotype, clinical phenotypes, and laboratory data were extracted and analyzed.Results: The 15 patients reported all had epilepsy and global developmental delay. Patients continued to attain motor milestones, though much later than their typically developing peers. Clinical diagnoses support abnormalities in communication, and low or mixed tone with several movement disorders, including, ataxia and dystonia. Serum citrate was elevated in the 3 patients in whom it was measured; other routine laboratory studies assessing renal, liver and blood function had normal values or no consistent abnormalities. Many electroencephalograms (EEGs) were performed (1 to 35 per patient), and most but not all were abnormal, with slowing and/or epileptiform activity. Fourteen of the patients had one or more brain magnetic resonance imaging (MRI) reports: 7 patients had at least one normal brain MRI, but not with any consistent findings except white matter signal changes.Discussion: These results show that in addition to the epilepsy phenotype, SLC13A5 citrate transporter disorder impacts global development, with marked abnormalities in motor abilities, tone, coordination, and communication skills. Further, utilizing cloud-based medical records allows industry, academic, and patient advocacy group collaboration to provide preliminary characterization of a rare genetic disorder. Additional characterization of the neurologic phenotype will be critical to future study and developing treatment for this and related rare genetic disorders.

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“…The plasma membrane citrate transporter (PMCT, SLC13A5), mitochondrial citrate carrier (CIC, SLC25A1), and ATP-dependent citrate lyase (ACLY) play pivotal roles in maintaining citrate homeostasis (Kumar et al, 2021;Mosaoa et al, 2021). Increasing evidence supports their potential as targets for treating NAFLD.…”

Section: Introductionmentioning

confidence: 99%

Bempedoic Acid Unveils Therapeutic Potential in Non-Alcoholic Fatty Liver Disease: Suppression of the Hepatic PXR-SLC13A5/ACLY Signaling Axis

Sun,

Guo,

et al. 2023

Drug Metab Dispos

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The hepatic SLC13A5/SLC25A1-ACLY signaling pathway, responsible for maintaining the citrate homeostasis, plays a crucial role in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Bempedoic acid (BA), an ACLY inhibitor commonly used for managing hypercholesterolemia, has shown promising results in addressing hepatic steatosis. This study aimed to elucidate the intricate relationships in processes of hepatic lipogenesis among SLC13A5, SLC25A1 and ACLY, and to examine the therapeutic potential of BA in NAFLD, providing insights into its underlying mechanism. In murine primary hepatocytes and HepG2 cells, the silencing or pharmacological inhibition of SLC25A1/ACLY resulted in significant upregulation of SLC13A5 transcription and activity. This increase in SLC13A5 activity subsequently led to enhanced lipogenesis, indicating a compensatory role of SLC13A5 when the SLC25A1/ACLY pathway was inhibited. However, BA effectively counteracted this upregulation, reduced lipid accumulation, and ameliorated various biomarkers of NAFLD. The disease-modifying effects of BA were further confirmed in NAFLD mice. Mechanistic investigations revealed that BA could reverse the elevated transcription levels of SLC13A5 and ACLY, and the subsequent lipogenesis induced by PXR activation in vitro and in vivo.Importantly, this effect was diminished when PXR was knocked down, suggesting the involvement of the hepatic PXR-SLC13A5/ACLY signaling axis in the mechanism of BA action. In conclusions, SLC13A5-mediated extracellular citrate influx emerges as an alternative pathway to SLC25A1/ACLY in the regulation of lipogenesis in hepatocytes, BA exhibits therapeutic potential in NAFLD by suppressing the hepatic

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NaCT (SLC13A5) facilitates citrate import and metabolism under nutrient-limited conditions

Cited by 3 publications

References 64 publications

Epileptic phenotypes inslc13a5loss-of-function zebrafish are rescued by blocking NMDA receptor signaling

Epileptic phenotypes inslc13a5loss-of-function zebrafish are rescued by blocking NMDA receptor signaling

Characterizing a rare neurogenetic disease, SLC13A5 citrate transporter disorder, utilizing clinical data in a cloud-based medical record collection system

Bempedoic Acid Unveils Therapeutic Potential in Non-Alcoholic Fatty Liver Disease: Suppression of the Hepatic PXR-SLC13A5/ACLY Signaling Axis

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