SLC16A9

Last update 08 May 2025

Basic Info

Synonyms

C10orf36, chromosome 10 open reading frame 36, FLJ43803

+ [9]

Introduction

Extracellular pH-and Na(+)-sensitive low-affinity creatine transporter (PubMed:31784090). Functions also as a pH-independent carnitine efflux transporter (PubMed:21886157).

100 Clinical Results associated with SLC16A9

100 Translational Medicine associated with SLC16A9

0 Patents (Medical) associated with SLC16A9

Literatures (Medical) associated with SLC16A9

01 Mar 2025·The FEBS Journal

A creatine efflux transporter in oligodendrocytes

Article

Author: Fischer, Dietmar ; Flögel, Svenja ; Strater, Miriam ; Gründemann, Dirk

Creatine is essential for ATP regeneration in energy‐demanding cells. Creatine deficiency results in severe neurodevelopmental impairments. In the brain, creatine is synthesized locally by oligodendrocytes to supply neighboring neurons. Neuronal uptake is mediated by SLC6A8. However, it is still unknown how creatine is released from the producing cells. Here, we investigated the function of the transporter SLC22A15, which exhibits strikingly high amino acid sequence conservation. The release of substrates from 293 cells via heterologously expressed human and rat SLC22A15 was analyzed by mass spectrometry. A number of zwitterions were identified as substrates, with similar efflux transport efficiencies. However, in absolute numbers, the efflux of creatine far outweighed all other substrates. In contrast to the permanent creatine efflux mediated by SLC16A12 and SLC16A9, SLC22A15 was, by default, completely inactive, thereby preventing continuous creatine loss from producing cells. External substrates such as guanidinoacetic acid, GABA, or MPP+ trigger creatine release through a one‐to‐one exchange. Human and mouse mRNA profiles indicate that SLC22A15 expression is highest in oligodendrocytes and bone marrow. Single‐cell RNA sequencing data substantiate the hypothesis that SLC22A15 depends on high intracellular creatine concentrations: high SLC22A15 counts, as in oligodendrocytes and macrophages, correlate with high counts of the creatine synthesis enzymes AGAT and GAMT in both humans and mice, whereas in proximal tubular cells and hepatocytes, AGAT counts are high, but SLC22A15 is absent. Our findings establish SLC22A15 as the pivotal transporter for controlled creatine release from oligodendrocytes, filling a critical gap in understanding creatine metabolism in the brain.

13 Jun 2024·Blood

Genetic regulation of carnitine metabolism controls lipid damage repair and aging RBC hemolysis in vivo and in vitro

Article

Author: Kleinman, Steve ; Busch, Michael P. ; Key, Alicia ; Stephenson, Daniel ; Stone, Mars ; Roubinian, Nareg ; Page, Grier P. ; Deng, Xutao ; Casimir, Madeleine ; Dzieciatkowska, Monika ; Zimring, James C. ; Dussiot, Michaël ; Keele, Gregory R. ; D’Alessandro, Angelo ; Hay, Ariel ; Reisz, Julie A. ; Hansen, Kirk C. ; Amireault, Pascal ; Norris, Philip J. ; Earley, Eric J. ; Nemkov, Travis ; Arduini, Arduino ; Spitalnik, Steven L. ; Churchill, Gary A.

AbstractRecent large-scale multiomics studies suggest that genetic factors influence the chemical individuality of donated blood. To examine this concept, we performed metabolomics analyses of 643 blood units from volunteers who donated units of packed red blood cells (RBCs) on 2 separate occasions. These analyses identified carnitine metabolism as the most reproducible pathway across multiple donations from the same donor. We also measured l-carnitine and acyl-carnitines in 13 091 packed RBC units from donors in the Recipient Epidemiology and Donor Evaluation study. Genome-wide association studies against 879 000 polymorphisms identified critical genetic factors contributing to interdonor heterogeneity in end-of-storage carnitine levels, including common nonsynonymous polymorphisms in genes encoding carnitine transporters (SLC22A16, SLC22A5, and SLC16A9); carnitine synthesis (FLVCR1 and MTDH) and metabolism (CPT1A, CPT2, CRAT, and ACSS2), and carnitine-dependent repair of lipids oxidized by ALOX5. Significant associations between genetic polymorphisms on SLC22 transporters and carnitine pools in stored RBCs were validated in 525 Diversity Outbred mice. Donors carrying 2 alleles of the rs12210538 SLC22A16 single-nucleotide polymorphism exhibited the lowest l-carnitine levels, significant elevations of in vitro hemolysis, and the highest degree of vesiculation, accompanied by increases in lipid peroxidation markers. Separation of RBCs by age, via in vivo biotinylation in mice, and Percoll density gradients of human RBCs, showed age-dependent depletions of l-carnitine and acyl-carnitine pools, accompanied by progressive failure of the reacylation process after chemically induced membrane lipid damage. Supplementation of stored murine RBCs with l-carnitine boosted posttransfusion recovery, suggesting this could represent a viable strategy to improve RBC storage quality.

02 May 2024·Cancer Research

A Metabolic–Epigenetic Mechanism Directs Cell Fate and Therapeutic Sensitivity in Breast Cancer

Article

Author: Goldstein, Andrew S. ; Bernard, Matthew J.

AbstractOver the past decade, studies have increasingly shed light on a reciprocal relationship between cellular metabolism and cell fate, meaning that a cell's lineage both drives and is governed by its specific metabolic features. A recent study by Zhang and colleagues, published in Cell Metabolism, describes a novel metabolic–epigenetic regulatory axis that governs lineage identity in triple-negative breast cancer (TNBC). Among the key findings, the authors demonstrate that the metabolic enzyme pyruvate kinase M2 (PKM2) directly binds to the histone methyltransferase enhancer of zeste homolog 2 (EZH2) in the nucleus to silence expression of a set of genes that includes the mitochondrial carnitine transporter SLC16A9. Perturbation of this metabolic–epigenetic regulatory mechanism induces a metabolic shift away from glycolysis and toward fatty acid oxidation. The ensuing influx of carnitine facilitates the deposition of the activating epigenetic mark H3K27Ac onto the promoter of GATA3, driving a committed luminal lineage state. Importantly, this metabolic–epigenetic axis represents a potentially targetable vulnerability for the treatment of TNBC, a subtype that currently lacks effective therapeutic strategies. These findings lend further support for the paradigm shift underlying our understanding of cancer metabolism: that a cellular fuel source functions not only to provide energy but also to direct the epigenetic regulation of cell fate.

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SLC16A9

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