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Abstract: TH-PO381

SLC25A48 Is a Human Mitochondrial Choline Transporter

Session Information

Category: Development, Stem Cells, and Regenerative Medicine

  • 600 Development, Stem Cells, and Regenerative Medicine

Authors

  • Patil, Suraj Dasharath, Department of Medicine IV - Nephrology and Primary Care, Faculty of Medicine and Medical Center, University of Freiburg, Freiburg im Breisgau, Germany
  • Borisov, Oleg, Institute of Genetic Epidemiology, Faculty of Medicine and Medical Center–University of Freiburg, Freiburg im Breisgau, Germany
  • Scherer, Nora, Institute of Genetic Epidemiology, Faculty of Medicine and Medical Center–University of Freiburg, Freiburg im Breisgau, Germany
  • Wirth, Christophe, Institute of Biochemistry and Molecular Biology, ZBMZ, Faculty of Medicine, University of Freiburg, Freiburg im Breisgau, Germany
  • Schlosser, Pascal, Department of Medicine IV - Nephrology and Primary Care, Faculty of Medicine and Medical Center, University of Freiburg, Freiburg im Breisgau, Germany
  • Wuttke, Matthias, Institute of Genetic Epidemiology, Faculty of Medicine and Medical Center–University of Freiburg, Freiburg im Breisgau, Germany
  • Hannibal, Luciana, Laboratory of Clinical Biochemistry and Metabolism, Department of General Pediatrics, Adolescent Medicine and Neonatology, Faculty of Medicine, Medical Center, University of Freiburg, Freiburg im Breisgau, Germany
  • Eckardt, Kai-Uwe, Department of Nephrology and Medical Intensive Care, Charité–Universitätsmedizin Berlin, Berlin, Germany
  • Neubauer, Bjoern, Department of Medicine IV - Nephrology and Primary Care, Faculty of Medicine and Medical Center, University of Freiburg, Freiburg im Breisgau, Germany
  • Kottgen, Anna, Institute of Genetic Epidemiology, Faculty of Medicine and Medical Center–University of Freiburg, Freiburg im Breisgau, Germany
  • Kottgen, Michael, Department of Medicine IV - Nephrology and Primary Care, Faculty of Medicine and Medical Center, University of Freiburg, Freiburg im Breisgau, Germany
Background

Choline has important physiological functions as a precursor for essential cell components and signalling molecules including phospholipids and the neurotransmitter acetylcholine. Choline is a water-soluble charged molecule and therefore requires transport proteins to cross biological membranes. Its transport across phospholipid bilayer membranes remains incompletely understood. Using metabolite genome-wide association studies, we uncovered that common variants of human SLC25A48 are associated with altered choline levels in plasma and urine supporting the hypothesis that the orphan solute carrier SLC25A48 may be a choline transporter.

Methods

We used mGWAS, mitochondrial isolation, radioactive uptake assay, LC/MS, immunofluorescence, western blotting, qPCR, and structural modelling.

Results

Overexpression of SLC25A48 revealed mitochondrial localization and increased choline uptake in human epithelial cells compared to control cells. We identified rare putatively damaging variants in SLC25A48 in humans, which showed an association with elevated urine and plasma choline levels. These mutations exhibited impaired choline transport into mitochondria. Through the combination of immunofluorescence, western blotting, and structural modelling, we revealed distinct mechanisms causing functional impairment of specific damaging variants in SLC25A48.

Conclusion

In summary, we showed that the physiological function of SLC25A48 in humans is choline import into mitochondria. The deorphanization of SLC25A48 defines its molecular function in humans and enables future studies addressing its role in health and disease.

Funding

  • Government Support – Non-U.S.