The membrane transporter SLC25A48 enables transport of choline into human mitochondria

Suraj Patil; Oleg Borisov; Nora Scherer; Christophe Wirth; Pascal Schlosser; Matthias Wuttke; Sandra Ehret; Luciana Hannibal; Kai-Uwe Eckardt; Carola Hunte; Björn Neubauer; Anna Köttgen; Michael Köttgen

doi:10.1016/j.kint.2024.06.022

The membrane transporter SLC25A48 enables transport of choline into human mitochondria

Kidney Int. 2024 Jul 29:S0085-2538(24)00526-X. doi: 10.1016/j.kint.2024.06.022. Online ahead of print.

Authors

Affiliations

¹ Department of Medicine IV-Nephrology and Primary Care, Faculty of Medicine and Medical Center, University of Freiburg, Freiburg, Germany; Institute of Genetic Epidemiology, Faculty of Medicine and Medical Center-University of Freiburg, Freiburg, Germany; Spemann Graduate School of Biology and Medicine (SGBM), University of Freiburg, Freiburg, Germany; Faculty of Biology, University of Freiburg, Freiburg, Germany.
² Institute of Genetic Epidemiology, Faculty of Medicine and Medical Center-University of Freiburg, Freiburg, Germany.
³ Institute of Genetic Epidemiology, Faculty of Medicine and Medical Center-University of Freiburg, Freiburg, Germany; Spemann Graduate School of Biology and Medicine (SGBM), University of Freiburg, Freiburg, Germany.
⁴ Institute of Biochemistry and Molecular Biology, ZBMZ, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
⁵ Institute of Genetic Epidemiology, Faculty of Medicine and Medical Center-University of Freiburg, Freiburg, Germany; CIBSS-Centre for Integrative Biological Signalling Studies, University of Freiburg, Freiburg, Germany.
⁶ Laboratory of Clinical Biochemistry and Metabolism, Department of General Pediatrics, Adolescent Medicine and Neonatology, Faculty of Medicine, Medical Center, University of Freiburg, Freiburg, Germany.
⁷ CIBSS-Centre for Integrative Biological Signalling Studies, University of Freiburg, Freiburg, Germany; Laboratory of Clinical Biochemistry and Metabolism, Department of General Pediatrics, Adolescent Medicine and Neonatology, Faculty of Medicine, Medical Center, University of Freiburg, Freiburg, Germany.
⁸ Department of Nephrology and Medical Intensive Care, Charité-Universitätsmedizin Berlin, Berlin, Germany; Department of Nephrology and Hypertension, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
⁹ Institute of Biochemistry and Molecular Biology, ZBMZ, Faculty of Medicine, University of Freiburg, Freiburg, Germany; CIBSS-Centre for Integrative Biological Signalling Studies, University of Freiburg, Freiburg, Germany; BIOSS-Centre for Biological Signalling Studies, University of Freiburg, Freiburg, Germany.
¹⁰ Department of Medicine IV-Nephrology and Primary Care, Faculty of Medicine and Medical Center, University of Freiburg, Freiburg, Germany.
¹¹ Institute of Genetic Epidemiology, Faculty of Medicine and Medical Center-University of Freiburg, Freiburg, Germany; CIBSS-Centre for Integrative Biological Signalling Studies, University of Freiburg, Freiburg, Germany. Electronic address: [email protected].
¹² Department of Medicine IV-Nephrology and Primary Care, Faculty of Medicine and Medical Center, University of Freiburg, Freiburg, Germany; CIBSS-Centre for Integrative Biological Signalling Studies, University of Freiburg, Freiburg, Germany. Electronic address: [email protected].

PMID: 39084256
DOI: 10.1016/j.kint.2024.06.022

Abstract

Choline has important physiological functions as a precursor for essential cell components, signaling molecules, phospholipids, and the neurotransmitter acetylcholine. Choline is a water-soluble charged molecule requiring transport proteins to cross biological membranes. Although transporters continue to be identified, membrane transport of choline is incompletely understood and knowledge about choline transport into intracellular organelles such as mitochondria remains limited. Here we show that SLC25A48 imports choline into human mitochondria. Human loss-of-function mutations in SLC25A48 show impaired choline transport into mitochondria and are associated with elevated urine and plasma choline levels. Thus, our studies may have implications for understanding and treating conditions related to choline metabolism.

Keywords: SLC25A48; choline transport; deorphanization; mGWAS; mitochondria.