This study presents a multiomic Gene–Metabolite Association Prediction (GeneMAP) platform for discovery of metabolic gene function and identifies SLC25A48 as a mediator of mitochondrial choline import.

Khan et al. outline key challenges in studying solute carrier (SLC) proteins, critical gatekeepers of metabolism, and propose directions for understanding their functions in physiology and disease.

Khan et al. apply machine learning to identify substrates of UNC93A, SLC45A4, and SLC25A45. Biochemical assays and in vivo metabolite tracing establish SLC25A45 as a key mediator of mitochondrial impo...

Dias et al. discover that the orphan solute carrier protein, SLC25A45, enables mitochondrial import of methylated amino acids. SLC25A45-dependent mitochondrial uptake of trimethyllysine drives carnitine biosynthesis. Mutation near its C terminus impacts SLC25A45 proteostasis and associates with altered methylated amino acid levels in human plasma.

Khan et al. apply machine learning to identify substrates of UNC93A, SLC45A4, and SLC25A45. Biochemical assays and in vivo metabolite tracing establish SLC25A45 as a key mediator of mitochondrial import of methylated amino acids and carnitine synthesis. Loss of Slc25a45 impairs fasting response by limiting carnitine availability for β-oxidation.

Solute carrier (SLC) proteins play critical roles in maintaining cellular and organismal homeostasis by transporting small molecules and ions. Despite…