SLC25A38 is required for mitochondrial pyridoxal 5’-phosphate (PLP) accumulation

Izabella A. Pena (), Jeffrey S. Shi, Sarah M. Chang, Jason Yang, Samuel Block, Charles H. Adelmann, Heather R. Keys, Preston Ge, Shveta Bathla, Isabella H. Witham, Grzegorz Sienski, Angus C. Nairn, David M. Sabatini, Caroline A. Lewis, Nora Kory, Matthew G. Vander Heiden and Myriam Heiman ()
Additional contact information
Izabella A. Pena: MIT
Jeffrey S. Shi: MIT
Sarah M. Chang: MIT
Jason Yang: MIT
Samuel Block: MIT
Charles H. Adelmann: MIT
Heather R. Keys: Whitehead Institute for Biomedical Research
Preston Ge: MIT
Shveta Bathla: Yale School of Medicine
Isabella H. Witham: MIT
Grzegorz Sienski: Whitehead Institute for Biomedical Research
Angus C. Nairn: Yale School of Medicine
David M. Sabatini: IOCB
Caroline A. Lewis: Whitehead Institute for Biomedical Research
Nora Kory: Harvard T.H. Chan School of Public Health
Matthew G. Vander Heiden: MIT
Myriam Heiman: MIT

Nature Communications, 2025, vol. 16, issue 1, 1-19

Abstract: Abstract Many essential proteins require pyridoxal 5’-phosphate, the active form of vitamin B6, as a cofactor for their activity. These include enzymes important for amino acid metabolism, one-carbon metabolism, polyamine synthesis, erythropoiesis, and neurotransmitter metabolism. A third of all mammalian pyridoxal 5’-phosphate-dependent enzymes are localized in the mitochondria; however, the molecular machinery involved in the regulation of mitochondrial pyridoxal 5’-phosphate levels in mammals remains unknown. In this study, we used a genome-wide CRISPR interference screen in erythroleukemia cells and organellar metabolomics to identify the mitochondrial inner membrane protein SLC25A38 as a regulator of mitochondrial pyridoxal 5’-phosphate. Loss of SLC25A38 causes depletion of mitochondrial, but not cellular, pyridoxal 5’-phosphate, and impairs cellular proliferation under both physiological and low vitamin B6 conditions. Metabolic changes associated with SLC25A38 loss suggest impaired mitochondrial pyridoxal 5’-phosphate-dependent enzymatic reactions, including serine to glycine conversion catalyzed by serine hydroxymethyltransferase-2 as well as ornithine aminotransferase. The proliferation defect of SLC25A38-null K562 cells in physiological and low vitamin B6 media can be explained by the loss of serine hydroxymethyltransferase-2-dependent production of one-carbon units and downstream de novo nucleotide synthesis. Our work points to a role for SLC25A38 in mitochondrial pyridoxal 5’-phosphate accumulation and provides insights into the pathology of congenital sideroblastic anemia.

Date: 2025
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DOI: 10.1038/s41467-025-56130-3

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