SLC25A38 is required for mitochondrial pyridoxal 5’-phosphate (PLP) accumulation
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 mam...
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| Format: | Article |
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Nature Portfolio
2025-01-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-56130-3 |
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| author | 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 Myriam Heiman |
| author_facet | 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 Myriam Heiman |
| author_sort | Izabella A. Pena |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-d30b229f3e3849fdad8548619b930e9e |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-d30b229f3e3849fdad8548619b930e9e2025-01-26T12:41:07ZengNature PortfolioNature Communications2041-17232025-01-0116111910.1038/s41467-025-56130-3SLC25A38 is required for mitochondrial pyridoxal 5’-phosphate (PLP) accumulationIzabella A. Pena0Jeffrey S. Shi1Sarah M. Chang2Jason Yang3Samuel Block4Charles H. Adelmann5Heather R. Keys6Preston Ge7Shveta Bathla8Isabella H. Witham9Grzegorz Sienski10Angus C. Nairn11David M. Sabatini12Caroline A. Lewis13Nora Kory14Matthew G. Vander Heiden15Myriam Heiman16The Picower Institute for Learning and Memory, MITThe Picower Institute for Learning and Memory, MITDepartment of Biology, MITDepartment of Biology, MITDepartment of Biology, MITDepartment of Biology, MITWhitehead Institute for Biomedical ResearchThe Picower Institute for Learning and Memory, MITDepartment of Psychiatry, Yale School of MedicineThe Picower Institute for Learning and Memory, MITWhitehead Institute for Biomedical ResearchDepartment of Psychiatry, Yale School of MedicineInstitute of Organic Chemistry and Biochemistry, IOCBWhitehead Institute for Biomedical ResearchHarvard T.H. Chan School of Public HealthDepartment of Biology, MITThe Picower Institute for Learning and Memory, MITAbstract 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.https://doi.org/10.1038/s41467-025-56130-3 |
| spellingShingle | 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 Myriam Heiman SLC25A38 is required for mitochondrial pyridoxal 5’-phosphate (PLP) accumulation Nature Communications |
| title | SLC25A38 is required for mitochondrial pyridoxal 5’-phosphate (PLP) accumulation |
| title_full | SLC25A38 is required for mitochondrial pyridoxal 5’-phosphate (PLP) accumulation |
| title_fullStr | SLC25A38 is required for mitochondrial pyridoxal 5’-phosphate (PLP) accumulation |
| title_full_unstemmed | SLC25A38 is required for mitochondrial pyridoxal 5’-phosphate (PLP) accumulation |
| title_short | SLC25A38 is required for mitochondrial pyridoxal 5’-phosphate (PLP) accumulation |
| title_sort | slc25a38 is required for mitochondrial pyridoxal 5 phosphate plp accumulation |
| url | https://doi.org/10.1038/s41467-025-56130-3 |
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