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The malate-aspartate shuttle is important for de novo serine biosynthesis.
Broeks, Melissa H; Meijer, Nils W F; Westland, Denise; Bosma, Marjolein; Gerrits, Johan; German, Hannah M; Ciapaite, Jolita; van Karnebeek, Clara D M; Wanders, Ronald J A; Zwartkruis, Fried J T; Verhoeven-Duif, Nanda M; Jans, Judith J M.
Afiliación
  • Broeks MH; Department of Genetics, Section Metabolic Diagnostics, University Medical Center Utrecht, Lundlaan 6, 3584 EA Utrecht, the Netherlands. Electronic address: m.h.broeks-3@umcutrecht.nl.
  • Meijer NWF; Department of Genetics, Section Metabolic Diagnostics, University Medical Center Utrecht, Lundlaan 6, 3584 EA Utrecht, the Netherlands.
  • Westland D; Department of Genetics, Section Metabolic Diagnostics, University Medical Center Utrecht, Lundlaan 6, 3584 EA Utrecht, the Netherlands.
  • Bosma M; Department of Genetics, Section Metabolic Diagnostics, University Medical Center Utrecht, Lundlaan 6, 3584 EA Utrecht, the Netherlands.
  • Gerrits J; Department of Genetics, Section Metabolic Diagnostics, University Medical Center Utrecht, Lundlaan 6, 3584 EA Utrecht, the Netherlands.
  • German HM; Department of Genetics, Section Metabolic Diagnostics, University Medical Center Utrecht, Lundlaan 6, 3584 EA Utrecht, the Netherlands.
  • Ciapaite J; Department of Genetics, Section Metabolic Diagnostics, University Medical Center Utrecht, Lundlaan 6, 3584 EA Utrecht, the Netherlands.
  • van Karnebeek CDM; Emma Center for Personalized Medicine, Departments of Pediatrics and Human Genetics, Amsterdam University Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands; Departments of Pediatrics and Laboratory Medicine, Laboratory Genetic Metabolic Diseases, Amsterdam University Medical Center,
  • Wanders RJA; Departments of Pediatrics and Laboratory Medicine, Laboratory Genetic Metabolic Diseases, Amsterdam University Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands.
  • Zwartkruis FJT; dLAB, Center for Molecular Medicine, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG Utrecht, the Netherlands.
  • Verhoeven-Duif NM; Department of Genetics, Section Metabolic Diagnostics, University Medical Center Utrecht, Lundlaan 6, 3584 EA Utrecht, the Netherlands.
  • Jans JJM; Department of Genetics, Section Metabolic Diagnostics, University Medical Center Utrecht, Lundlaan 6, 3584 EA Utrecht, the Netherlands. Electronic address: j.j.m.jans@umcutrecht.nl.
Cell Rep ; 42(9): 113043, 2023 09 26.
Article en En | MEDLINE | ID: mdl-37647199
The malate-aspartate shuttle (MAS) is a redox shuttle that transports reducing equivalents across the inner mitochondrial membrane while recycling cytosolic NADH to NAD+. We genetically disrupted each MAS component to generate a panel of MAS-deficient HEK293 cell lines in which we performed [U-13C]-glucose tracing. MAS-deficient cells have reduced serine biosynthesis, which strongly correlates with the lactate M+3/pyruvate M+3 ratio (reflective of the cytosolic NAD+/NADH ratio), consistent with the NAD+ dependency of phosphoglycerate dehydrogenase in the serine synthesis pathway. Among the MAS-deficient cells, those lacking malate dehydrogenase 1 (MDH1) show the most severe metabolic disruptions, whereas oxoglutarate-malate carrier (OGC)- and MDH2-deficient cells are less affected. Increasing the NAD+-regenerating capacity using pyruvate supplementation resolves most of the metabolic disturbances. Overall, we show that the MAS is important for de novo serine biosynthesis, implying that serine supplementation could be used as a therapeutic strategy for MAS defects and possibly other redox disorders.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Ácido Aspártico / Malatos Límite: Humans Idioma: En Revista: Cell Rep Año: 2023 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Ácido Aspártico / Malatos Límite: Humans Idioma: En Revista: Cell Rep Año: 2023 Tipo del documento: Article Pais de publicación: Estados Unidos