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Weisshaar, Nina; Ma, Sicong; Ming, Yanan; Madi, Alaa; Mieg, Alessa; Hering, Marvin; Zettl, Ferdinand; Mohr, Kerstin; Ten Bosch, Nora; Stichling, Diana; Buettner, Michael; Poschet, Gernot; Klinke, Glynis; Schulz, Michael; Kunze-Rohrbach, Nina; Kerber, Carolin; Klein, Isabel Madeleine; Wu, Jingxia; Wang, Xi; Cui, Guoliang

The malate shuttle detoxifies ammonia in exhausted T cells by producing 2-ketoglutarate

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  • Media type: E-Article
  • Title: The malate shuttle detoxifies ammonia in exhausted T cells by producing 2-ketoglutarate
  • Contributor: Weisshaar, Nina; Ma, Sicong; Ming, Yanan; Madi, Alaa; Mieg, Alessa; Hering, Marvin; Zettl, Ferdinand; Mohr, Kerstin; Ten Bosch, Nora; Stichling, Diana; Buettner, Michael; Poschet, Gernot; Klinke, Glynis; Schulz, Michael; Kunze-Rohrbach, Nina; Kerber, Carolin; Klein, Isabel Madeleine; Wu, Jingxia; Wang, Xi; Cui, Guoliang
  • Published: Springer Science and Business Media LLC, 2023
  • Published in: Nature Immunology, 24 (2023) 11, Seite 1921-1932
  • Language: English
  • DOI: 10.1038/s41590-023-01636-5
  • ISSN: 1529-2908; 1529-2916
  • Origination:
  • Footnote:
  • Description: AbstractThe malate shuttle is traditionally understood to maintain NAD+/NADH balance between the cytosol and mitochondria. Whether the malate shuttle has additional functions is unclear. Here we show that chronic viral infections induce CD8+ T cell expression of GOT1, a central enzyme in the malate shuttle. Got1 deficiency decreased the NAD+/NADH ratio and limited antiviral CD8+ T cell responses to chronic infection; however, increasing the NAD+/NADH ratio did not restore T cell responses. Got1 deficiency reduced the production of the ammonia scavenger 2-ketoglutarate (2-KG) from glutaminolysis and led to a toxic accumulation of ammonia in CD8+ T cells. Supplementation with 2-KG assimilated and detoxified ammonia in Got1-deficient T cells and restored antiviral responses. These data indicate that the major function of the malate shuttle in CD8+ T cells is not to maintain the NAD+/NADH balance but rather to detoxify ammonia and enable sustainable ammonia-neutral glutamine catabolism in CD8+ T cells during chronic infection.