%0 Journal Article
%A Weisshaar, Nina
%A Ma, Sicong
%A Ming, Yanan
%A Madi, Alaa Abdelghani Mohamed
%A Mieg, Alessa
%A Hering, Marvin
%A Zettl, Ferdinand
%A Mohr, Kerstin
%A ten Bosch, Nora
%A Stichling, Diana
%A Buettner, Michael
%A Poschet, Gernot
%A Klinke, Glynis
%A Schulz, Michael
%A Kunze-Rohrbach, Nina
%A Kerber, Carolin
%A Klein, Isabel Madeleine
%A Wu, Jingxia
%A Wang, Xi
%A Cui, Guoliang
%T The malate shuttle detoxifies ammonia in exhausted T cells by producing 2-ketoglutarate.
%J Nature immunology
%V 24
%N 11
%@ 1529-2908
%C London
%I Springer Nature Limited
%M DKFZ-2023-02034
%P 1921-1932
%D 2023
%Z 2023 Nov;24(11):1921-1932 / #EA:D192#LA:D192# / HI-TRON
%X The 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.
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:37813964
%R 10.1038/s41590-023-01636-5
%U https://inrepo02.dkfz.de/record/284615