TY  - JOUR
AU  - Weisshaar, Nina
AU  - Ma, Sicong
AU  - Ming, Yanan
AU  - Madi, Alaa Abdelghani Mohamed
AU  - Mieg, Alessa
AU  - Hering, Marvin
AU  - Zettl, Ferdinand
AU  - Mohr, Kerstin
AU  - ten Bosch, Nora
AU  - Stichling, Diana
AU  - Buettner, Michael
AU  - Poschet, Gernot
AU  - Klinke, Glynis
AU  - Schulz, Michael
AU  - Kunze-Rohrbach, Nina
AU  - Kerber, Carolin
AU  - Klein, Isabel Madeleine
AU  - Wu, Jingxia
AU  - Wang, Xi
AU  - Cui, Guoliang
TI  - The malate shuttle detoxifies ammonia in exhausted T cells by producing 2-ketoglutarate.
JO  - Nature immunology
VL  - 24
IS  - 11
SN  - 1529-2908
CY  - London
PB  - Springer Nature Limited
M1  - DKFZ-2023-02034
SP  - 1921-1932
PY  - 2023
N1  - 2023 Nov;24(11):1921-1932 / #EA:D192#LA:D192# / HI-TRON
AB  - 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.
LB  - PUB:(DE-HGF)16
C6  - pmid:37813964
DO  - DOI:10.1038/s41590-023-01636-5
UR  - https://inrepo02.dkfz.de/record/284615
ER  -