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| Home > Publications database > The malate shuttle detoxifies ammonia in exhausted T cells by producing 2-ketoglutarate. |
| Home > Publications database > The malate shuttle detoxifies ammonia in exhausted T cells by producing 2-ketoglutarate. |
| Journal Article | DKFZ-2023-02034 |
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2023
Springer Nature Limited
London
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Please use a persistent id in citations: doi:10.1038/s41590-023-01636-5
Abstract: 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.
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