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

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.