| First Author | Weisshaar N | Year | 2023 |
| Journal | Nat Immunol | Volume | 24 |
| Issue | 11 | Pages | 1921-1932 |
| PubMed ID | 37813964 | Mgi Jnum | J:354125 |
| Mgi Id | MGI:7548910 | Doi | 10.1038/s41590-023-01636-5 |
| Citation | Weisshaar N, et al. (2023) The malate shuttle detoxifies ammonia in exhausted T cells by producing 2-ketoglutarate. Nat Immunol 24(11):1921-1932 |
| abstractText | 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. |
