Summary Mitochondrial function is important for aspartate biosynthesis in proliferating cells. Here, we show that mitochondrial aspartate export via the aspartate-glutamate carrier 1 (AGC1) supports cell proliferation and cellular redox homeostasis. Insufficient cytosolic aspartate delivery leads to cell death when TCA cycle carbon is reduced following glutamine withdrawal and/or glutaminase inhibition. Moreover, loss of AGC1 reduces allograft tumor growth that is further compromised by treatment with the glutaminase inhibitor CB-839. Together, these findings argue that mitochondrial aspartate export sustains cell survival in low-glutamine environments and AGC1 inhibition can synergize with glutaminase inhibition to limit tumor growth.

HighlightsEndogenous N-acetylaspartate (NAA) production boosts tumor growth NAA supports cell survival in low glucose via suppressing ER stress Breaking down NAA limits tumor growth and induces ER stress in vivoThe role of NAA to rescue low glucose is independent of donating acetate or aspartate In briefCancer cells need N-acetylaspartate to avoid ER stress and cell death when glucose availability is low. SummaryN-acetylasparate (NAA), previously considered a brain-specific metabolite, is found in several cancers. However, whether it plays a role in tumor growth or survival is not fully understood.We provide evidence that NAA prevents cell death in low-glucose conditions via sustaining intracellular UDP-N-acetylglucosamine (UDP-GlcNac) levels, suppressing endoplasmic reticulum (ER) stress, and enabling continued protein synthesis. NAA production is critical for in vivo tumor growth where lower glucose levels are present than those in cell culture.Furthermore, the breakdown of NAA leads to ER stress and cell death, suggesting that the role of NAA in low-glucose is independent of its catabolism to produce aspartate or acetate.Together, these data suggest NAA can support the growth of some tumors by helping them cope with glucose limitations in vivo.

No abstract