Glucose‐1‐phosphate regulates orphan nuclear receptor NR4A1 and apoptosis

Abstract

Mitochondrial metabolic reprogramming is important for many different processes like apoptosis and inflammation. NR4A1 is necessary for many different pro‐apoptotic and inflammatory stimuli to induce mitochondrial metabolic reprogramming. However, despite the importance for small molecule ligands in the regulation of nuclear receptors, biological ligands regulating NR4A1 have not been identified. Here we report that glucose‐1‐phosphate (G1P), an intracellular metabolite from glycogen metabolism and glycolysis, is an NR4A1 ligand. In vitro, G1P specifically bound to NR4A1 ligand‐binding domain (NR4A1LBD) and alters its oligomerization state. In cells, a synthetic cell‐permeable G1P analog regulates transcriptional activity of NR4A1. This G1P analog suppressed mitochondrial respiration and induced apoptosis of H1299 lung adenocarcinoma cells in an NR4A1‐dependent manner. This result suggests that G1P might be an endogenous ligand regulating NR4A1 and NR4A1‐dependent mitochondrial metabolic reprogramming. It represents a rare case where a polar water‐soluble intracellular metabolite modulates a nuclear receptor function.