Mannose metabolic pathway senses glucose supply and regulates cell fate decisions.

Mammalian cells exploit diverse metabolic pathways to regulate cell fates during glucose deprivation. We previously reported that glucose deprivation lowers the metabolic activity of the mannose pathway, which is interconnected with glycolysis, leading to biosynthetic arrest and degradation of the glycan precursors for asparagine-linked glycosylation (N-glycosylation) in the endoplasmic reticulum. However, the cellular role of this sequential metabolic response remains unknown, largely because of metabolic complications caused by glucose deprivation. Here, we genetically engineered cells to separate the mannose pathway from glycolysis, allowing precise control of mannose pathway activity by adjusting mannose supply levels instead of changing glucose supply. Moderate decrease in mannose supply severely suppressed N-glycosylation, leading to activation of prosurvival protein kinase R-like endoplasmic reticulum kinase-eukaryotic initiation factor 2 signals. Although a further decrease in mannose supply to the minimal levels did not compromise cell survival, it depleted the luminal protective glycocalyx of lysosomes and increased the risk of cell death by impairing lysosome integrity. These results indicate that low metabolic flux of glucose into the mannose pathway initiates alterations in homeostasis of the endoplasmic reticulum and lysosomes, at least in part through N-glycosylation defects, leading to cell fate decisions.