Spatial Partitioning of Glucose Metabolism Supports Tissue-Specific Metabolic Programs In Vivo

Abstract

Tissues exhibit metabolic heterogeneity that tailors conserved pathways to distinct physiological demands, yet how this heterogeneity is achieved in vivo remains poorly understood. Here, we use Caenorhabditis elegans to investigate tissue-specific requirements for glucose-6-phosphate isomerase (GPI-1), a conserved reversible enzyme that links glycolysis and the pentose phosphate pathway (PPP). Tissue-specific metabolic-network modeling predicted differential glycolytic and PPP flux potential across adult tissues and identified tissue-specific biases in GPI-1 reaction directionality. Genetic disruption of gpi-1 produced germline defects consistent with impaired PPP-associated anabolic metabolism and somatic defects consistent with impaired glycolysis, indicating that GPI-1 supports distinct metabolic functions across tissues. We further discovered that two GPI-1 isoforms are differentially expressed and localized: GPI-1A is broadly expressed and cytosolic, whereas GPI-1B is enriched in the germline and localizes to endoplasmic reticulum-associated compartments. Isoform-specific perturbations revealed distinct requirements for GPI-1A and GPI-1B in somatic glycolysis and reproductive physiology. These findings implicate isoform-specific subcellular localization as a possible contributor to the partition of the functions of a conserved reversible enzyme, enabling tissue-specific anabolic and catabolic metabolism in vivo.