A lysosomal DRAM1-GLUT1-NADPH axis coordinates glucose sensing with metabolic reprogramming.

Authors

Jia Li, Jaclyn S Long, Alejandro Huerta Uribe, Annabel Minton, Jing Hui Neo, Paula Fernández-Palanca, Engy Shokry, Jim O'Prey, David McEwan, David Sumpton, Kevin M Ryan

Published in

Molecular cell. Nov 12, 2026. Epub Nov 12, 2026.

Abstract

Perturbed glucose homeostasis is a hallmark of metabolic disease and cancer, and cellular responses to excess glucose are tightly controlled. We report here a lysosomal glucose sensing axis linking the transporter GLUT1 with the lysosomal protein DRAM1. Pathophysiological glucose induces DRAM1 via the MLX/ChREBP transcriptional complex. DRAM1 then binds newly synthesized GLUT1 and promotes its traffic to lysosomes without degradation, reducing surface GLUT1 and acting as a reversible brake on glucose entry. Hexokinase or glucose-6-phosphate (G6P) dehydrogenase disruption weakens DRAM1-GLUT1 complex formation, whereas nicotinamide adenine dinucleotide phosphate(NADPH) oxidase (NOX) inhibition enhances assembly, implicating NADPH as a key metabolic signal downstream of elevated glucose. Sequestration of GLUT1 suppresses glucose uptake and glycolysis and rewires metabolism toward glutamine anaplerosis, creating vulnerability to glutaminase (GLS) inhibition. In vivo, Dram1^-/- tumors display a glycolytic metabolite profile, consistent with loss of this brake. Together, these data define an mTORC1- and AMPK-independent lysosomal mechanism that protects metabolic homeostasis under hyperglycemic conditions.

PMID:
43020070
Bibliographic data and abstract were imported from PubMed on 13 Nov 2026.

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