Nicotinamide nucleotide transhydrogenase directly couples redox homeostasis to proline biosynthesis in human glioma.

ABSTRACT: Cancer cell proliferation requires a precise balance between biomass production and nutrient catabolism. The pyridine nucleotide cofactors nicotinamide adenine dinucleotide NAD(H) and NAD phosphate NADP(H) are central to this process, but their compartment-specific regulation is incompletely understood. Using in vivo isotope-labeled metabolite tracing in an orthotopic xenograft model, we find that human gliomas extensively synthesize proline, an amino acid previously associated with hypoxia tolerance. In glioma cells, we identify a hypoxia-enhanced proliferative sensitivity to environmental proline dependent on NADH to NADPH transhydrogenation from a spatially compartmentalized mitochondrial pool by the enzyme nicotinamide nucleotide transhydrogenase (NNT). We demonstrate NNT-dependent gen

SUBMITTER: Vettore LA 

PROVIDER: S-EPMC13650111 | biostudies-literature | 2026 Oct

REPOSITORIES: biostudies-literature