biostudies-literatureLane ARNIA NIH HHSNIEHS NIH HHSNINDS NIH HHSNCI NIH HHSNIGMS NIH HHSar33https://www.ebi.ac.uk/biostudies/studies/S-EPMC11974963biostudies-literatureUnknown36(3)Rare inherited diseases caused by mutations in the copper transporters <i>SLC31A1</i> (CTR1) or <i>ATP7A</i> induce copper deficiency in the brain, causing seizures and neurodegeneration in infancy through poorly understood mechanisms. Here, we used multiple model systems to characterize the molecular mechanisms by which neuronal cells respond to copper deficiency. Targeted deletion of CTR1 in neuroblastoma cells produced copper deficiency that produced a metabolic shift favoring glycolysis over oxidative phosphorylation. Proteomic and transcriptomic analysis of CTR1 knockout (KO) cells revealed simultaneous up-regulation of mTORC1 and S6K signaling and reduced PERK signaling. Patterns of gene and protein expression and pharmacogenomics show increased activation of the mTORC1-S6K pathway aMolecular biology of the cellAdaptive protein synthesis in genetic models of copper deficiency and childhood neurodegeneration.PMC11974963K00 NS108539R01 NS086082RF1 AG060285R01 ES034796P30 CA138292R15 AG074113T34 GM131939R01 NS133344F31 NS127419Roberts AMDuong DMMoctezuma FGRRoberts BRMcKenna MBaiju AGokhale ASingleton KSLiu WLPetris MJVrailas-Mortimer ADScher NETran TClayton LBLane ARCox DNPatgiri APatel AAWood LBFaundez VWerner EBhattacharjee SZlatic SAfalseAdaptive protein synthesis in genetic models of copper deficiency and childhood neurodegeneration.Rare inherited diseases caused by mutations in the copper transporters <i>SLC31A1</i> (CTR1) or <i>ATP7A</i> induce copper deficiency in the brain, causing seizures and neurodegeneration in infancy through poorly understood mechanisms. Here, we used multiple model systems to characterize the molecular mechanisms by which neuronal cells respond to copper deficiency. Targeted deletion of CTR1 in neuroblastoma cells produced copper deficiency that produced a metabolic shift favoring glycolysis over oxidative phosphorylation. Proteomic and transcriptomic analysis of CTR1 knockout (KO) cells revealed simultaneous up-regulation of mTORC1 and S6K signaling and reduced PERK signaling. Patterns of gene and protein expression and pharmacogenomics show increased activation of the mTORC1-S6K pathway a2025-01-01T00:00:00Z2025 Mar2026-06-01T07:50:48.864Z2025-07-03T03:04:47.631ZS-EPMC119749633987865410.1091/mbc.E24-11-0512