{"doi":"10.1016/j.bbrc.2025.151900","title":"Gene-dose effect of the glutathione biosynthesis gene on ascorbate deficiency in mice","abstract":"Glutathione (GSH) and ascorbate (vitamin C) are key antioxidants with well-established biochemical and clinical interplay in protecting against oxidative stress . Glutamate-cysteine ligase is the rate-limiting enzyme in GSH biosynthesis ; its modifier subunit (GCLM) regulates tissue GSH levels. L -gulono-γ-lactone oxidase (GULO) catalyzes a critical step in ascorbate biosynthesis ; Gulo -knockout ( Gulo KO ) mice, like humans, require dietary vitamin C. Previous work using double-knockout ( Gclm KO /Gulo KO ) mice revealed an essential role of GSH-ascorbate interaction in brain function. Herein, we report an allelic dosage effect of Gclm on redox imbalance and phenotypic outcomes under states of ascorbate deficiency. Gclm WT /Gulo KO mice remained overtly healthy with low-ascorbic acid (AA) supplementation at 1.25 mM (mM) in drinking water. In contrast, lacking one copy of the functional Gclm allele ( Gclm HET /Gulo KO ) resulted in increased vulnerability to scurvy development, which was clinically evident with 1.25 mM AA and was mitigated by 2.5 mM AA. Redox profiling revealed insufficient ascorbate retention and a more oxidized glutathione pool in Gclm HET /Gulo KO liver and brain tissues at 1.25 mM AA. These results highlight a gene-dose-dependent role of Gclm in maintaining ascorbate homeostasis and redox balance during ascorbate deficiency, with implications for human populations facing limited access to dietary vitamin C and carrying functional GCLM polymorphisms.","journal":"Biochemical and Biophysical Research Communications","year":2025,"id":564864,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9613,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":313595,"name":"David J. Orlicky","orcid":"0000-0002-0417-1400","position":1,"is_corresponding":false},{"id":698473,"name":"Ying Chen","orcid":"0000-0002-1044-0865","position":2,"is_corresponding":false},{"id":1468089,"name":"Reagan Strand","orcid":"0009-0001-7149-930X","position":0,"is_corresponding":true}],"reference_count":29,"raw_metadata":null,"created_at":"2026-07-19T02:56:24.872312Z","pmid":"40294460","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}