{"doi":"10.1016/j.jbc.2023.102994","title":"β-cell–selective inhibition of DNA damage response signaling by nitric oxide is associated with an attenuation in glucose uptake","abstract":"Nitric oxide (NO) plays a dual role in regulating DNA damage response (DDR) signaling in pancreatic β-cells. As a genotoxic agent, NO activates two types of DDR signaling; however, when produced at micromolar levels by the inducible isoform of NO synthase, NO inhibits DDR signaling and DDR-induced apoptosis in a β-cell–selective manner. DDR signaling inhibition by NO correlates with mitochondrial oxidative metabolism inhibition and decreases in ATP and NAD + . Unlike most cell types, β-cells do not compensate for impaired mitochondrial oxidation by increasing glycolytic flux, and this metabolic inflexibility leads to a decrease in ATP and NAD + . Here, we used multiple analytical approaches to determine changes in intermediary metabolites in β-cells and non–β-cells treated with NO or complex I inhibitor rotenone. In addition to ATP and NAD + , glycolytic and tricarboxylic acid cycle intermediates as well as NADPH are significantly decreased in β-cells treated with NO or rotenone. Consistent with glucose-6-phosphate residing at the metabolic branchpoint for glycolysis and the pentose phosphate pathway (NADPH), we show that mitochondrial oxidation inhibitors limit glucose uptake in a β-cell–selective manner. Our findings indicate that the β-cell–selective inhibition of DDR signaling by NO is associated with a decrease in ATP to levels that fall significantly below the K M for ATP of glucokinase (glucose uptake) and suggest that this action places the β-cell in a state of suspended animation where it is metabolically inert until NO is removed, and metabolic function can be restored.","journal":"Journal of Biological Chemistry","year":2023,"id":350811,"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":9,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9468,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":933771,"name":"Erin M. Kropp","orcid":"0000-0002-8597-3025","position":1,"is_corresponding":false},{"id":299559,"name":"Polly A. Hansen","orcid":"0000-0002-2095-2493","position":2,"is_corresponding":false},{"id":434293,"name":"Michaela Pereckas","orcid":"0000-0002-7287-5450","position":3,"is_corresponding":false},{"id":526266,"name":"Bryndon J. Oleson","orcid":null,"position":4,"is_corresponding":false},{"id":916173,"name":"Aaron Naatz","orcid":null,"position":5,"is_corresponding":false},{"id":525271,"name":"Jennifer S. Stancill","orcid":"0000-0002-1612-4695","position":6,"is_corresponding":false},{"id":1095180,"name":"Kyle A. Ross","orcid":"0000-0002-0471-169X","position":7,"is_corresponding":false},{"id":148300,"name":"Rebekah L. Gundry","orcid":"0000-0002-9263-833X","position":8,"is_corresponding":false},{"id":299560,"name":"John A. Corbett","orcid":"0000-0002-1134-4664","position":9,"is_corresponding":false},{"id":1095179,"name":"Chay Teng Yeo","orcid":"0000-0002-0845-3480","position":0,"is_corresponding":true}],"reference_count":76,"raw_metadata":null,"created_at":"2026-07-19T01:12:37.409066Z","pmid":"36773802","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":[]}