{"doi":"10.1002/ctm2.1653","title":"Mitochondrial dysfunction induced by HIF‐1α under hypoxia contributes to the development of gastric mucosal lesions","abstract":"<jats:title>Abstract</jats:title><jats:sec><jats:title>Introduction</jats:title><jats:p>Hypoxia is an important characteristic of gastric mucosal diseases, and hypoxia‐inducible factor‐1α (HIF‐1α) contributes to microenvironment disturbance and metabolic spectrum abnormalities. However, the underlying mechanism of HIF‐1α and its association with mitochondrial dysfunction in gastric mucosal lesions under hypoxia have not been fully clarified.</jats:p></jats:sec><jats:sec><jats:title>Objectives</jats:title><jats:p>To evaluate the effects of hypoxia‐induced HIF‐1α on the development of gastric mucosal lesions.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>Portal hypertensive gastropathy (PHG) and gastric cancer (GC) were selected as representative diseases of benign and malignant gastric lesions, respectively. Gastric tissues from patients diagnosed with the above diseases were collected. Portal hypertension (PHT)‐induced mouse models in <jats:italic>METTL3</jats:italic> mutant or <jats:italic>NLRP3</jats:italic>‐deficient littermates were established, and nude mouse gastric graft tumour models with relevant inhibitors were generated. The mechanisms underlying hypoxic condition, mitochondrial dysfunction and metabolic alterations in gastric mucosal lesions were further analysed.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>HIF‐1α, which can mediate mitochondrial dysfunction via upregulation of METTL3/IGF2BP3‐dependent dynamin‐related protein 1 (Drp1) N6‐methyladenosine modification to increase mitochondrial reactive oxygen species (mtROS) production, was elevated under hypoxic conditions in human and mouse portal hypertensive gastric mucosa and GC tissues. While blocking HIF‐1α with PX‐478, inhibiting Drp1‐dependent mitochondrial fission via mitochondrial division inhibitor 1 (Mdivi‐1) treatment or <jats:italic>METTL3</jats:italic> mutation alleviated this process. Furthermore, HIF‐1α influenced energy metabolism by enhancing glycolysis via lactate dehydrogenase A. In addition, HIF‐1α‐induced Drp1‐dependent mitochondrial fission also enhanced glycolysis. Drp1‐dependent mitochondrial fission and enhanced glycolysis were associated with alterations in antioxidant enzyme activity and dysfunction of the mitochondrial electron transport chain, resulting in massive mtROS production, which was needed for activation of NLRP3 inflammasome to aggravate the development of the PHG and GC.</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>Under hypoxic conditions, HIF‐1α enhances mitochondrial dysfunction via Drp1‐dependent mitochondrial fission and influences the metabolic profile by altering glycolysis to increase mtROS production, which can trigger NLRP3 inflammasome activation and mucosal microenvironment alterations to contribute to the development of benign and malignant gastric mucosal lesions.</jats:p></jats:sec>","journal":"Clinical and Translational Medicine","year":2024,"id":645563,"datarank":0.519860385419959,"base_score":3.4657359027997265,"endowment":3.4657359027997265,"self_citation_contribution":0.519860385419959,"citation_network_contribution":0.0,"self_endowment_contribution":0.519860385419959,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":31,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1681036,"name":"Xianzhi Liu","orcid":null,"position":1,"is_corresponding":false},{"id":1681037,"name":"Kaiduan Xie","orcid":null,"position":2,"is_corresponding":false},{"id":1681038,"name":"Jiajie Luo","orcid":null,"position":3,"is_corresponding":false},{"id":1681039,"name":"Yiwang Zhang","orcid":null,"position":4,"is_corresponding":false},{"id":691209,"name":"Xiaoli Huang","orcid":"0000-0002-6438-5435","position":5,"is_corresponding":false},{"id":1681040,"name":"Jinni Luo","orcid":null,"position":6,"is_corresponding":false},{"id":1681041,"name":"Siwei Tan","orcid":"0000-0003-4053-9898","position":7,"is_corresponding":false},{"id":1681035,"name":"Yuelin Xiao","orcid":null,"position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Mitochondrial dysfunction induced by HIF‐1α under hypoxia contributes to the development of gastric mucosal lesions","abstract":"<jats:title>Abstract</jats:title><jats:sec><jats:title>Introduction</jats:title><jats:p>Hypoxia is an important characteristic of gastric mucosal diseases, and hypoxia‐inducible factor‐1α (HIF‐1α) contributes to microenvironment disturbance and metabolic spectrum abnormalities. However, the underlying mechanism of HIF‐1α and its association with mitochondrial dysfunction in gastric mucosal lesions under hypoxia have not been fully clarified.</jats:p></jats:sec><jats:sec><jats:title>Objectives</jats:title><jats:p>To evaluate the effects of hypoxia‐induced HIF‐1α on the development of gastric mucosal lesions.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>Portal hypertensive gastropathy (PHG) and gastric cancer (GC) were selected as representative diseases of benign and malignant gastric lesions, respectively. Gastric tissues from patients diagnosed with the above diseases were collected. Portal hypertension (PHT)‐induced mouse models in <jats:italic>METTL3</jats:italic> mutant or <jats:italic>NLRP3</jats:italic>‐deficient littermates were established, and nude mouse gastric graft tumour models with relevant inhibitors were generated. The mechanisms underlying hypoxic condition, mitochondrial dysfunction and metabolic alterations in gastric mucosal lesions were further analysed.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>HIF‐1α, which can mediate mitochondrial dysfunction via upregulation of METTL3/IGF2BP3‐dependent dynamin‐related protein 1 (Drp1) N6‐methyladenosine modification to increase mitochondrial reactive oxygen species (mtROS) production, was elevated under hypoxic conditions in human and mouse portal hypertensive gastric mucosa and GC tissues. While blocking HIF‐1α with PX‐478, inhibiting Drp1‐dependent mitochondrial fission via mitochondrial division inhibitor 1 (Mdivi‐1) treatment or <jats:italic>METTL3</jats:italic> mutation alleviated this process. Furthermore, HIF‐1α influenced energy metabolism by enhancing glycolysis via lactate dehydrogenase A. In addition, HIF‐1α‐induced Drp1‐dependent mitochondrial fission also enhanced glycolysis. Drp1‐dependent mitochondrial fission and enhanced glycolysis were associated with alterations in antioxidant enzyme activity and dysfunction of the mitochondrial electron transport chain, resulting in massive mtROS production, which was needed for activation of NLRP3 inflammasome to aggravate the development of the PHG and GC.</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>Under hypoxic conditions, HIF‐1α enhances mitochondrial dysfunction via Drp1‐dependent mitochondrial fission and influences the metabolic profile by altering glycolysis to increase mtROS production, which can trigger NLRP3 inflammasome activation and mucosal microenvironment alterations to contribute to the development of benign and malignant gastric mucosal lesions.</jats:p></jats:sec>","is_dataset_classified":null,"base_score":3.1354942159291497,"endowment":3.1354942159291497,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"38616702","pmcid":"PMC11016940","openalex_id":"https://openalex.org/W4394816200","authors":[],"funders":[{"funder_name":"National Natural Science Foundation of China","grant_id":"82170569","title":null},{"funder_name":"Natural Science Foundation of Guangdong Province","grant_id":"2022A1515012546","title":null},{"funder_name":"Natural Science Foundation of Guangdong Province","grant_id":"2023A1515011204","title":null},{"funder_name":"Science and Technology Planning Projects of Guangzhou City","grant_id":"2024A04J6565","title":null},{"funder_name":"Major Talent Project Training Program of the Third Affiliated Hospital of Sun Yat-Sen University","grant_id":"P02089","title":null}],"total_grants":5,"fwci":3.971,"citation_percentile":0.95093384,"influential_citations":0,"citation_trend":[{"year":2024,"count":2},{"year":2025,"count":10},{"year":2026,"count":10}],"oa_status":"gold","license":"cc-by","oa_locations":[{"url":"https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/ctm2.1653","host_type":"journal"},{"url":"https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/ctm2.1653","host_type":"publisher"},{"url":"https://onlinelibrary.wiley.com/doi/pdf/10.1002/ctm2.1653","host_type":"publisher"},{"url":"https://doi.org/10.1002/ctm2.1653","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/38616702","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/11016940","host_type":"repository"},{"url":"https://doaj.org/article/244db09b4d2e466fbb75ed6d2e496e9e","host_type":"repository"},{"url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC11016940/pdf/CTM2-14-e1653.pdf","host_type":"repository"},{"url":"https://europepmc.org/articles/PMC11016940","host_type":"Europe_PMC"},{"url":"https://europepmc.org/articles/PMC11016940?pdf=render","host_type":"Europe_PMC"}],"fields_of_study":["Cancer, Hypoxia, and Metabolism","Mitochondrial Function and Pathology","Adrenal and Paraganglionic Tumors"],"mesh_terms":["NLR Family, Pyrin Domain-Containing 3 Protein","Animals","Antioxidants","Humans","Methyltransferases","Stomach Neoplasms","Mitochondrial Diseases","Mice","Hypoxia-Inducible Factor 1, alpha Subunit","Inflammasomes","Tumor Microenvironment"],"keywords":["Hypoxia (environmental)","Medicine","Chemistry","Oxygen","glycolysis","Mitochondrial Dysfunction","Mitochondrial Fission","Nlrp3","Drp1","Mettl3","Gastric Mucosal Lesions","Hif‐1α"],"sdg_mappings":[{"sdg_number":0,"sdg_label":"Good health and well-being"}],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-09T09:16:15.632394Z","pmid":null,"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":[]}