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pmid:40274954
Identification and verification of mitochondria-related genes biomarkers associated with immune infiltration for COPD using WGCNA and machine learning algorithms.
Meijuan Peng · Chen Jiang · Ziyu Dai · Bin Xie · Qiong Chen · Jianing Lin
Scientific reports · 2025 doi:10.1038/s41598-025-99002-y
Paper
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Experiment
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Complete file
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This study combines bioinformatics analysis with machine learning to elucidate potential key mitochondrial-related genes associated with COPD and its immune microenvironment. We utilized the limma package and Weighted Gene Co-expression Network Analysis (WGCNA) to analyze datasets from the Gene Expression Omnibus (GEO) database (GSE57148), identifying 12 key differentially expressed mitochondrial genes (MitoDEGs). Using 12 distinct machine learning algorithms (comprising 143 predictive models), we identified the optimal diagnostic model, which includes five pivotal MitoDEGs: ERN1, FASTK, HIGD1B, NDUFA7 and NDUFB7. The diagnostic specificity and sensitivity of each gene, as well as the diagnostic model itself, were evaluated using Receiver operating characteristic (ROC) curves. This model demonstrated high specificity in the validation cohorts (GSE76925, GSE151052, GSE239897). Expression analysis revealed upregulation of ERN1 and downregulation of FASTK, HIGD1B, NDUFA7 and NDUFB7 in COPD patients. Spearman's correlation analysis indicated a significant association between MitoDEGs and immune cell infiltration, with ERN1 expression positively correlated with neutrophil infiltration and the other genes negatively correlated. The GABA receptor modulator androstenol was identified as a potential therapeutic candidate. In vivo studies confirmed reduced mRNA expression of HIGD1B and NDUFB7 in COPD mice. 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To ensure the reproducibility of our results, the complete ML code and all R code used in the research are available and provided as a separate document in the Supplementary Material.", "access_statement_kind": "data_availability_statement", "sample_accessions": ["GSM1375986", "GSM1375987", "GSM1375988", "GSM1375989", "GSM1375990", "GSM1375991", "GSM1375992", "GSM1375993", "GSM1375994", "GSM1375995", "GSM1375996", "GSM1375997", "GSM1375998", "GSM1375999", "GSM1376000", "GSM1376001", "GSM1376002", "GSM1376003", "GSM1376004", "GSM1376005", "GSM1376006", "GSM1376007", "GSM1376008", "GSM1376009", "GSM1376010", "GSM1376011", "GSM1376012", "GSM1376013", "GSM1376014", "GSM1376015", "GSM1376016", "GSM1376017", "GSM1376018", "GSM1376019", "GSM1376020", "GSM1376021", "GSM1376022", "GSM1376023", "GSM1376024", "GSM1376025", "GSM1376026", "GSM1376027", "GSM1376028", "GSM1376029", "GSM1376030", "GSM1376031", "GSM1376032", "GSM1376033", "GSM1376034", "GSM1376035", "GSM1376036", "GSM1376037", "GSM1376038", "GSM1376039", "GSM1376040", "GSM1376041", "GSM1376042", "GSM1376043", "GSM1376044", "GSM1376045", "GSM1376046", "GSM1376047", "GSM1376048", "GSM1376049", "GSM1376050", "GSM1376051", "GSM1376052", "GSM1376053", "GSM1376054", "GSM1376055", "GSM1376056", "GSM1376057", "GSM1376058", "GSM1376059", "GSM1376060", "GSM1376061", "GSM1376062", "GSM1376063", "GSM1376064", "GSM1376065", "GSM1376066", "GSM1376067", "GSM1376068", "GSM1376069", "GSM1376070", "GSM1376071", "GSM1376072", "GSM1376073", "GSM1376074", "GSM1376075", "GSM1376076", "GSM1376077", "GSM1376078", "GSM1376079", "GSM1376080", "GSM1376081", "GSM1376082", "GSM1376083", "GSM1376084", "GSM1376085", "GSM1376086", "GSM1376087", "GSM1376088", "GSM1376089", "GSM1376090", "GSM1376091", "GSM1376092", "GSM1376093", "GSM1376094", "GSM1376095", "GSM1376096", "GSM1376097", "GSM1376098", "GSM1376099", "GSM1376100", "GSM1376101", "GSM1376102", "GSM1376103", "GSM1376104", "GSM1376105", "GSM1376106", "GSM1376107", "GSM1376108", "GSM1376109", "GSM1376110", "GSM1376111", "GSM1376112", "GSM1376113", "GSM1376114", "GSM1376115", "GSM1376116", "GSM1376117", "GSM1376118", "GSM1376119", "GSM1376120", "GSM1376121", "GSM1376122", "GSM1376123", "GSM1376124", "GSM1376125", "GSM1376126", "GSM1376127", "GSM1376128", "GSM1376129", "GSM1376130", "GSM1376131", "GSM1376132", "GSM1376133", "GSM1376134", "GSM1376135", "GSM1376136", "GSM1376137", "GSM1376138", "GSM1376139", "GSM1376140", "GSM1376141", "GSM1376142", "GSM1376143", "GSM1376144", "GSM1376145", "GSM1376146", "GSM1376147", "GSM1376148", "GSM1376149", "GSM1376150", "GSM1376151", "GSM1376152", "GSM1376153", "GSM1376154", "GSM1376155", "GSM1376156", "GSM1376157", "GSM1376158", "GSM1376159", "GSM1376160", "GSM1376161", "GSM1376162", "GSM1376163", "GSM1376164", "GSM1376165", "GSM1376166", "GSM1376167", "GSM1376168", "GSM1376169", "GSM1376170", "GSM1376171", "GSM1376172", "GSM1376173", "GSM1376174"], "sample_count": 189, "group_sizes": null, "group_sizes_basis": null, "platform": "11154", "taxon": "Homo sapiens", "title": "Characterizing gene expression in lung tissue of COPD subjects using RNA-seq", "resolution_checked_at": "2026-11-01T17:30:42Z", "resolution_check": "identifier_resolution_only_no_download_no_licence_read", "downloaded": false, "licence_read": false}}, {"id": "data:geo:GSE76925", "role": "raw", "format": "geo-series", "media_type": "application/vnd.ncbi.geo-series+json", "uri": "https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE76925", "sha256": null, "bytes": null, "access": "open", "state": "resolved", "reader": null, "reader_status": "reader_required", "identifier": "GSE76925", "version": null, "note": "The transcriptome datasets analyzed during the current study are available in the public NCBI GEO database (https://www.ncbi.nlm.nih.gov/geo/). Accession numbers and link URL are GSE57148 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE57148), GSE76925 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE76925), GSE151052 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE151052) and GSE239897 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE239897). To ensure the reproducibility of our results, the complete ML code and all R code used in the research are available and provided as a separate document in the Supplementary Material.", "structure": {"repository": "GEO", "access_route": "GEO accession URL", "access_statement_verbatim": "The transcriptome datasets analyzed during the current study are available in the public NCBI GEO database (https://www.ncbi.nlm.nih.gov/geo/). Accession numbers and link URL are GSE57148 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE57148), GSE76925 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE76925), GSE151052 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE151052) and GSE239897 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE239897). To ensure the reproducibility of our results, the complete ML code and all R code used in the research are available and provided as a separate document in the Supplementary Material.", "access_statement_kind": "data_availability_statement", "sample_accessions": ["GSM2040792", "GSM2040793", "GSM2040794", "GSM2040795", "GSM2040796", "GSM2040797", "GSM2040798", "GSM2040799", "GSM2040800", "GSM2040801", "GSM2040802", "GSM2040803", "GSM2040804", "GSM2040805", "GSM2040806", "GSM2040807", "GSM2040808", "GSM2040809", "GSM2040810", "GSM2040811", "GSM2040812", "GSM2040813", "GSM2040814", "GSM2040815", "GSM2040816", "GSM2040817", "GSM2040818", "GSM2040819", "GSM2040820", "GSM2040821", "GSM2040822", "GSM2040823", "GSM2040824", "GSM2040825", "GSM2040826", "GSM2040827", "GSM2040828", "GSM2040829", "GSM2040830", "GSM2040831", "GSM2040832", "GSM2040833", "GSM2040834", "GSM2040835", "GSM2040836", "GSM2040837", "GSM2040838", "GSM2040839", "GSM2040840", "GSM2040841", "GSM2040842", "GSM2040843", 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"asset:data:geo:GSE239897 licence not read", "asset:data:geo:GSE57148 not downloaded", "asset:data:geo:GSE57148 licence not read", "asset:data:geo:GSE76925 not downloaded", "asset:data:geo:GSE76925 licence not read"]}, "analysis": {"state": "complete", "methods": [{"id": "method-1", "family": "differential_expression", "specific": "limma_voom", "label": "Differential expression analysis", "dsl_operations": ["normalise_counts", "differential_expression_fit", "fdr_bh"], "missing_operations": [], "expressible": true, "parameters": {}, "data_shapes": ["count_matrix_with_condition"], "evidence": {"score": 1.0, "band": "verbatim", "quote": "We utilized the limma package and Weighted Gene Co-expression Network Analysis (WGCNA) to analyze datasets from the Gene Expression Omnibus (GEO) database (GSE57148), identifying 12 key differentially expressed mitochondrial genes (MitoDEGs)."}}, {"id": "method-2", "family": "correlation_analysis", "specific": "spearman", "label": "Correlation analysis", "dsl_operations": ["spearman_rho"], "missing_operations": [], "expressible": true, "parameters": {}, "data_shapes": ["paired_numeric_columns"], "evidence": {"score": 0.7, "band": "medium", "quote": "Spearman's correlation"}}, {"id": "method-3", "family": "network_analysis", "specific": "pathway_enrichment", "label": "Network / pathway analysis", "dsl_operations": ["pathway_enrich"], "missing_operations": [], "expressible": true, "parameters": {}, "data_shapes": ["edge_list"], "evidence": {"score": 0.8, "band": "high", "quote": "Pathway enrichment"}}], "targets": [], "gaps": []}, "capability": {"state": "complete", "requirements": [{"capability_id": "capability:computational_analysis", "label": "Computational analysis platform", "assay_families": ["meta_analysis", "machine_learning", "survival_analysis", "statistical_regression", "pca", "molecular_docking", "network_analysis", "differential_expression", "gwas"], "availability_state": "owned", "tier_unlocked": "R1", "candidate": 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The physical bench the paper used is not, so a physical validation cannot be run here."}, "data": {"tier": "R1", "reachable": true, "accessions": ["GSE57148", "GSE76925", "GSE151052", "GSE239897"], "resolved_accessions": ["GSE57148", "GSE76925", "GSE151052", "GSE239897"], "statements": ["The transcriptome datasets analyzed during the current study are available in the public NCBI GEO database (https://www.ncbi.nlm.nih.gov/geo/). Accession numbers and link URL are GSE57148 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE57148), GSE76925 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE76925), GSE151052 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE151052) and GSE239897 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE239897). To ensure the reproducibility of our results, the complete ML code and all R code used in the research are available and provided as a separate document in the Supplementary Material."], "basis": "The paper names GSE57148, GSE76925, GSE151052, GSE239897 in NCBI Gene Expression Omnibus (GEO) and the accession resolves in the repository. No dataset was downloaded and no licence was read."}}, "can_run": {"dsl_operations": ["normalise_counts", "differential_expression_fit", "fdr_bh"], "assets": ["source:pmid:40274954", "data:geo:GSE151052"], "steps": ["run_analysis"]}, "must_build": {"dsl_operations": [], "converters": [], "readers": [], "capabilities": [], "data_gaps": ["data:geo:GSE151052"]}, "gaps": []}, "review": {"state": "partial", "machine_critique": {"kind": "extraction_review", "reader": {"model": "MiniMax-M3.1-Flash", "provider": "minimax", "provider_family": "minimax", "read_at": "2026-11-01T19:51:01Z", "independence": "single_reader"}, "evidence_check": {"method": "verbatim", "availability": "verbatim"}, "calls": 5, "usage": {"prompt_tokens": 13282, "completion_tokens": 1765, "cached_tokens": 256}}, "human_critique": null, "stages": [{"id": "extraction", "state": "complete", "reader": "MiniMax-M3.1-Flash", "provider": "minimax"}], "gaps": ["review.independent_reader", "review.machine_critique", "review.human_critique"]}, "execution": {"state": "absent", "status": "not_run", "mode": null, "runs": [], "gaps": ["execution.not_run"]}, "provenance": {"entities": [{"id": "pmid:40274954", "type": "paper", "label": "pmid:40274954"}, {"id": "source:pmid:40274954", "type": "manuscript", "label": "PMID 40274954 full text"}, {"id": "data:geo:GSE151052", "type": "dataset", "label": "GEO GSE151052"}], "activities": [{"id": "activity-reading-sci-2026-11-01", "type": "classification", "used": [{"id": "pmid:40274954", "type": "paper", "label": "pmid:40274954"}, {"id": "source:pmid:40274954", "type": "manuscript", "label": "PMID 40274954 full text"}, {"id": "data:geo:GSE151052", "type": "dataset", "label": "GEO GSE151052"}], "agent": "agent:corpus-assay-engine"}, {"id": "activity-read-40274954", "type": "extraction", "used": ["source:pmid:40274954"], "agent": "agent:minimax-reader"}, {"id": "activity-resolve-GSE151052", "type": "accession_resolution", "used": ["data:geo:GSE151052"], "agent": "agent:corpus-assay-engine"}], "agents": [{"id": "agent:corpus-assay-engine", "type": "software", "label": "Corpus assay engine"}, {"id": "agent:minimax-reader", "type": "software", "label": "MiniMax literature reader"}], "source_run_id": "reading-sci-2026-11-01", "dsl_catalogue_fingerprint": "343fb30756ba6ec3", "capability_table_fingerprint": "2cb3e42f047d2ecf", "snapshot_id": "ba34b49490d9bfaf"}, "lineage": {"parent_id": "pmid:40274954", "parent_hash": "sha256:60559498d0f1a2bddc066533836d5c45408b19fa4d8f826f10f8626f9ea38f02", "fork_of": null, "generation": 3}, "gaps": ["asset:data:geo:GSE151052 licence not read", "asset:data:geo:GSE151052 not downloaded", "asset:data:geo:GSE239897 licence not read", "asset:data:geo:GSE239897 not downloaded", "asset:data:geo:GSE57148 licence not read", "asset:data:geo:GSE57148 not downloaded", "asset:data:geo:GSE76925 licence not read", "asset:data:geo:GSE76925 not downloaded", "execution.not_run", "review.human_critique", "review.independent_reader", "review.machine_critique"], "assays": [{"role": "data_generation", "definition_id": "animal_model", "definition_version": "99e1195c7d6f", "definition_digest": null, "required_operations": [], "support_state": "partial", "source_hashes": {"assay_lexicon": "99e1195c7d6f"}, "confidence": 0.77, "evidence": ["tified as a potential therapeutic candidate. In vivo studies confirmed reduced mRNA expression of"], "order_basis": "paper_text_order:1569", "id": "assay:1"}, {"role": "data_generation", "definition_id": "microarray", "definition_version": "99e1195c7d6f", "definition_digest": null, "required_operations": [], "support_state": "partial", "source_hashes": {"assay_lexicon": "99e1195c7d6f"}, "confidence": 0.93, "evidence": ["Materials and methods Microarray data collection and analysis of differential"], "order_basis": "paper_text_order:1822", "id": "assay:2"}, {"role": "analysis", "definition_id": "differential_expression", "definition_version": "f2132e96ae6c7a4e", "definition_digest": null, "required_operations": ["normalise_counts", "differential_expression_fit", "fdr_bh"], "support_state": "supported", "source_hashes": {"dsl_catalogue": "f2132e96ae6c7a4e"}, "confidence": 1.0, "evidence": ["We utilized the limma package and Weighted Gene Co-expression Network Analysis (WGCNA) to analyze datasets from the Gene Expression Omnibus (GEO) database (GSE57148), identifying 12 key differentially expressed mitochondrial genes (MitoDEGs)."], "order_basis": "consumes_earlier_output", "id": "assay:3"}]}