LETM2 regulates mitochondrial function and autophagy in diabetic foot ulcers: implications for oxidative stress and therapeutic targeting.

{"sci_version": "1.2", "schema": "https://corpus.bntrg.co.uk/sci/1.0/sci.schema.json", "id": "pmid:41272316", "kind": "science-record", "revision": 4, "content_hash": "sha256:8c62b53e195b5a041385ce9aadd19781c52a98563cc16114d60cf7404969caac", "created_at": "2026-11-01T20:31:18Z", "updated_at": "2026-11-01T22:57:30Z", "generator": {"name": "corpus-assay-engine", "run_id": "reading-sci-2026-11-01"}, "paper": {"state": "complete", "title": "LETM2 regulates mitochondrial function and autophagy in diabetic foot ulcers: implications for oxidative stress and therapeutic targeting.", "doi": "10.1007/s10142-025-01748-1", "pmid": "41272316", "authors": ["Nan Su", "Jiwei Wang", "Zhiwei Xue", "Shujie Peng", "Wenchen Xing", "Haoyong Jin", "Jiangli Zhao", "Yanya He", "Jiaqi Shi", "Wenbo Li", "Qijian Wei", "Bin Huang", "Chao Li", "Xinyu Wang", "Pei Liu", "Ning Yang"], "journal": "Functional & integrative genomics", "year": 2025, "abstract": "Background A major complication of diabetes, diabetic foot ulcers (DFU), has been linked to mitochondrial dysfunction and oxidative stress. Here, we performed analysis of RNA sequencing data from publicly available databases, including single-cell assays, to identify dysregulated genes associated with these processes in DFU and the specific cell types involved. Methods Analysis of transcriptome sequencing was performed on GSE134431 and GSE80178 datasets from the GEO database to identify differentially expressed mitochondrial-related genes (DE-MRGs) in DFU samples relative to controls. LASSO and SVM-RFE algorithms were used to identify critical genes, and functional enrichment analyses were conducted to identify associated pathways. Results were validated in a cohort of DFU samples and controls processed at our institution, and single-cell RNA sequencing data from GSE245703 was used to determine expression of candidate genes in endothelial cells from DFU relative to non-DFU samples. SiRNA knockdown of one candidate gene, LETM2, was performed in human umbilical vein endothelial cells (HUVECs) exposed to H2O2 as a model system for oxidative stress. Results LETM2 emerged as key gene significantly associated with DFU from our integrated analysis of the DFU RNA sequencing datasets. Single-cell RNA sequencing data revealed increased expression of LETM2 in endothelial cells from DFU samples compared to controls. Transcriptome sequencing of RNA from HUVECs with LETM2 knockdown under oxidative stress conditions revealed corelated expression with other genes involved in mitochondrial function. HUVECs with LETM2 knockdown furthermore showed impaired mitochondrial fission and mitophagy, as well as decreased cell viability and increased apoptosis in vitro. Conclusions These findings indicate a role for LETM2 in preserving mitochondrial function in HUVECs under oxidative stress and underscore its potential as a therapeutic target for mitigating mitochondrial dysfunction in diabetic complications such as DFU.", "claims": [{"id": "claim-method", "statement": "A dual-algorithm strategy combining LASSO regression and SVM-RFE was employed to identify characteristic genes related to DFU from the GSE134431 and GSE80178 datasets.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:41272316", "locator": "sections[23] \"Identification of DFU-related characteristic differentially expressed mitochondrial-related genes (DE-MRGs)\" paragraph 2", "quote": "A dual-algorithm strategy combining LASSO regression and SVM-RFE was employed to identify characteristic genes related to DFU from the GSE134431 and GSE80178 datasets."}], "state": "complete"}, {"id": "claim-data-access", "statement": "Datasets and other files generated, analyzed, or used during this study are available from the corresponding author upon reasonable request.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:41272316", "locator": "sections[33] \"Data availability\" paragraph 2", "quote": "Datasets and other files generated, analyzed, or used during this study are available from the corresponding author upon reasonable request."}], "state": "complete"}, {"id": "claim-target-result", "statement": "LETM2 emerged as a key gene associated with DFU, with increased endothelial-cell expression in DFU and a protective role in mitochondrial function under oxidative stress.", "kind": "qualitative", "target": null, "evidence": [{"asset": "source:pmid:41272316", "locator": "sections[0] \"Abstract\" paragraph 1", "quote": "LETM2 emerged as key gene significantly associated with DFU from our integrated analysis of the DFU RNA sequencing datasets."}, {"asset": "source:pmid:41272316", "locator": "sections[0] \"Abstract\" paragraph 1", "quote": "Single-cell RNA sequencing data revealed increased expression of LETM2 in endothelial cells from DFU samples compared to controls."}, {"asset": "source:pmid:41272316", "locator": "sections[0] \"Abstract\" paragraph 1", "quote": "HUVECs with LETM2 knockdown furthermore showed impaired mitochondrial fission and mitophagy, as well as decreased cell viability and increased apoptosis in vitro."}], "state": "complete"}], "gaps": []}, "experiment": {"state": "complete", "objective": "LETM2 emerged as a key gene associated with DFU, with increased endothelial-cell expression in DFU and a protective role in mitochondrial function under oxidative stress.", "steps": [{"id": "read_published_estimate", "order": 1, "name": "Read the published estimate from the source", "kind": "other", "state": "complete", "blocked_on": null, "description": "The claim, method and evidence span published with the source article.", "duration_hours": null, "parameters": {}, "inputs": ["source:pmid:41272316"], "outputs": ["the published estimate and its evidence"], "instruments": [], "reagents": []}, {"id": "obtain_source_data", "order": 2, "name": "Obtain the source data from the named repository", "kind": "data-preparation", "state": "complete", "blocked_on": null, "description": "The GEO series accession resolves and its sample accessions are listed. 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Here, we performed analysis of RNA sequencing data from publicly available databases, incl", "rocessed at our institution, and single-cell RNA sequencing data from GSE245703 was used to determine ex", "DFU from our integrated analysis of the DFU RNA sequencing datasets. Single-cell RNA sequencing data re", "the DFU RNA sequencing datasets. Single-cell RNA sequencing data revealed increased expression of LETM2"], "order_basis": "paper_text_order:265", "id": "assay:1"}, {"role": "data_generation", "definition_id": "scrna_seq", "definition_version": "99e1195c7d6f", "definition_digest": null, "required_operations": [], "support_state": "unsupported", "source_hashes": {"assay_lexicon": "99e1195c7d6f"}, "confidence": 0.99, "evidence": ["d controls processed at our institution, and single-cell RNA sequencing data from GSE245703 was used to determine ex", "analysis of the DFU RNA sequencing datasets. Single-cell RNA sequencing data revealed increased expression of LETM2", "analysis of the LETM2 expression profile Raw single-cell RNA-seq data underwent the following quality control", "from DFU samples A comprehensive analysis of single-cell RNA sequencing data from 5 DFU and 7 non-diabetic ulcer sam"], "order_basis": "paper_text_order:933", "id": "assay:2"}, {"role": "data_generation", "definition_id": "transfection", "definition_version": "99e1195c7d6f", "definition_digest": null, "required_operations": [], "support_state": "partial", "source_hashes": {"assay_lexicon": "99e1195c7d6f"}, "confidence": 0.99, "evidence": ["from DFU relative to non-DFU samples. SiRNA knockdown of one candidate gene, LETM2, was performed", "ome sequencing of RNA from HUVECs with LETM2 knockdown under oxidative stress conditions revealed c", "in mitochondrial function. HUVECs with LETM2 knockdown furthermore showed impaired mitochondrial fi", "cells from DFU relative to non-DFU samples. SiRNA knockdown of one candidate gene, LETM2, was"], "order_basis": "paper_text_order:1092", "id": "assay:3"}, {"role": "data_generation", "definition_id": "apoptosis_assay", "definition_version": "99e1195c7d6f", "definition_digest": null, "required_operations": [], "support_state": "partial", "source_hashes": {"assay_lexicon": "99e1195c7d6f"}, "confidence": 0.93, "evidence": ["ll as decreased cell viability and increased apoptosis in vitro. Conclusions These findings indicat", "species (ROS) production, inflammation, and apoptosis, which together impair wound healing (Fang e"], "order_basis": "paper_text_order:1847", "id": "assay:4"}, {"role": "data_generation", "definition_id": "ihc", "definition_version": "99e1195c7d6f", "definition_digest": null, "required_operations": [], "support_state": "partial", "source_hashes": {"assay_lexicon": "99e1195c7d6f"}, "confidence": 0.93, "evidence": ["VECs with 300 µM hydrogen peroxide for 48 h. Immunofluorescence and cytoskeletal staining revealed significa"], "order_basis": "paper_text_order:12853", "id": "assay:5"}, {"role": "data_generation", "definition_id": "western_blot", "definition_version": "99e1195c7d6f", "definition_digest": null, "required_operations": [], "support_state": "partial", "source_hashes": {"assay_lexicon": "99e1195c7d6f"}, "confidence": 0.93, "evidence": ["rked increase in LETM2 expression (Fig. 3E). Western blot and qPCR analyses confirmed that LETM2 expre"], "order_basis": "paper_text_order:13007", "id": "assay:6"}, {"role": "data_generation", "definition_id": "qpcr", "definition_version": "99e1195c7d6f", "definition_digest": null, "required_operations": [], "support_state": "partial", "source_hashes": {"assay_lexicon": "99e1195c7d6f"}, "confidence": 0.93, "evidence": ["LETM2 expression (Fig. 3E). Western blot and qPCR analyses confirmed that LETM2 expression was"], "order_basis": "paper_text_order:13024", "id": "assay:7"}, {"role": "analysis", "definition_id": "machine_learning", "definition_version": "f2132e96ae6c7a4e", "definition_digest": null, "required_operations": ["train_classifier", "cross_validate", "roc_auc"], "support_state": "supported", "source_hashes": {"dsl_catalogue": "f2132e96ae6c7a4e"}, "confidence": 1.0, "evidence": ["A dual-algorithm strategy combining LASSO regression and SVM-RFE was employed to identify characteristic genes related to DFU from the GSE134431 and GSE80178 datasets."], "order_basis": "consumes_earlier_output", "id": "assay:8"}]}