{"doi":"10.1016/j.mitoco.2025.03.001","title":"Exploring the oncogenic impact of heteroplasmic de novo MT-ND5 truncating mutations","abstract":"Numerous mitochondrial DNA (mtDNA) variants are associated with cancers, yet the causal link remains inconclusive. Using DddA-derived cytosine base editors, we induced de novo truncating mutations in MT-ND5 in HEK293 cells, establishing heteroplasmy, the coexistence of mutant and wild-type mtDNA. This study aimed to investigate the full molecular etiology following these deleterious mtDNA mutations, particularly in oncogenesis. We found that low to moderate heteroplasmic levels of the mutants were sufficient to impair mitochondrial functions and alter cellular redox status. Cellular adaptation to elevated ROS (Reactive Oxygen Species), energy crisis, and altered redox status was observed across varying heteroplasmy levels. Increased oncogenic potential was confirmed through in vitro oncogenesis and in vivo xenograft assays. Transcriptomic analysis revealed upregulated migration, invasion, and genome instability pathways, and downregulated ROS scavenging pathways. Our results demonstrate that MT-ND5 mutations drive cancer progression by increasing cellular ROS and genome instability, and by altering the redox balance and epigenetic landscapes. • Induced MT-ND5 mutations impair mitochondrial functions and enhance oncogenic potential. • Total ATP production fully recovers but not NAD + /NADH ratio as MT-ND5 mutation rate decreases. • Heteroplasmic levels of MT-ND5 mutants increase ROS levels and genome instability. • Transcriptomic analysis reveals pathways linked to cell migration, invasion, and altered redox balance. • This study establishes a causal link between deleterious mtDNA variants and oncogenesis.","journal":"Mitochondrial Communications","year":2025,"id":528064,"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":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9609,"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":267791,"name":"Jiangbin Ye","orcid":"0000-0003-1117-4869","position":1,"is_corresponding":false},{"id":424592,"name":"Zhenglong Gu","orcid":"0000-0002-7733-432X","position":2,"is_corresponding":false},{"id":1405475,"name":"Yuanyuan Wu","orcid":"0000-0002-4599-0162","position":0,"is_corresponding":true}],"reference_count":111,"raw_metadata":null,"created_at":"2026-07-19T02:50:44.062153Z","pmid":"40671877","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":[]}