{"doi":"10.1101/2025.11.19.688750","title":"Copper deficiency drives OXPHOS impairment and mitochondrial hyperfusion via MTCH2 in skeletal muscle","abstract":"Summary Copper is an essential trace element for mitochondrial respiration and cellular metabolism, yet its physiological role in skeletal muscle remains incompletely understood. Here, we show that skeletal muscle-specific deletion of the high-affinity copper importer Ctr1 (SMKO) in mice causes local copper deficiency, resulting in exercise intolerance, systemic metabolic dysfunction, and hallmarks of mitochondrial myopathy such as ragged-red fibers, lactic acidosis, and aberrant mitochondrial morphology. Mechanistically, copper starvation disrupted the electron transport chain proteome and drove pathological mitochondrial hyperfusion. We identified mitochondrial carrier homolog 2 (MTCH2), an outer mitochondrial membrane protein, as a copper-binding regulator that coordinates mitochondrial copper distribution and morphology. Restoring copper levels via a copper ionophore or AAV-mediated Ctr1 re-expression rescued mitochondrial function and alleviated myopathic features in SMKO. These findings uncover the functional coupling of CTR1 and MTCH2 as a critical mechanistic link between copper homeostasis and mitochondrial remodeling required for skeletal muscle function.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":581708,"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":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.951,"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":319509,"name":"Hee Soo Kim","orcid":null,"position":1,"is_corresponding":false},{"id":1493603,"name":"Phuc L. Nguyen","orcid":null,"position":2,"is_corresponding":false},{"id":1493273,"name":"Junhyeong Lee","orcid":"0000-0001-9040-7231","position":3,"is_corresponding":false},{"id":640864,"name":"Dong‐Il Kim","orcid":"0000-0002-5313-9554","position":4,"is_corresponding":false},{"id":1356471,"name":"Jeongmin Lee","orcid":"0000-0003-2554-4285","position":5,"is_corresponding":false},{"id":443108,"name":"Changjong Moon","orcid":"0000-0003-2451-0374","position":6,"is_corresponding":false},{"id":1493274,"name":"Kyoung‐Oh Cho","orcid":"0000-0002-5477-7021","position":7,"is_corresponding":false},{"id":1493604,"name":"Byung-Eun Kim","orcid":null,"position":8,"is_corresponding":false},{"id":1493275,"name":"Jiyun Ahn","orcid":"0000-0002-5930-2957","position":9,"is_corresponding":false},{"id":301826,"name":"Timothy F. Osborne","orcid":"0000-0002-5150-4300","position":10,"is_corresponding":false},{"id":1493276,"name":"Taner Duysak","orcid":"0000-0001-7603-0458","position":11,"is_corresponding":false},{"id":1493277,"name":"Jeong‐Sun Kim","orcid":"0000-0003-4401-2890","position":12,"is_corresponding":false},{"id":1493605,"name":"Chang Hwa Jung","orcid":null,"position":13,"is_corresponding":false},{"id":1493606,"name":"Tae Il Jeon","orcid":null,"position":14,"is_corresponding":false},{"id":1493602,"name":"Young-Seung Lee","orcid":null,"position":0,"is_corresponding":true}],"reference_count":56,"raw_metadata":null,"created_at":"2026-07-19T02:58:51.328454Z","pmid":"41332672","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":[]}