{"doi":"10.1371/journal.pgen.1009971","title":"Patient-derived iPSCs link elevated mitochondrial respiratory complex I function to osteosarcoma in Rothmund-Thomson syndrome","abstract":"Rothmund-Thomson syndrome (RTS) is an autosomal recessive genetic disorder characterized by poikiloderma, small stature, skeletal anomalies, sparse brows/lashes, cataracts, and predisposition to cancer. Type 2 RTS patients with biallelic RECQL4 pathogenic variants have multiple skeletal anomalies and a significantly increased incidence of osteosarcoma. Here, we generated RTS patient-derived induced pluripotent stem cells (iPSCs) to dissect the pathological signaling leading to RTS patient-associated osteosarcoma. RTS iPSC-derived osteoblasts showed defective osteogenic differentiation and gain of in vitro tumorigenic ability. Transcriptome analysis of RTS osteoblasts validated decreased bone morphogenesis while revealing aberrantly upregulated mitochondrial respiratory complex I gene expression. RTS osteoblast metabolic assays demonstrated elevated mitochondrial respiratory complex I function, increased oxidative phosphorylation (OXPHOS), and increased ATP production. Inhibition of mitochondrial respiratory complex I activity by IACS-010759 selectively suppressed cellular respiration and cell proliferation of RTS osteoblasts. Furthermore, systems analysis of IACS-010759-induced changes in RTS osteoblasts revealed that chemical inhibition of mitochondrial respiratory complex I impaired cell proliferation, induced senescence, and decreased MAPK signaling and cell cycle associated genes, but increased H19 and ribosomal protein genes. In summary, our study suggests that mitochondrial respiratory complex I is a potential therapeutic target for RTS-associated osteosarcoma and provides future insights for clinical treatment strategies.","journal":"PLoS Genetics","year":2021,"id":180904,"datarank":0.5262599451206214,"base_score":2.8903717578961645,"endowment":2.8903717578961645,"self_citation_contribution":0.4335557636844247,"citation_network_contribution":0.09270418143619667,"self_endowment_contribution":0.4335557636844247,"citer_contribution":0.09270418143619667,"corpus_percentile":null,"corpus_rank":null,"citation_count":17,"citer_count":7,"citers_with_citation_signal":5,"citers_with_endowment":5,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9124,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":731044,"name":"An Xu","orcid":"0000-0003-1776-7972","position":1,"is_corresponding":false},{"id":731045,"name":"Dandan Zhu","orcid":"0000-0003-4609-1238","position":2,"is_corresponding":false},{"id":731046,"name":"Mo-Fan Huang","orcid":"0000-0002-2209-1236","position":3,"is_corresponding":false},{"id":731047,"name":"Linchao Lu","orcid":"0000-0002-5560-0025","position":4,"is_corresponding":false},{"id":731048,"name":"Mo Liu","orcid":"0000-0001-8649-1514","position":5,"is_corresponding":false},{"id":294372,"name":"Erica L. 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