Patient-derived iPSCs link elevated mitochondrial respiratory complex I function to osteosarcoma in Rothmund-Thomson syndrome

• Published in: PLoS genetics Vol. 17; no. 12; p. e1009971
• Main Authors: Jewell, Brittany E., Xu, An, Zhu, Dandan, Huang, Mo-Fan, Lu, Linchao, Liu, Mo, Underwood, Erica L., Park, Jun Hyoung, Fan, Huihui, Gingold, Julian A., Zhou, Ruoji, Tu, Jian, Huo, Zijun, Liu, Ying, Jin, Weidong, Chen, Yi-Hung, Xu, Yitian, Chen, Shu-Hsia, Rainusso, Nino, Berg, Nathaniel K., Bazer, Danielle A., Vellano, Christopher, Jones, Philip, Eltzschig, Holger K., Zhao, Zhongming, Kaipparettu, Benny Abraham, Zhao, Ruiying, Wang, Lisa L., Lee, Dung-Fang
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 29.12.2021; Public Library of Science (PLoS)
• Subjects: Adenosine Triphosphate - biosynthesis; Analysis; Biology and Life Sciences; Care and treatment; Cell Proliferation - drug effects; Cell Respiration - drug effects; Cellular Senescence - genetics; Electron Transport Complex I - antagonists & inhibitors; Electron Transport Complex I - genetics; Gene expression; Gene Expression Regulation, Developmental - genetics; Genetic aspects; Humans; Induced Pluripotent Stem Cells - drug effects; Induced Pluripotent Stem Cells - metabolism; Medicine and Health Sciences; Mitogen-Activated Protein Kinase Kinases - genetics; Mutation - genetics; Osteoblasts - drug effects; Osteogenesis - genetics; Osteosarcoma; Osteosarcoma - complications; Osteosarcoma - genetics; Osteosarcoma - pathology; Oxadiazoles - pharmacology; Oxidative Phosphorylation - drug effects; Piperidines - pharmacology; RecQ Helicases - genetics; RNA, Long Noncoding - genetics; Rothmund-Thomson syndrome; Rothmund-Thomson Syndrome - complications; Rothmund-Thomson Syndrome - genetics; Rothmund-Thomson Syndrome - pathology; Stem cells; United States
• ISSN: 1553-7404; 1553-7390; 1553-7404
• DOI: 10.1371/journal.pgen.1009971

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.