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

Brittany E. Jewell, An Xu, Dandan Zhu, Mo Fan Huang, Linchao Lu, Mo Liu, Erica L. Underwood, Jun Hyoung Park, Huihui Fan, Julian A. Gingold, Ruoji Zhou, Jian Tu, Zijun Huo, Ying Liu, Weidong Jin, Yi Hung Chen, Yitian Xu, Shu Hsia Chen, Nino Rainusso, Nathaniel K. BergDanielle A. Bazer, Christopher Vellano, Philip Jones, Holger K. Eltzschig, Zhongming Zhao, Benny Abraham Kaipparettu, Ruiying Zhao, Lisa L. Wang, Dung Fang Lee

Research output: Contribution to journalArticlepeer-review

7 Scopus citations


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.

Original languageEnglish (US)
Article numbere1009971
JournalPLoS Genetics
Issue number12
StatePublished - Dec 29 2021

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Molecular Biology
  • Genetics
  • Genetics(clinical)
  • Cancer Research


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