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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Dec 29, 2021
- Source ID
- 10.1371/journal.pgen.1009971
Entities
People
- An Xu
- Benny Abraham Kaipparettu
- Brittany E Jewell
- Christopher Vellano
- Dandan Zhu
- Danielle Bazer
- Dung-Fang Lee
- Erica L. Underwood
- Holger K. Eltzschig
- Huihui Fan
- Jian Tu
- Julian A. Gingold
- Jun Hyoung Park
- Linchao Lu
- Lisa L. Wang
- Mo Liu
- Mo-Fan Huang
- Nathaniel Berg
- Nino Rainusso
- Philip Jones
- Ruiying Zhao
- Ruoji Zhou
- Shu‐Hsia Chen
- Weidong Jin
- Ying Liu
- Yitian Xu
- Yi‐Hung Chen
- Zhongming Zhao
- Zijun Huo
Organizations
- Amschwand Sarcoma Cancer Foundation
- Cancer Prevention and Research Institute of Texas
- Congressionally Directed Medical Research Programs
- Curtis and Doris K. Hankamer Foundation
- Doris Duke Charitable Foundation
- Eunice Kennedy Shriver National Institute of Child Health and Human Development
- Gillson Longenbaugh Foundation
- National Cancer Institute
- National Institutes of Health