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

PLoS Genet. 2021 Dec 29;17(12):e1009971. doi: 10.1371/journal.pgen.1009971. eCollection 2021 Dec.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adenosine Triphosphate / biosynthesis
  • Cell Proliferation / drug effects
  • Cell Respiration / drug effects
  • Cellular Senescence / genetics
  • Electron Transport Complex I / antagonists & inhibitors
  • Electron Transport Complex I / genetics*
  • Gene Expression Regulation, Developmental / genetics
  • Humans
  • Induced Pluripotent Stem Cells / drug effects
  • Induced Pluripotent Stem Cells / metabolism
  • Mitogen-Activated Protein Kinase Kinases / genetics
  • Mutation / genetics
  • Osteoblasts / drug effects
  • Osteogenesis / genetics
  • Osteosarcoma / complications
  • Osteosarcoma / genetics*
  • Osteosarcoma / pathology
  • Oxadiazoles / pharmacology
  • Oxidative Phosphorylation / drug effects
  • Piperidines / pharmacology
  • RNA, Long Noncoding / genetics*
  • RecQ Helicases / genetics*
  • Rothmund-Thomson Syndrome / complications
  • Rothmund-Thomson Syndrome / genetics*
  • Rothmund-Thomson Syndrome / pathology

Substances

  • H19 long non-coding RNA
  • IACS-010759
  • Oxadiazoles
  • Piperidines
  • RNA, Long Noncoding
  • Adenosine Triphosphate
  • Mitogen-Activated Protein Kinase Kinases
  • RECQL4 protein, human
  • RecQ Helicases
  • Electron Transport Complex I