Patient-derived iPSCs link elevated mitochondrial respiratory complex I function to osteosarcoma in Rothmund-Thomson syndrome
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 an...
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| Published in | PLoS genetics Vol. 17; no. 12; p. e1009971 |
|---|---|
| Main Authors | , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
United States
Public Library of Science
29.12.2021
Public Library of Science (PLoS) |
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| 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. |
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| AbstractList | 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. 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. Rothmund-Thomson syndrome (RTS) is an autosomal recessive genetic disease characterized by an array of clinical phenotypes affecting multiple tissues. Type 2 RTS is caused by pathogenic variants in the RECQL4 gene encoding the RECQL4 DNA helicase. Type 2 RTS patients are prone to developing multiple primary osteosarcomas and have limited chemotherapy options due to organ toxicities or lifetime limits on active agents such as anthracyclines. There is currently no available RTS model that recapitulates the bone malignancy phenotype in this disease, severely limiting the ability to explore new treatment avenues which are greatly needed for these patients. To overcome this problem, we established a Type 2 RTS disease model using a human induced pluripotent stem cell platform. We then applied an unbiased approach to explore novel molecular mechanisms involved in RECQL4 mutation-induced osteosarcoma to explore therapeutic interventions. Our findings indicate that mitochondrial respiratory complex I is an “Achilles’ heel” of RTS osteosarcoma and that cancers harboring RECQL4 mutations/deletions, in general, may be vulnerable to mitochondrial respiratory complex I inhibition. 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. 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.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. |
| Audience | Academic |
| Author | Park, Jun Hyoung Lee, Dung-Fang Zhu, Dandan Gingold, Julian A. Jin, Weidong Eltzschig, Holger K. Underwood, Erica L. Wang, Lisa L. Huo, Zijun Vellano, Christopher Jones, Philip Kaipparettu, Benny Abraham Liu, Mo Lu, Linchao Rainusso, Nino Zhao, Zhongming Chen, Shu-Hsia Xu, An Huang, Mo-Fan Liu, Ying Berg, Nathaniel K. Zhao, Ruiying Jewell, Brittany E. Tu, Jian Fan, Huihui Zhou, Ruoji Chen, Yi-Hung Bazer, Danielle A. Xu, Yitian |
| AuthorAffiliation | 10 Department of Anesthesiology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, Texas, United States of America 9 Center for Immunotherapy Research, Cancer Center of Excellence, Houston Methodist Research Institute, Houston, Texas, United States of America 11 Department of Neurology, Renaissance School of Medicine at Stony Brook University, Stony Brook, New York, United States of America 5 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America 1 Department of Integrative Biology and Pharmacology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, Texas, United States of America 8 Department and Institute of Pharmacology, National Yang Ming Chiao Tung University, Taipei, Taiwan 3 Department of Pediatrics, Baylor College of Medicine, Texas Children’s Hospital, Houston, Texas, United States of America 13 Center for Stem Cell and Regenerative Medicine, Th |
| AuthorAffiliation_xml | – name: 1 Department of Integrative Biology and Pharmacology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, Texas, United States of America – name: 8 Department and Institute of Pharmacology, National Yang Ming Chiao Tung University, Taipei, Taiwan – name: 12 TRACTION Platform, Therapeutics Discovery Division, University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America – name: 3 Department of Pediatrics, Baylor College of Medicine, Texas Children’s Hospital, Houston, Texas, United States of America – name: 5 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America – name: 7 Department of Obstetrics & Gynecology and Women’s Health, Einstein/Montefiore Medical Center, New York City, New York, United States of America – name: 11 Department of Neurology, Renaissance School of Medicine at Stony Brook University, Stony Brook, New York, United States of America – name: 9 Center for Immunotherapy Research, Cancer Center of Excellence, Houston Methodist Research Institute, Houston, Texas, United States of America – name: 4 Department of Neurobiology and Anatomy, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, Texas, United States of America – name: 10 Department of Anesthesiology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, Texas, United States of America – name: 6 Center for Precision Health, School of Biomedical Informatics, The University of Texas Health Science Center at Houston, Houston, Texas, United States of America – name: 13 Center for Stem Cell and Regenerative Medicine, The Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases, The University of Texas Health Science Center at Houston, Houston, Texas, United States of America – name: St Jude Children’s Research Hospital, UNITED STATES – name: 2 The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, Texas, United States of America |
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| Snippet | Rothmund-Thomson syndrome (RTS) is an autosomal recessive genetic disorder characterized by poikiloderma, small stature, skeletal anomalies, sparse... |
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| SubjectTerms | 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 |
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| Title | Patient-derived iPSCs link elevated mitochondrial respiratory complex I function to osteosarcoma in Rothmund-Thomson syndrome |
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