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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| Language: | English |
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Public Library of Science (PLoS)
2021-12-01
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| Series: | PLoS Genetics |
| Online Access: | https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1009971&type=printable |
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| author | 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 Berg Danielle A Bazer Christopher Vellano Philip Jones Holger K Eltzschig Zhongming Zhao Benny Abraham Kaipparettu Ruiying Zhao Lisa L Wang Dung-Fang Lee |
| author_facet | 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 Berg Danielle A Bazer Christopher Vellano Philip Jones Holger K Eltzschig Zhongming Zhao Benny Abraham Kaipparettu Ruiying Zhao Lisa L Wang Dung-Fang Lee |
| author_sort | Brittany E Jewell |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-c2342e4657584eb5b330edbc4ecee86b |
| institution | Kabale University |
| issn | 1553-7390 1553-7404 |
| language | English |
| publishDate | 2021-12-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Genetics |
| spelling | doaj-art-c2342e4657584eb5b330edbc4ecee86b2025-01-30T05:30:43ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042021-12-011712e100997110.1371/journal.pgen.1009971Patient-derived iPSCs link elevated mitochondrial respiratory complex I function to osteosarcoma in Rothmund-Thomson syndrome.Brittany E JewellAn XuDandan ZhuMo-Fan HuangLinchao LuMo LiuErica L UnderwoodJun Hyoung ParkHuihui FanJulian A GingoldRuoji ZhouJian TuZijun HuoYing LiuWeidong JinYi-Hung ChenYitian XuShu-Hsia ChenNino RainussoNathaniel K BergDanielle A BazerChristopher VellanoPhilip JonesHolger K EltzschigZhongming ZhaoBenny Abraham KaipparettuRuiying ZhaoLisa L WangDung-Fang LeeRothmund-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.https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1009971&type=printable |
| spellingShingle | 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 Berg Danielle A Bazer Christopher Vellano Philip Jones Holger K Eltzschig Zhongming Zhao Benny Abraham Kaipparettu Ruiying Zhao Lisa L Wang Dung-Fang Lee Patient-derived iPSCs link elevated mitochondrial respiratory complex I function to osteosarcoma in Rothmund-Thomson syndrome. PLoS Genetics |
| title | Patient-derived iPSCs link elevated mitochondrial respiratory complex I function to osteosarcoma in Rothmund-Thomson syndrome. |
| title_full | Patient-derived iPSCs link elevated mitochondrial respiratory complex I function to osteosarcoma in Rothmund-Thomson syndrome. |
| title_fullStr | Patient-derived iPSCs link elevated mitochondrial respiratory complex I function to osteosarcoma in Rothmund-Thomson syndrome. |
| title_full_unstemmed | Patient-derived iPSCs link elevated mitochondrial respiratory complex I function to osteosarcoma in Rothmund-Thomson syndrome. |
| title_short | Patient-derived iPSCs link elevated mitochondrial respiratory complex I function to osteosarcoma in Rothmund-Thomson syndrome. |
| title_sort | patient derived ipscs link elevated mitochondrial respiratory complex i function to osteosarcoma in rothmund thomson syndrome |
| url | https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1009971&type=printable |
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