In:
PLOS Genetics, Public Library of Science (PLoS), Vol. 17, No. 12 ( 2021-12-29), p. e1009971-
Kurzfassung:
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.
Materialart:
Online-Ressource
ISSN:
1553-7404
DOI:
10.1371/journal.pgen.1009971
DOI:
10.1371/journal.pgen.1009971.g001
DOI:
10.1371/journal.pgen.1009971.g002
DOI:
10.1371/journal.pgen.1009971.g003
DOI:
10.1371/journal.pgen.1009971.g004
DOI:
10.1371/journal.pgen.1009971.g005
DOI:
10.1371/journal.pgen.1009971.t001
DOI:
10.1371/journal.pgen.1009971.s001
DOI:
10.1371/journal.pgen.1009971.s002
DOI:
10.1371/journal.pgen.1009971.s003
DOI:
10.1371/journal.pgen.1009971.s004
DOI:
10.1371/journal.pgen.1009971.s005
DOI:
10.1371/journal.pgen.1009971.s006
DOI:
10.1371/journal.pgen.1009971.s007
DOI:
10.1371/journal.pgen.1009971.r001
DOI:
10.1371/journal.pgen.1009971.r002
DOI:
10.1371/journal.pgen.1009971.r003
DOI:
10.1371/journal.pgen.1009971.r004
Sprache:
Englisch
Verlag:
Public Library of Science (PLoS)
Publikationsdatum:
2021
ZDB Id:
2186725-2
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