Department of Integrative Biology and Pharmacology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, Texas, United States of America.
The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, Texas, United States of America.
PLoS Genet. 2021 Dec 29;17(12):e1009971. doi: 10.1371/journal.pgen.1009971. eCollection 2021 Dec.
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 综合征（RTS）是一种常染色体隐性遗传疾病，其特征为斑驳皮肤、身材矮小、骨骼异常、稀疏的眉毛/睫毛、白内障和癌症易感性。具有双等位基因 RECQL4 致病变异的 2 型 RTS 患者有多种骨骼异常，骨肉瘤的发病率显著增加。在这里，我们生成了 RTS 患者来源的诱导多能干细胞（iPSC），以剖析导致 RTS 患者骨肉瘤的病理信号。RTS iPSC 衍生的成骨细胞表现出成骨分化缺陷和体外致瘤能力增加。RTS 成骨细胞的转录组分析验证了骨形态发生的减少，同时揭示了异常上调的线粒体呼吸复合物 I 基因表达。RTS 成骨细胞代谢测定表明线粒体呼吸复合物 I 功能升高、氧化磷酸化（OXPHOS）增加和 ATP 产生增加。线粒体呼吸复合物 I 活性的抑制通过 IACS-010759 选择性地抑制 RTS 成骨细胞的细胞呼吸和增殖。此外，对 IACS-010759 诱导的 RTS 成骨细胞变化的系统分析表明，线粒体呼吸复合物 I 的化学抑制会抑制细胞增殖、诱导衰老、降低 MAPK 信号和细胞周期相关基因，而增加 H19 和核糖体蛋白基因。总之，我们的研究表明，线粒体呼吸复合物 I 是 RTS 相关骨肉瘤的潜在治疗靶点，并为临床治疗策略提供了未来的见解。
