Zhang Xu, Zhang Zhengyang, Wan Sitong, Qi Jingyi, Hao Yanling, An Peng, Luo Yongting, Luo Junjie
Department of Nutrition and Health, China Agricultural University, Beijing 100193, China.
Int J Mol Sci. 2024 Feb 25;25(5):2662. doi: 10.3390/ijms25052662.
Mutations of the gene lead to Marfan syndrome (MFS), which is an autosomal dominant connective tissue disorder featured by thoracic aortic aneurysm risk. There is currently no effective treatment for MFS. Here, we studied the role of mitochondrial dysfunction in the phenotypic transformation of human smooth muscle cells (SMCs) and whether a mitochondrial boosting strategy can be a potential treatment. We knocked down in SMCs to create an MFS cell model and used rotenone to induce mitochondrial dysfunction. Furthermore, we incubated the SMCs with Coenzyme Q10 (CoQ10) to assess whether restoring mitochondrial function can reverse the phenotypic transformation. The results showed that SMCs had decreased (mitochondrial transcription factor A), mtDNA levels and mitochondrial mass, lost their contractile capacity and had increased synthetic phenotype markers. Inhibiting the mitochondrial function of SMCs can decrease the expression of contractile markers and increase the expression of synthetic genes. Imposing mitochondrial stress causes a double-hit effect on the level, oxidative phosphorylation and phenotypic transformation of -knockdown SMCs while restoring mitochondrial metabolism with CoQ10 can rapidly reverse the synthetic phenotype. Our results suggest that mitochondria function is a potential therapeutic target for the phenotypic transformation of SMCs in MFS.
该基因的突变会导致马凡综合征（MFS），这是一种常染色体显性遗传性结缔组织疾病，其特征是存在胸主动脉瘤风险。目前尚无针对MFS的有效治疗方法。在此，我们研究了线粒体功能障碍在人类平滑肌细胞（SMC）表型转化中的作用，以及线粒体增强策略是否可能成为一种潜在的治疗方法。我们在SMC中敲低该基因以创建MFS细胞模型，并使用鱼藤酮诱导线粒体功能障碍。此外，我们用辅酶Q10（CoQ10）孵育SMC，以评估恢复线粒体功能是否能逆转表型转化。结果显示，SMC中的（线粒体转录因子A）、线粒体DNA水平和线粒体质量下降，失去收缩能力，且合成表型标志物增加。抑制SMC的线粒体功能可降低收缩标志物的表达，并增加合成基因的表达。施加线粒体应激会对敲低该基因的SMC的水平、氧化磷酸化和表型转化产生双重打击效应，而用CoQ10恢复线粒体代谢可迅速逆转合成表型。我们的结果表明，线粒体功能是MFS中SMC表型转化的一个潜在治疗靶点。
