College of Life Science, Zhejiang University, Hangzhou, Zhejiang, China.
The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
J Clin Invest. 2023 Jul 17;133(14):e164660. doi: 10.1172/JCI164660.
Hypertrophic cardiomyopathy (HCM) is the most prominent cause of sudden cardiac death in young people. Due to heterogeneity in clinical manifestations, conventional HCM drugs have limitations for mitochondrial hypertrophic cardiomyopathy. Discovering more effective compounds would be of substantial benefit for further elucidating the pathogenic mechanisms of HCM and treating patients with this condition. We previously reported the MT-RNR2 variant associated with HCM that results in mitochondrial dysfunction. Here, we screened a mitochondria-associated compound library by quantifying the mitochondrial membrane potential of HCM cybrids and the survival rate of HCM-induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) in galactose media. 1-Deoxynojirimycin (DNJ) was identified to rescue mitochondrial function by targeting optic atrophy protein 1 (OPA1) to promote its oligomerization, leading to reconstruction of the mitochondrial cristae. DNJ treatment further recovered the physiological properties of HCM iPSC-CMs by improving Ca2+ homeostasis and electrophysiological properties. An angiotensin II-induced cardiac hypertrophy mouse model further verified the efficacy of DNJ in promoting cardiac mitochondrial function and alleviating cardiac hypertrophy in vivo. These results demonstrated that DNJ could be a potential mitochondrial rescue agent for mitochondrial hypertrophic cardiomyopathy. Our findings will help elucidate the mechanism of HCM and provide a potential therapeutic strategy.
肥厚型心肌病(HCM)是年轻人心脏性猝死的最主要原因。由于临床表现存在异质性,传统的 HCM 药物对于线粒体型肥厚型心肌病的治疗存在局限性。发现更有效的化合物将对进一步阐明 HCM 的发病机制和治疗该疾病的患者具有重要意义。我们之前曾报道过与 HCM 相关的 MT-RNR2 变异,该变异导致线粒体功能障碍。在这里,我们通过量化 HCM 杂种细胞的线粒体膜电位和半乳糖培养基中 HCM 诱导多能干细胞衍生心肌细胞(iPSC-CMs)的存活率,对线粒体相关化合物库进行了筛选。1-脱氧野尻霉素(DNJ)被鉴定为通过靶向视神经萎缩蛋白 1(OPA1)来促进其寡聚化,从而恢复线粒体嵴,从而挽救线粒体功能。DNJ 处理通过改善 Ca2+稳态和电生理特性,进一步恢复了 HCM iPSC-CMs 的生理特性。血管紧张素 II 诱导的心肌肥厚小鼠模型进一步验证了 DNJ 在体内促进心肌线粒体功能和减轻心肌肥厚的功效。这些结果表明,DNJ 可能是一种潜在的线粒体拯救剂,适用于线粒体型肥厚型心肌病。我们的研究结果将有助于阐明 HCM 的发病机制,并提供一种潜在的治疗策略。