1-Deoxynojirimycin promotes cardiac function and rescues mitochondrial cristae in mitochondrial hypertrophic cardiomyopathy
Qianqian Zhuang, … , Zhong Liu, Qingfeng Yan
Qianqian Zhuang, … , Zhong Liu, Qingfeng Yan
Published May 18, 2023
Citation Information: J Clin Invest. 2023;133(14):e164660. https://doi.org/10.1172/JCI164660.
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Research Article Cardiology

1-Deoxynojirimycin promotes cardiac function and rescues mitochondrial cristae in mitochondrial hypertrophic cardiomyopathy

Abstract

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.

Authors

Qianqian Zhuang, Fengfeng Guo, Lei Fu, Yufei Dong, Shaofang Xie, Xue Ding, Shuangyi Hu, Xuanhao D. Zhou, Yangwei Jiang, Hui Zhou, Yue Qiu, Zhaoying Lei, Mengyao Li, Huajian Cai, Mingjie Fan, Lingjie Sang, Yong Fu, Dong Zhang, Aifu Lin, Xu Li, Tilo Kunath, Ruhong Zhou, Ping Liang, Zhong Liu, Qingfeng Yan

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Figure 1

Compound screening method in HCM cybrids and HCM iPSC-CMs with mutant mtDNA.

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Compound screening method in HCM cybrids and HCM iPSC-CMs with mutant mt...
(A) Schematic of the 2-step drug screening in HCM cybrids and HCM iPSC-CMs with mutant mtDNA. (B) Screening of 41 chemical compounds from the mitochondrial drug bank (all 30 μM in 0.1% DMSO) for MMP analysis in 1 HCM cybrid cell clone with the MT-RNR2 mutation. HCM cybrids treated with 0.1% DMSO (orange) were used as baseline. Values represent the mean ± SEM. n = 3 biological replicates. 2-tailed t test. Top candidates (P < 0.05) were highlighted in green. (C) Analysis of MMP (dark blue) from selected compounds. The MMP of 143B is shown in grey. Con, control. (D) Examination of total ATP production in response to DNJ, astragalus polyphenols (Astra), or verbenalin (Verb) administration. Values represent the mean ± SEM. n = 3 biologically independent experiments in 3 lines. 1-way ANOVA followed by Tukey’s test. ***P < 0.001. (E) Relative mitochondrial ATP production was measured using recording buffer (containing 5 mM 2-DG and 5mM pyruvate). Values represent the mean ± SEM. n = 3 biologically independent experiments in 3 lines. 1-way ANOVA followed by Tukey’s test. ***P < 0.001. (F) Galactose-induced cell death assay in HCM iPSC-CMs. Time course (left) and survival rate quantification (right) are shown as the mean ± SEM, n = 3 biologically independent experiments. 2-way ANOVA analysis. ***P < 0.001. Data are representative of 3 independent experiments.