Key result
1-Deoxynojirimycin rescued mitochondrial function and alleviated cardiac hypertrophy by targeting OPA1 to promote its oligomerization and reconstruct mitochondrial cristae in models of mitochondrial hypertrophic cardiomyopathy.
Why the study?
Due to heterogeneity in clinical manifestations, conventional HCM drugs have limitations for mitochondrial hypertrophic cardiomyopathy, necessitating more effective compounds.
Does 1-Deoxynojirimycin improve mitochondrial and cardiac function in preclinical models of mitochondrial hypertrophic cardiomyopathy?
Does 1-Deoxynojirimycin improve mitochondrial and cardiac function in preclinical models of mitochondrial hypertrophic cardiomyopathy?
1-Deoxynojirimycin acts as a potential mitochondrial rescue agent for mitochondrial hypertrophic cardiomyopathy by targeting OPA1 to promote cristae reconstruction.
DNJ may merit testing in mitochondrial HCM patients; leaves open clinical translation from iPSC and mouse models.
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.
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Zhuang et al. (2023) studied Mitochondrial hypertrophic cardiomyopathy. 1-Deoxynojirimycin (DNJ) vs. Vehicle/Control was evaluated on Mitochondrial function and cardiac hypertrophy. 1-Deoxynojirimycin rescued mitochondrial function and alleviated cardiac hypertrophy by targeting OPA1 to promote its oligomerization and reconstruct mitochondrial cristae in models of mitochondrial hypertrophic cardiomyopathy.
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