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 Ca 2+ 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.

Preserving mitochondria to treat hypertrophic cardiomyopathy: From rare mitochondrial DNA mutation to heart failure therapy?

“…As another example, the development of myosin modulators to prevent cardiac myocyte hypercontractility with sarcomeric mutations ( 2 ) now provides a treatment for hypertrophic cardiomyopathy. In this issue of the JCI , Zhuang and authors discovered a small molecule by screening a library of mitochondrially-targeted compounds that preserved mitochondrial membrane potential in cells carrying defective mitochondria due to the MT-RNR2 ( 3 ) mutation, which was previously described in a multigenerational family with hypertrophic cardiomyopathy ( 4 ). These studies raise hopes for developing a class of therapies that preserve healthy mitochondria to counter cardiomyopathy and heart failure, where mitochondrial dysfunction is triggered by diverse pathologies.…”

“…Intriguingly, an emerging body of literature has probed maternal inheritance of hypertrophic cardiomyopathy and implicated mitochondrial DNA mutations in the pathogenesis of hypertrophic cardiomyopathy. These include mutations in mitochondrial tRNA (specifically Leu (UUR) in MT-TL1 ), in ND5 (12338T>C, a mitochondrial gene encoding for NADH dehydrogenase 5, a part of complex I), and the specific mutation in mitochondrial 16sRNA (2336T>C in MT-RNR2 ( 6 )), which is the focus of this chemical screen ( 3 ). The latter mutation impaired mitochondrial membrane potential in cybrids (hybrid cells engineered to carry patient-derived mitochondria) and induced mitochondrial defects in induced pluripotent stem cell (iPS)-derived cardiac myocytes ( 3 ) that were reversed by 1-deoxynojirimycin (DNJ).…”

“…These include mutations in mitochondrial tRNA (specifically Leu (UUR) in MT-TL1 ), in ND5 (12338T>C, a mitochondrial gene encoding for NADH dehydrogenase 5, a part of complex I), and the specific mutation in mitochondrial 16sRNA (2336T>C in MT-RNR2 ( 6 )), which is the focus of this chemical screen ( 3 ). The latter mutation impaired mitochondrial membrane potential in cybrids (hybrid cells engineered to carry patient-derived mitochondria) and induced mitochondrial defects in induced pluripotent stem cell (iPS)-derived cardiac myocytes ( 3 ) that were reversed by 1-deoxynojirimycin (DNJ). Zhuang, et al presented a comprehensive dataset in cell-culture studies to demonstrate the efficacy of DNJ in preventing cellular hypertrophy and restoring mitochondrial structure, membrane potential, oxidative phosphorylation, and ATP production ( 3 ).…”

Noninvasive Assessment of hiPSC Differentiation toward Cardiomyocytes Using Pretrained Convolutional Neural Networks and the Channel Pruning Algorithm

“…For example, common laboratory methods for evaluating the effectiveness of differentiation include immunofluorescence staining 12 and flow cytometry with the specific protein markers 13 and polymerase chain reaction (PCR) to check the expression of specific genes. 14 However, these methods involve complex operations that are extremely time-consuming and costly. Sometimes, the epigenetic and transcriptional changes need days or weeks to occur to be detected.…”

“…Currently, cellular conditions are still mostly checked manually. For example, common laboratory methods for evaluating the effectiveness of differentiation include immunofluorescence staining and flow cytometry with the specific protein markers and polymerase chain reaction (PCR) to check the expression of specific genes . However, these methods involve complex operations that are extremely time-consuming and costly.…”