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

Area of Science:

• Cardiology
• Mitochondrial Biology
• Pharmacology

Background:

• Hypertrophic cardiomyopathy (HCM) is a leading cause of sudden cardiac death in young individuals.
• Existing treatments for HCM are limited, particularly for mitochondrial forms of the disease.
• Mitochondrial dysfunction, linked to the MT-RNR2 variant, is implicated in HCM pathogenesis.

Purpose of the Study:

• To identify novel compounds that can rescue mitochondrial function in hypertrophic cardiomyopathy.
• To elucidate the therapeutic potential of identified compounds for mitochondrial HCM.

Main Methods:

• Screened a mitochondria-associated compound library using HCM cybrids and induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs).
• Quantified mitochondrial membrane potential and cell survival rates in galactose media.
• Investigated the mechanism of action, including targeting of optic atrophy protein 1 (OPA1) and effects on Ca2+ homeostasis and electrophysiology in vitro and in vivo.

Main Results:

• 1-Deoxynojirimycin (DNJ) was identified as a compound that rescues mitochondrial function.
• DNJ promotes OPA1 oligomerization, reconstructing mitochondrial cristae and improving cardiac iPSC-CMs' physiological properties.
• DNJ demonstrated efficacy in an angiotensin II-induced cardiac hypertrophy mouse model, improving mitochondrial function and alleviating cardiac hypertrophy.

Conclusions:

• DNJ is a potential mitochondrial rescue agent for mitochondrial hypertrophic cardiomyopathy.
• The findings provide insights into HCM mechanisms and suggest a novel therapeutic strategy.
• DNJ's ability to restore mitochondrial function and cardiac physiology warrants further investigation for HCM treatment.