Circ Res. 2025 Dec 29. doi: 10.1161/CIRCRESAHA.125.327407. Online ahead of print.
ABSTRACT
BACKGROUND: Pathological cardiac hypertrophy, an abnormal enlargement of cardiomyocytes and interstitial fibrosis in response to sustained injury or pressure overload, may lead to heart failure or even sudden death. Affected patients often also exhibit myocardial mitochondrial dysfunction and associated structural damage. Discovering more potent mitochondrial-targeting compounds may therefore hold great benefit, both for elucidating the mechanisms of cardiac hypertrophy and for treating affected patients.
METHODS: A series of novel 1-deoxynojirimycin (DNJ) derivatives was designed based on the unique binding mode of DNJ with OPA1 (optic atrophy 1). Two-step phenotypic screening was then performed using patient-specific cytoplasmic hybrid cells and iPSC-derived cardiomyocytes to identify promising candidates. Molecular dynamics simulations, combined with proteomic, biochemical, and physiological assays, were used to assess potential therapeutic mechanisms for mitochondrial disorders. OPA1 mutant cell lines were established to test candidate compound target specificity. Pathological cardiac hypertrophy models were established in mice and rats through angiotensin II induction and abdominal aortic constriction, enabling comprehensive evaluation of the candidates’ preventive and therapeutic efficacy.
RESULTS: DNJ occupies a cavity formed by the GTPase domain of the OPA1 dimer, acting as an additional linker at the dimeric OPA1 interface. Here, we have designed and identified a novel DNJ derivative, DNJ5a. Compared with DNJ, DNJ5a exhibits enhanced in silico and in vitro binding specificity, providing additional anchor sites for direct OPA1 interaction. This interaction facilitates the stabilization of the OPA1 dimeric form to repair mitochondrial cristae damage and maintain inner membrane integrity. Comprehensive improvements in mitochondrial bioenergetics, Ca2+ homeostasis, mitophagy, and multidimensional functional responses are seen to result. In 2 rodent animal cardiac hypertrophy models, DNJ5a administration showed excellent preventive and therapeutic efficacy towards promoting mitochondrial health and cardiac function in vivo.
CONCLUSIONS: Unlike conventional mitochondrial drugs, which act to alleviate symptoms, DNJ5a can specifically target OPA1-GTPase and comprehensively improve mitochondrial health to ameliorate cardiac hypertrophy. These findings underscore mitochondrial abnormality as a primary contributor to pathological cardiac remodeling and present OPA1 as a strong potential drug target. The underlying mechanism of this novel agonist DNJ5a may pave the way towards developing many other promising mitochondrial-targeted therapeutics.
PMID:41457984 | DOI:10.1161/CIRCRESAHA.125.327407