Loganin epigenetically rescues mitochondrial complex III dysfunction via DNMT1-UQCRC1 demethylation to halt cardiac remodeling after myocardial infarction

Abstract

Background and purpose

Loganin, an iridoid glycoside from Cornus officinalis, exhibits cardioprotective potential. While previous studies focused on its antioxidant and anti-inflammatory properties, its role in myocardial infarction (MI) remodeling remains unexplored. This study identifies the DNMT1-UQCRC1 methylation axis as a novel therapeutic target of Loganin, providing the first evidence of mitochondrial complex III regulation through DNA methylation in cardiac injury.

Approach and results

In a mouse model of MI, 7-day pretreatment with Loganin (15/30 mg/kg) markedly reduced infarct area, attenuated cardiac fibrosis, and improved functional recovery. RNA sequencing and functional analyses revealed Loganin restores mitochondrial complex III function by reversing MI-induced suppression of UQCRC1—a core subunit regulated through DNA hypermethylation. Loganin’s rescue of UQCRC1 expression and mitochondrial respiration depended on DNMT1, evidenced by reduced promoter methylation and restored complex III activity. Molecular docking and surface plasmon resonance confirmed Loganin directly binds DNMT1’s catalytic domain (KD = 13.5 μM), with in vitro assays showing DNMT1 enzymatic inhibition. Collectively, these results suggest Loganin addresses the epigenetic origin of mitochondrial failure to prevent post-MI remodeling.

Conclusions

Our study identifies Loganin as an epigenetic modulator that mitigates post-MI cardiac remodeling through DNMT1 inhibition, reversing methylation-dependent UQCRC1 repression to restore mitochondrial respiration. These findings define the DNMT1-UQCRC1 axis as an actionable therapeutic target for cardiac repair.