Deficiency of mitophagy receptor FUNDC1 accentuates E-cigarette component propylene glycol-evoked myocardial anomalies through cuproptosis

While E-cigarette use is closely linked to a cascade of health complications, its precise underlying mechanisms remain elusive. This study examines the impact of propylene glycol, the primary solvent in e-liquids, on myocardial structure and function, alongside the underlying mechanism with a specific focus on mitophagy receptor FUNDC1. Adult wild-type (WT) and FUNDC1 knockout ( FUNDC1 ^-/-) mice are administered propylene glycol (160 mg/kg/day, i.p., for 60 days) prior to assessment of cardiac morphology and function. Chronic propylene glycol exposure induces overt cardiac remodeling (hypertrophy and interstitial fibrosis), compromises echocardiographic parameters [enlarged left ventricular end systolic diameter (LVESD), left ventricular end diastolic diameter (LVEDD); reduced ejection fraction and fractional shortening], and impairs cardiomyocyte contractile capacity [declined peak shortening, maximal velocity of shortening/relengthening (±dL/dt), prolonged time-to-90% relengthening]. These functional deficits are accompanied by mitochondrial ultrastructural damage, oxidative stress, and apoptosis. Notably, propylene glycol suppresses mitophagy (decreased LC3BII-to-LC3BI ratio and FUNDC1, elevated p62 and TOM20) and triggers cuproptosis [upregulated ferredoxin 1 (FDX1), dihydrolipoamide acetyltransferase (DLAT), and intracellular Cu ²⁺, and downregulated Fe-S cluster proteins]. While FUNDC1 ablation alone does not affect cardiac geometry and function, it significantly exacerbates propylene glycol-induced myocardial pathologies. In vitro, propylene glycol-evoked cardiomyocyte contractile anomalies are rescued by the mitophagy inducer urolithin A and the cuproptosis inhibitor tetrathiomolybdate, whereas the Cu ²⁺ ionophore elesclomol nullifies the protective effect of urolithin A. Interaction interface and co-immunoprecipitation analyses note an evident physical interaction between FDX1 and FUNDC1. Cycloheximide chase assay reveals that FUNDC1 facilitates FDX1 destabilization. Collectively, these findings indicate that FUNDC1 deficiency aggravates propylene glycol-elicited cardiac geometric and functional anomalies, possibly through cuproptosis.