Mitofusin 2 deficiency causes atrial lipid accumulation in experimental and human atrial fibrillation and diabetes mellitus

BACKGROUND: Atrial fibrillation (AF) is the most common tachyarrhythmia, with diabetes mellitus (DM) as a key risk factor. DM is linked to cardiac lipid toxicity. We previously found that the mitochondrial outer membrane protein Mitofusin 2 (MFN2) is reduced in AF and further suppressed in DM. However, whether MFN2 contributes to altered lipid metabolism remains unclear. METHODS: Atrial tissue from diabetic (db/db) and wild-type mice and atrial appendages from patients with AF or sinus rhythm were analyzed. AF- and DM-like conditions were modeled in human, rat, and mouse atrial myocytes using tachypacing (TP) and high glucose (HG). MFN2 expression was modulated by siRNA knockdown or plasmid-based overexpression. Lipid droplets (LDs), intracellular fatty acid distribution, LD-mitochondria colocalization, carnitine-dependent fatty acid metabolic activity, and mitochondrial respiration were assessed. RESULTS: DM model db/db mice and AF patients exhibited reduced MFN2 expression and increased LD accumulation. Similarly, TP and HG treatments reduced MFN2 levels, increased LD content, and decreased LD-mitochondria colocalization in atrial myocytes across species. MFN2 knockdown increased LD accumulation, whereas MFN2 overexpression attenuated lipid accumulation under basal and stress conditions. Functionally, MFN2 reduction was associated with decreased FAO capacity and redistribution of fatty acids toward lipid droplets and away from mitochondria. These effects were not observed with MFN1 manipulation, suggesting isoform-specific regulation. CONCLUSIONS: MFN2 regulates atrial lipid metabolism and is associated with lipid accumulation and altered lipid droplet-mitochondria organization in AF and DM. These findings identify a potential link between mitochondrial dynamics and lipid metabolic remodeling in atrial disease.