Leptin-induced cardiomyocyte hypertrophy is associated with enhanced mitochondrial fission.

ABSTRACT

Cardiac pathology including hypertrophy has been associated with an imbalance between mitochondrial fission and fusion. Generally, well-balanced mitochondrial fission and fusion are essential for proper functions of mitochondria. Leptin is a 16-kDa appetite-suppressing protein which has been shown to induce cardiomyocyte hypertrophy. In the present study, we determined whether leptin can influence mitochondrial fission or fusion and whether this can be related to its hypertrophic effect. Cardiomyocytes treated for 24 h with 3.1 nM leptin (50 ng/ml), a concentration representing plasma levels in obese individuals, demonstrated an increase in surface area and a significant 1.6-fold increase in the expression of the ß-myosin heavy chain. Mitochondrial staining with MitoTracker Green dye showed elongated structures in control cells with an average length of 4.5 µm. Leptin produced a time-dependent increase in mitochondrial fragmentation with decreasing mitochondrial length. The hypertrophic response to leptin was also associated with increased protein levels of the mitochondrial fission protein dynamin-related protein1 (Drp1) although gene expression of Drp1 was unaffected possibly suggesting post-translational modifications of Drp1. Indeed, leptin treatment was associated with decreased levels of phosphorylated Drp1 and increased translocation of Drp1 to the mitochondria thereby demonstrating a pro-fission effect of leptin. As calcineurin may dephosphorylate Drp1, we determined the effect of a calcineurin inhibitor, FK506, which prevented leptin-induced hypertrophy as well as mitochondrial fission and mitochondrial dysfunction. In conclusion, our data show that leptin-induced cardiomyocyte hypertrophy is associated with enhanced mitochondrial fission via a calcineurin-mediated pathway. The ability of leptin to stimulate mitochondrial fission may be important in understanding the role of this protein in cardiac pathology especially that related to mitochondrial dysfunction.