134: MITOCHONDRIAL FISSION & CELL-FREE MITOCHONDRIA MEDIATE CARDIAC DYSFUNCTION IN OBESITY CARDIOMYOPATHY

Introduction: Previous studies have demonstrated that excessive mitochondrial fission mediates release of extracellular mitochondria (exMito) and associated byproducts in response to inflammatory cues. However, the exact role of this mechanism on obesity cardiomyopathy (OCM) has not been explored. This project aims to determine if Drp1/Fis1 dependent excessive mitochondrial fission mediates the release of damaged mitochondria and propagate cardiomyocyte injury in OCM. Methods: H9c2 cardiomyoblast were treated with 200 μM palmitate (PA) to induce lipotoxicity. Simultaneously, exMito were collected and characterized from supernatant. Using peptide P110 co-treatment, we determined the impact of pharmacologic inhibition of Drp1/Fis1 dependent mitochondrial fission on cardiomyocyte mitochondrial function as well as the quality and quantity of exMito. Results: H9c2 cells treated with PA demonstrated excessive mitochondrial fragmentation, increased mitochondrial oxidative stress and decreased ATP production. The excessive mitochondrial fragmentation seen following PA treatment was associated with the release of damaged exMito. The exMito isolated from PA treated cells were noted to mediate cytotoxicity to healthy cardiomyocytes independent of PA. P110 treatment was protective against PA mediated mitochondrial damage, represented by improved bioenergetic profile, increased ATP and lower mitochondrial oxidative stress. P110 treatment also lowered the release of damaged mitochondria from PA treated H9c2s. Conclusions: PA treatment induced mitochondrial fragmentation, disrupted mitochondrial function and induced release of dysfunctional mitochondria from H9c2 cells. P110 limited PA mediated alterations in mitochondrial dynamics, mitochondrial function and extracellular release of damaged mitochondria. These data suggests that pathologic fission and excessive release of damaged mitochondria plays a role in cardiomyocyte injury from lipotoxicity.