Excessive mitochondrial fission and associated extracellular mitochondria mediate cardiac dysfunction in obesity cardiomyopathy

Abstract

Aims

Obesity cardiomyopathy (OCM) is associated with mitochondrial dysfunction caused by altered mitochondrial dynamics. Extracellular mitochondria (exMito) are released following tissue injury under various conditions. While the excessive mitochondrial fission-mediated release of exMito as a mechanism for mitochondrial quality control in several inflammatory disorders, its role in OCM remains unclear. The present work aimed to determine if excessive mitochondrial fission and associated exMito mediate the chronic inflammatory response and cardiac remodeling in OCM.

Materials and methods

H9c2 cardiomyoblasts were treated with 200 μM palmitate (PA) to induce lipotoxicity. C57BL/6J mice were fed a high-fat diet (HFD) for 12 weeks to induce OCM. P110, a peptide inhibitor of Drp1/Fis1 interaction, was used to evaluate the impact of excessive mitochondrial fission on cardiac mitochondrial function, quality, and quantity of exMito, systemic inflammatory response, and cardiac contractile function in both models of OCM.

Key findings

PA induced excessive mitochondrial fission, increased oxidative stress, decreased ATP level, and damaged exMito release in vitro. Exposure of naïve cardiomyoblasts to exMito isolated from PA treated cells resulted in mitochondrial dysfunction and a pro-inflammatory response. In vivo, HFD induced cardiac mitochondrial and contractile dysfunction, exMito release, and a pro-inflammatory response. Inhibition of Drp1/Fis1 interaction with P110 attenuated the observed effects both in vitro and in vivo.

Significance

P110 limited lipid-induced mitochondrial dysfunction and decreased exMito release, subsequently improving the inflammatory state and contractile function in our OCM model. Drp1/Fis1 dependent fission and associated exMito release might serve as a therapeutic target for obesity induced cardiomyopathy.