Dysregulation of Mfn2 and Drp-1 proteins in heart failure.

Therapeutic approaches for cardiac regenerative mechanisms have been explored over the past decade to target various cardiovascular diseases (CVD). Structural and functional aberrations of mitochondria have been observed in CVD. The significance of mitochondrial maturation and function in cardiomyocytes is distinguished by their attribution to embryonic stem cell differentiation into adult cardiomyocytes. An abnormal fission process has been implicated in heart failure, and treatment with mitochondrial division inhibitor 1 (Mdivi-1), a specific inhibitor of dynamin related protein-1 (Drp-1), has been shown to improve cardiac function. We recently observed that the ratio of mitofusin 2 (Mfn2; a fusion protein) and Drp-1 (a fission protein) was decreased during heart failure, suggesting increased mitophagy. Treatment with Mdivi-1 improved cardiac function by normalizing this ratio. Aberrant mitophagy and enhanced oxidative stress in the mitochondria contribute to abnormal activation of MMP-9, leading to degradation of the important gap junction protein connexin-43 (Cx-43) in the ventricular myocardium. Reduced Cx-43 levels were associated with increased fibrosis and ventricular dysfunction in heart failure. Treatment with Mdivi-1 restored MMP-9 and Cx-43 expression towards normal. In this review, we discuss mitochondrial dynamics, its relation to MMP-9 and Cx-43, and the therapeutic role of fission inhibition in heart failure.