Dysregulation of Mfn2 and Drp-1 proteins in heart failure

Abstract

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.

Mitochondrial dysfunction in cardiac aging

“…Drp1 is localized to the cytosol until it is attracted to the mitochondrial surface for a fission event [164]. Drp1 has recently been suggested to help protect cardiac cells from IR injury by allowing them to be less reliant on oxidative phosphorylation and delaying or suppressing apoptosis [164, 165]. The depletion of Drp1 in cardiomyocytes or in mouse hearts leads to mitochondrial dysfunction and heart disease, respectively [166].…”

Moderate intensity exercise prevents diabetic cardiomyopathy associated contractile dysfunction through restoration of mitochondrial function and connexin 43 levels in db/db mice

“…Myocyte coupling in the cardiac tissue is maintained through gap junctions. Connexin 43 (Cx43) is the main constituent in the gap junctions of adult hearts [3] and is crucial for nutrient and electrolyte coupling of myocyte networks, mitochondrial networks and microvascular endothelial networks in the cardiac tissue [4, 5]. Significant alterations in the Cx43 levels indicates poor prognosis.…”

“…Significant alterations in the Cx43 levels indicates poor prognosis. Diabetes alters Cx43 levels and/or distribution in different tissues including the heart tissue [3-8]. Diabetes has also been shown to inhibit Cx43 levels in the microvessels [5].…”

Epigenetic revival of a dead cardiomyocyte through mitochondrial interventions

“…There is an increase in calcium uptake, increased ROS production and increased cytochrome c leakage which is detrimental to the cell. The use of mitochondrial division inhibitor was able to ameliorate the damage done by pressure overload-induced HF (63,64). Mitophagy is related to increased calcium uptake and intracellular calcium concentration.…”