Epigenetic revival of a dead cardiomyocyte through mitochondrial interventions

Abstract

Mitochondrial dysfunction has been reported to underline heart failure, and our earlier report suggests that mitochondrial fusion and fission contributes significantly to volume overload heart failure. Although ample studies highlight mitochondrial dysfunction to be a major cause, studies are lacking to uncover the role of mitochondrial epigenetics, i.e. epigenetic modifications of mtDNA in cardiomyocyte function. Additionally, mitochondrial proteases like calpain and Lon proteases are underexplored. Cardiomyopathies are correlated to mitochondrial damage via increased reactive oxygen species production and free calcium within cardiomyocytes. These abnormalities drive increased proteolytic activity from matrix metalloproteinases and calpains, respectively. These proteases degrade the cytoskeleton of the cardiomyocyte and lead to myocyte death. mtDNA methylation is another factor that can lead to myocyte death by silencing several genes of mitochondria or upregulating the expression of mitochondrial proteases by hypomethylation. Cardiomyocyte resuscitation can occur through mitochondrial interventions by decreasing the proteolytic activity and reverting back the epigenetic changes in the mtDNA which lead to myocyte dysfunction. Epigenetic changes in the mtDNA are triggered by environmental factors like pollution and eating habits with cigarette smoking. An analysis of mitochondrial epigenetics in cigarette-smoking mothers will reveal an underlying novel mechanism leading to mitochondrial dysfunction and eventually heart failure. This review is focused on the mitochondrial dysfunction mechanisms that can be reverted back to resuscitate cardiomyocytes.

Mechanisms of TFAM-mediated cardiomyocyte protection

“…TFAM's regulation of Serca2a decreases cytoplasmic calcium levels, effectively decreasing protease Calpain1 expression. Calcium-driven calpain proteases are responsible for the proteolytic degradation of both contractile and cytosolic proteins (Kunkel et al 2015a). Studies show that calpain upregulation is a major factor in cardiomyocyte functional decline (Takahashi et al 2006).…”

“…ROS-driven Matrix-metalloproteinases (MMPs) are zincdependent endopeptidases capable of degrading the exctracellular matrix (ECM) of cardiomyocytes. We have assessed the expression of MMP-9 in cardiac hypertrophy (Givvimani et al 2012) and described MMP upregulation in heart failure as it pertains to ROS generation (Kunkel et al 2015a).…”

The Impact of Environmental Factors in Influencing Epigenetics Related to Oxidative States in the Cardiovascular System

“…From a biological and clinical standpoint, the hypomethylation negatively drives the angiogenic and endothelial gene expression, resulting in vascular complications. The mitochondria dynamic also plays a key role in heart failure, as their damage via enhanced ROS runs parallel to free calcium in the cardiomyocytes and volume overload [ 98 ].…”

Mitochondrial biogenesis as an underlying mechanism involved in the cardioprotective effects of Gallic acid against D‐galactose-induced aging

“…Moreover, a previous study has exhibited that GA treatment involves in the improvement of metabolic pro le through regulation the gene expression of PGC-1α and SIRT1 in brown adipose tissue of obese mice [52].TFAM as a mitochondrial factor plays a key role in suppressing cardiac remodeling factors, which cause cardiac hypertrophy and heart failure [3]. It has been reported that enhanced TFAM gene expression leads to cellular/functional recovery by decreasing cardiac remodeling [53,54]. Previous investigations indicated that TFAM knockdown results in decreased mitochondrial biogenesis, and dilated cardiomyopathy, indicating TFAM's potential to decrease modulatory factors involve in mitochondrial function and cardiac hypertrophy [55].…”