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.