Heart disease has complicated etiology, however, in most of the cases studied there has been bioenergetic impairment observed which is associated with unmet cellular energy demands, mtDNA damage and other abnormalities linked to mitochondrial function. Thus, we studied whether mitochondrial replacement plays a role during heart disease, and whether suppressing mitochondrial damage can prevent or possibly reverse heart failure. In these efforts, we used the cardioprotective drugs DRZ and HNG and the combined therapy of these to study their effects against DOX-induced cardiomyopathy. DRZ and HNG are known to have protective effects in mitochondria through different pathways, but we observed that the combination therapy of the two had even greater protective effect, completely restoring heart function. Next, we studied mitochondrial stability in a TAC-induced cardiomyopathy and during the recovery. We observed that at the very start of functional recovery, there are changes occurring in the expression of genes involved in mitochondrial homeostasis. We conclude that pathways involved in mitochondrial clearance and replacement may be involved in the functional recovery of the heart.