Mitochondria are crucial to myocardial function; they have an essential role in energy generation, cell redox potential, calcium homeostasis, fatty acid and glucose metabolism, ROS generation and mitochondria-dependent apoptosis. Various stress factors including humoral factors, mechanical pressure and toxins lead to abnormal mitochondrial metabolism and increased ROS generation and apoptosis and necrosis of cardiac cells. All these are detrimental to failing hearts regardless of their etiology. As important regulators of apoptosis and oxidative stress, mitochondria play a decisive role in cell death, thereby determining the extent of loss of cardiomyocytes, coronary endothelial cells and vascular smooth muscle cells. Loss of these cells leads to cardiac remodeling events such as cardiomyocyte hypertrophy, replacement fibrosis and inflammation and ultimately overt HF. So far, regulation of HF by targeting the mitochondria has mostly focused on preventing mitochondria-dependent apoptosis. Here we suggest that there are a number of other potential mitochondrial targets that may affect the progression of HF. To maintain normal mitochondrial structure, function and number, both under basal and under stress conditions, regulation of the PQC system, fusion-fission machinery and autophagy mechanisms are all required (). In HF, aggregation and improper folding of proteins and damaged cell elements by protein adduct formation with free radicals are implicated in the disease pathogenesis. Therefore PQC holds significant importance in determining the mitochondrial fate (). Abnormal fusion and fission processes (either an increase or decrease) lead to a disproportionate number of mitochondria, altered intramitochondrial contents and disorganized shape during stress. Therefore drugs that shift the balance towards normal mitochondrial numbers and proper intra-mitochondrial contents and shape by regulating the fusion and fission machinery may provide novel therapeutic approaches for HF (). Removal of damaged mitochondria by mitophagy is crucial for maintaining a healthy population of mitochondria and could potentially be targeted for the treatment of HF (). Further studies are required to confirm whether maintaining or restoring normal function and structure and shape of this critical organelle by regulating the mitochondrial PQC system, the fusion-fission machinery and the autophagy machinery can serve as novel mitochondrial therapeutic targets for a variety of diseases associated with mitochondrial damage, including HF.
Mitochondrial regulatory mechanisms in heart failure
Mitochondrial regulation-based therapeutic targets