Protective Effect of Natural Medicinal Plants on Cardiomyocyte Injury in Heart Failure: Targeting the Dysregulation of Mitochondrial Homeostasis and Mitophagy

Figure 1

Mitochondrial dysfunction-mediated apoptosis and necroptosis. Oxidative stress injury is the main mechanism of decreased defense function caused by increased mitochondrial ROS generation and decreased activity of antioxidant enzymes such as SOD/GSH/CAT. When myocardial ischemia, hypoxia, and other pathological changes occur, dysfunction in mitochondrial oxidative phosphorylation leads to mitochondrial respiratory chain damage, which directly or indirectly damages myocardial cells. Mitochondrial oxygen free radicals can regulate cellular signal transduction pathways, causing lipid peroxidation, protein function inhibition, and G protein-effector coupling dysregulation, resulting in heart failure. Additionally, the ROS can mediate apoptosis through the caspase pathway. It can inhibit cardiac diastolic and systolic function by modifying myocardial myofibrillar proteins through ROS oxidation, resulting in decreased cardiac function. ROS can also regulate the activity of NF-κB, thereby activating the signaling pathway that induces cardiac hypertrophy and the transcriptional expression of related genes. Mitochondria can also maintain calcium balance in the body by uptake and excretion of Ca²⁺. The concentration of mitochondrial Ca²⁺ plays substantial role in the generation of mitochondrial ATP, the permeability of ion channels, and the regulation of calcium signal transduction pathways. The number of mitochondria is reduced in exhausted cardiomyocytes, and the uptake capacity of the sarcoplasmic reticulum is reduced. Consequently, the cellular accumulation Ca²⁺ becomes excessive, which in turn affects the oxidative phosphorylation process, thereby reducing ATP synthesis and inducing cardiomyocyte apoptosis through the caspase pathway. When calcium overload occurs, excessive cytoplasmic Ca²⁺ is taken up by the mitochondria, the mitochondrial membrane potential decreases, the osmotic transport channels are opened, ATP consumption increases, and myocardial injury occurs. Decreased calcium content in the sarcoplasmic reticulum of cardiomyocytes leads to impaired calcium release and weakened myocardial contractility aggravating the degree of heart failure. Increased Ca²⁺ concentration will activate calcium ion-dependent protein kinases and phospholipases, degrade membrane phospholipids and structural proteins, and increase mitochondrial membrane permeability, causing mitochondrial deformation and swelling. This affects ATP synthesis and aggravates energy metabolism disorders.