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

Figure 6

Mitochondrial autophagy dominated mitochondrial quality control and intracellular environmental homeostasis. Interaction of receptor-mediated and non-receptor-mediated mitophagy with cellular homeostasis. In conditions causing mitochondrial stress, the mitochondrial fission kinesins Drp1 and Fis1 mediated mitochondrial fission. Additionally, the expression of Opa1 and Mfn1/2 decreased, the Opa1- and Mfn1/2-mediated mitochondrial fusion decreased, and the mitochondrial fragmentation increased the level of chemistry. Elevated levels of mitochondrial fragmentation led to insufficient mitochondrial ATP production, increased dysfunctional and incomplete mitochondria, activation of receptor-dependent mitophagy mediated by FUNDC1 and BNIP3, and activation of PINK/Parkin-mediated nonreceptor mitochondrial autophagy. Body-dependent mitophagy levels were also activated; however, neither autophagy pathway could completely eliminate or digest the incomplete mitochondrial debris. The intervention of mitophagy-targeted drugs or activators/inhibitors led to inhibition of Drp1 and Fis1 and increases of Opa1 and Mfn1/2 expression. Mitochondrial fission was also excessively inhibited, and mitochondrial fusion was activated. In a balanced state of mitochondrial fusion and fission, the level of mitochondrial fragmentation decreases. The receptor-dependent mitophagy mediated by FUNDC1 and BNIP3 and receptor-independent mitophagy mediated by PINK/Parkin can clear or degrade mitochondria, maintain mitochondrial and cellular homeostasis, and protect cardiomyocytes. Mitophagy is transiently activated in mouse myocardial injury and downregulated in response to stress overload. Mitophagy plays key roles in mediating mitochondrial dysfunction and heart failure development. Restoration of mitophagy alleviates cardiac dysfunction during stress overload. During cardiac decompensation, pathological remodeling of the myocardium is associated with Drp1-mediated mitophagy. An insufficient level of mitophagy also accelerates the process of decompensation and promotes heart failure progression. This may be closely related to mitochondrial fusion/fission.