Mitophagy in ischemic heart disease: molecular mechanisms and clinical management

Abstract

The influence of the mitochondrial control system on ischemic heart disease has become a major focus of current research. Mitophagy, as a very crucial part of the mitochondrial control system, plays a special role in ischemic heart disease, unlike mitochondrial dynamics. The published reviews have not explored in detail the unique function of mitophagy in ischemic heart disease, therefore, the aim of this paper is to summarize how mitophagy regulates the progression of ischemic heart disease. We conclude that mitophagy affects ischemic heart disease by promoting cardiomyocyte hypertrophy and fibrosis, the progression of oxidative stress, the development of inflammation, and cardiomyocyte death, and that the specific mechanisms of mitophagy are worthy of further investigation.

Fig. 1. The mechanism of mitophagy.

Mitophagy can be divided into approximately four key steps: 1. In the early stage of mitochondrial damage, permeability transition occurs, leading to mitochondrial depolarization, loss of membrane potential, and induction of mitochondrial autocorrelation protein activation. 2. In the early stage, autophagosomes wrap around damaged mitochondria, forming mitophagy. 3. In the middle stage, mitochondrial autophagosomes fuse with lysosomes to form mature mitochondrial autophagosomes. 4. Lysosomal acidic hydrolytic enzymes flow into autophagosomes to degrade mitochondria, allowing nutrients to be recycled and reused. The molecular mechanism of mitophagy can be mainly divided into ubiquitin dependent pathway and non ubiquitin dependent pathway. The key proteins in the ubiquitin dependent pathway are PINK1 and Parkin. In addition, besides the PINK1 Parkin pathway, there is also a non Parkin dependent ubiquitin dependent pathway. That is to say, PINK1 can also recruit self receptor proteins (such as NIX, BNIP3, and FUNDC1) directly to mitochondria through ubiquitin phosphorylation, and the receptor proteins recruit LC3, which enables the self to engulf mitochondria. Non ubiquitin dependent mitophagy is dominated by mitophagy receptors, which differs significantly from the ubiquitin dependent pathway.

Fig. 2. Mitophagy promotes oxidative stress in ischemic cardiomyopathy.

The inflammatory signals in myocardial cells usually begin with the accumulation of myocardial cell mitochondria caused by stress response. Research has shown that YQHX can alleviate hypoxia induced damage by targeting mitophagy. On the other hand, quercetin alleviates mitochondrial oxidative stress through DNA-PKcs-SIRT5. DUSP12 can inhibit cell apoptosis caused by hypoxia through HSPB8. Inhibition of Parkin mediated mitophagy leads to excessive accumulation of mitochondrial ROS, which in turn promotes the progression of progressive myocardial injury and heart failure. Under low oxygen conditions, mitophagy regulates myocardial ischemia-reperfusion injury through the HIF/BNIP3 pathway. Similarly, studies have shown that JMJD5 can alleviate myocardial cell damage by regulating the HIF-BNIP3 pathway. Other studies have shown that exosomes rich in Sirt6 inhibit cell pyroptosis in AIM2 and enhance mitophagy through the p62 and Beclin-1 pathways, thereby improving myocardial cell damage. The knockdown of ZIP7 has also been confirmed to reduce mitochondrial ROS generation and myocardial infarction by increasing Zn²⁺in mitochondria, leading to mitochondrial depolarization, as well as the accumulation of PINK1 and Parkin in mitochondria.

Fig. 3. Mitophagy promotes myocardial cell death.

The research results indicate that TBC1D15 plays a key role in myocardial injury through mitophagy regulated by Fis1/RAB7. Parkin inhibits mPTP opening and myocardial cell necrosis by catalyzing the ubiquitination of CypD. Upregulation of MCU helps to inhibit calpain/OPA-1 mediated mitophagy and suppress excessive cell apoptosis through OPA1. Thyroid hormones can provide cardiac protection by enhancing PINK1 dependent mitophagy. MiR-494-3p can target and negatively regulate PGC1- α mediated mitophagy in cardiomyocytes, inhibiting cardiomyocyte apoptosis. Rich hydrogen saline alleviates inflammation and cell apoptosis in myocardial I/R injury through PINK1/Parkin mediated mitophagy. RR can inhibit cell apoptosis by inhibiting USP33 to promote mitophagy. Similarly, PPENK can promote mitophagy and reduce myocardial ischemia-reperfusion injury through the PINK1 Parkin pathway. Drp1 induced mitophagy disruption has tolerance to hypoxia induced damage. RIPK3 inhibits AMPK to prevent PINK1-PRKN induced mitophagy, thereby promoting myocardial cell necrosis. Ischemia reperfusion can trigger upregulation of RIPK3, promote phosphorylation of FUNDC1, and induce cell apoptosis.

Fig. 4

Summary of the role of mitophagy in promoting the progression of ischemic heart disease: 1. Mitophagy promotes myocardial cell hypertrophy and fibrosis. 2. Mitophagy promotes inflammation. 3. Mitophagy promotes oxidative stress progression. 4. Mitophagy promotes cell death.