Molecular Mechanisms of Mitochondrial Quality Control in Ischemic Cardiomyopathy

Abstract

Ischemic cardiomyopathy (ICM) is a special type of coronary heart disease or an advanced stage of the disease, which is related to the pathological mechanism of primary dilated cardiomyopathy. Ischemic cardiomyopathy mainly occurs in the long-term myocardial ischemia, resulting in diffuse myocardial fibrosis. This in turn affects the cardiac ejection function, resulting in a significant impact on myocardial systolic and diastolic function, resulting in a decrease in the cardiac ejection fraction. The pathogenesis of ICM is closely related to coronary heart disease. Mainly due to coronary atherosclerosis caused by coronary stenosis or vascular occlusion, causing vascular inflammatory lesions and thrombosis. As the disease progresses, it leads to long-term myocardial ischemia and eventually ICM. The pathological mechanism is mainly related to the mechanisms of inflammation, myocardial hypertrophy, fibrosis and vascular remodeling. Mitochondria are organelles with a double-membrane structure, so the composition of the mitochondrial outer compartment is basically similar to that of the cytoplasm. When ischemia-reperfusion induces a large influx of calcium into the cell, the concentration of calcium ions in the mitochondrial outer compartment also increases. The subsequent opening of the membrane permeability transition pore in the inner mitochondrial membrane and the resulting calcium overload induces the homeostasis of cardiomyocytes and activates the mitochondrial pathway of apoptosis. Mitochondrial Quality Control (MQC), as an important mechanism for regulating mitochondrial function in cardiomyocytes, affects the morphological structure/function and lifespan of mitochondria. In this review, we discuss the role of MQC (including mitophagy, mitochondrial dynamics, and mitochondrial biosynthesis) in the pathogenesis of ICM and provide important evidence for targeting MQC for ICM.

Keywords: Ischemic cardiomyopathy; calcium signal; mitochondrial biogenesis; mitochondrial dynamics; mitochondrial quality control; mitophagy.

Figure 1

ROS-mediated mitochondrial dysfunction in ICM. Legend: Oxidative stress damage caused by excessive accumulation of ROS can seriously damage mitochondrial function. When mitochondria are dysfunctional, mitochondrial inner and outer membrane permeability (OMM) functions are also dysfunctional, which leads to abnormal opening of mitochondrial permeability transition pore (mPTP). It is also accompanied by calcium homeostasis disorder and tricarboxylic acid circulation disorder. Calcium signal conduction dysfunction and mitochondrial energy metabolism (mitochondrial respiration) dysfunction also occur.

Figure 2

Regulatory mechanisms involved in MQC in cell homeostasis and ICM. MQC directly or indirectly regulates cellular internal and external stress signaling pathways, affects the activity of cardiomyocytes and microvascular endothelial cells, and contributes to multiple pathological mechanisms, including oxidative stress, cardiomyocyte hypertrophy, fibrosis, and Ca²⁺ homeostasis disorders, as well as apoptotic/necroptotic processes.

Figure 3

Mechanisms underlying mitochondrial homeostasis in cellular energy metabolism. Myocardial ischemia/reperfusion injuries contribute to the pathogenesis of ICM. During myocardial hypoxia/ischemia, and nutrients decline while Ca²⁺, Na⁺ and K⁺ channels open, lead to intracellular Ca²⁺ overload and disruption of intracellular ion homeostasis leading to a loss of mitochondrial membrane potential and decline of oxidative phosphorylation. This in turn will lead to a decline in ATP synthesis and cell energy metabolism disorders. After reperfusion, intracellular oxygen levels rise sharply, as do nutrient levels. In addition, cardiomyocytes exhibit Ca²⁺ overload and mitochondrial MCU dysfunction, exacerbation the exacerbating the Ca²⁺ overload. The transient increase in in oxygen supply leads to accumulation of ROS and increases in the mitochondrial membrane potential, which stimulates the abnormal opening of mPTPs. Oxidative phosphorylation and the tricarboxylic acid cycle are over-activated due the oversupply of blood oxygen and nutrients, leading to the overproduction of ATP and ROS, ultimately causing oxidative stress and disruption of mitochondrial homeostasis.

Figure 4

Mechanisms of mitochondrial calcium overload-mediated oxidative stress injury and dysregulated mitochondrial. The mitochondrial calcium homeostasis mechanism is controlled by the mitochondrial calcium uptake and release system. Sarcoplasmic/Endoplasmic Reticulum Ca 2+ -ATPase (SERCA) is a pump that transports calcium ions from the cytoplasm to the ER. The activation of SERCA can inhibit the excessive release of calcium, thereby inhibiting the excessive production of mitochondrial ROS and improving mitochondrial function. At the same time, mitochondrial homeostasis disorder caused by mitochondrial calcium overload will further induce mitochondrial PTP activation and mitochondrial energy metabolism dysfunction, leading to excessive mitochondrial division and mitochondrial quality control network disorder.

Figure 5

Mitochondrial and myocardial/coronary microvascular endothelial cell injury. Mitochondrial injury is accompanied by reduced ATP production and oxidative stress during coronary microvascular injury in end-stage IM and ICM. This stimulates increased levels of mitochondrial fragmentation. Excessive stress stimulation affects mitochondrial function and also leads to mitochondrial DNA damage, which can damage the transcription and translation of mitochondrial electron transport chain proteins and induce mitochondrial fusion dysfunction. Excessive mitochondrial damage and stress will promote mitochondrial division, thus transforming the reticular mitochondrial network into point and fragment mitochondria. However, FUNDC1 and PINK/Parkin mediated mitophagy cannot completely remove fragmented mitochondria, which will lead to dysfunction of mitochondrial energy metabolism, which will reduce ATP production and affect the life of myocardial cells. Furthermore, PGC1α- and Tfam-mediated mitochondrial biosynthesis dysfunction also affects mitochondrial neogenesis. lead to the death of coronary microvascular endothelial cells.