Coronary microvascular injury in myocardial infarction: perception and knowledge for mitochondrial quality control

Abstract

Endothelial cells (ECs) constitute the innermost layer in all blood vessels to maintain the structural integrity and microcirculation function for coronary microvasculature. Impaired endothelial function is demonstrated in various cardiovascular diseases including myocardial infarction (MI), which is featured by reduced myocardial blood flow as a result of epicardial coronary obstruction, thrombogenesis, and inflammation. In this context, understanding the cellular and molecular mechanisms governing the function of coronary ECs is essential for the early diagnosis and optimal treatment of MI. Although ECs contain relatively fewer mitochondria compared with cardiomyocytes, they function as key sensors of environmental and cellular stress, in the regulation of EC viability, structural integrity and function. Mitochondrial quality control (MQC) machineries respond to a broad array of stress stimuli to regulate fission, fusion, mitophagy and biogenesis in mitochondria. Impaired MQC is a cardinal feature of EC injury and dysfunction. Hence, medications modulating MQC mechanisms are considered as promising novel therapeutic options in MI. Here in this review, we provide updated insights into the key role of MQC mechanisms in coronary ECs and microvascular dysfunction in MI. We also discussed the option of MQC as a novel therapeutic target to delay, reverse or repair coronary microvascular damage in MI. Contemporary available MQC-targeted therapies with potential clinical benefits to alleviate coronary microvascular injury during MI are also summarized.

Keywords: ECs; coronary microvasculature; mitochondrial quality control; myocardial infarction.

Figure 1

Diagrammatic representation shows the relationship between pathological alterations in vasculature during myocardial infarction and mitochondrial quality control mechanisms. Intrinsic and extrinsic stress signals such as hypoxia, ischemia, reperfusion, inflammation or oxidative stress activate mitochondrial fission or fusion. Mitophagy promotes degradation of damaged mitochondria. Mitochondrial biogenesis regulates synthesis of mitochondrial DNA, proteins, and lipids to restore optimal mitochondrial mass. Outer mitochondrial membrane permeabilization (OMM) is induced and mitochondrial permeability transition pore (mPTP) opening is enhanced when mitochondrial damage becomes excessive. OMM promotes cellular apoptosis, whereas, mPTP opening induces necrosis or necroptosis. Dysregulated mitochondrial quality control (MQC) mechanisms induce aberrant calcium signaling, excessive ROS, changes in gene expression of proteins related to bioenergetics, senescence, telomere erosion, metabolic reprogramming, (de)differentiation, or cell death (apoptosis or necrosis) in the coronary microvascular endothelial cells. These changes in endothelial cells, coronary arteries or cardiac microcirculation induce vascular degeneration, stiffness, or fibrosis and reduce angiogenesis.

Figure 2

Overview of mitochondrial quality control. Mitochondria regulate several key biological processes in the endothelial cells including energy production, redox signaling, cellular senescence, calcium homeostasis, angiogenesis, coagulation, apoptosis and inflammation response.

Figure 3

The coagulation process in endothelial cells.

Figure 4

A mitochondrial-centric view of coronary endothelial homeostasis. Ischemia/hypoxia promotes enhanced phosphorylation of Drp1. Subsequently, phosphorylated Drp1 (p-Drp1) oligomerizes around the mitochondrial outer membrane after being recruited and stabilized by mitochondrial receptors such as Fis1 and Mff and induces mitochondrial fission. In general, enhanced p-Drp1-mediated mitochondrial fission is accompanied by increased mitophagy and mitochondrial biogenesis. Fragmented mitochondria with low membrane potential induce PINK1 localization into the mitochondria. PINK1 recruits Parkin to the mitochondria. Concurrently, Fundc1, the mitochondria-localized mitophagy receptor, is activated through post-transcriptional phosphorylation. Mitochondria interact with LC3 on the lysosomes through Parkin and Fundc1, and form autophagosomes. Mitophagy promotes degradation of fragmented mitochondria to sustain mitochondrial homeostasis. Mitochondrial biogenesis is activated in response to mitochondrial fission or mitophagy. PGC1α is a major regulator of mitochondrial biogenesis that acts as a compensatory mechanism to mitochondrial fission or mitophagy. The other transcription factors involved in mitochondrial biogenesis are NRF1, NRF2, ERR, and PPAR. Mitochondrial biogenesis upregulates OXPHOS, TCA cycle, mtDNA and TFAM levels. Note: Drp1, dynamin-related protein 1; Fis1, mitochondrial fission factor 1; Mff, mitochondrial fission factor; NRF, nuclear respiratory factor; OXPHOS, oxidative phosphorylation; PGC1α, peroxisome proliferator-activated receptor g coactivator 1α; PINK1, phosphatase and tensin homolog-induced putative kinase 1; ROS, reactive oxygen species; TCA, tricarboxylic acid; TFAM, mitochondrial transcription factor A.

Figure 5

Mitochondrial quality control mechanisms. Mild mitochondrial stress is accompanied by decreased ATP production and mitochondrial oxidative stress. This stimulates mitochondrial anti-oxidative enzymes such as superoxidase dismutase (SOD), glutathione reductase (GR), glutathione peroxidases (GPXs), thioredoxin reductase (TrxR), and peroxiredoxin (PRx) to reduce the levels of mitochondrial reactive oxygen species (mROS). Mitochondrial injury is followed by mitochondrial DNA damage, which impairs transcription and translation of mitochondria-encoded electron transport chain proteins. Severe mitochondrial stress is characterized by aberrant alterations in the mitochondrial structure and function. This induces mitochondrial fusion mediated by mitofusin 1 (Mfn1), mitofusin 2 (Mfn2), and optic atrophy 1 (OPA1). Mitochondrial fusion allows mixing of damaged and healthy mitochondria to restore functional homeostasis. Meanwhile, mitochondrial fission is activated by cytosolic dynamin-1-like protein (Drp1) and its receptors, and results in segregation of damaged mitochondria that are then targeted for degradation by mitophagy through specific adaptors such as FUN14 domain-containing 1 (Fundc1), Parkin, and BCL-2/adenovirus E1B 19 kDa protein-interacting protein 3 (Bnip3). Excessive mitochondrial damage and stress promotes increased mitochondrial fission that converts reticular mitochondrial network into punctate and fragmented mitochondria. This reduces ATP production and affects cellular growth and survival. Besides, excessive mitophagy significantly reduces mitochondrial mass leading to bioenergetic crisis and cell death or apoptosis. Newer mitochondria are synthesized by mitochondrial biogenesis through specific transcription factors such as peroxisome proliferator-activated receptor-γ co-activator 1α (PGC1α). However, excessive mitochondrial damage induces cell death.