Novel Strategies in the Early Detection and Treatment of Endothelial Cell-Specific Mitochondrial Dysfunction in Coronary Artery Disease

Abstract

Although elevated cholesterol and other recognised cardiovascular risk factors are important in the development of coronary artery disease (CAD) and heart attack, the susceptibility of humans to this fatal process is distinct from other animals. Mitochondrial dysfunction of cells in the arterial wall, particularly the endothelium, has been strongly implicated in the pathogenesis of CAD. In this manuscript, we review the established evidence and mechanisms in detail and explore the potential opportunities arising from analysing mitochondrial function in patient-derived cells such as endothelial colony-forming cells easily cultured from venous blood. We discuss how emerging technology and knowledge may allow us to measure mitochondrial dysfunction as a potential biomarker for diagnosis and risk management. We also discuss the "pros and cons" of animal models of atherosclerosis, and how patient-derived cell models may provide opportunities to develop novel therapies relevant for humans. Finally, we review several targets that potentially alleviate mitochondrial dysfunction working both via direct and indirect mechanisms and evaluate the effect of several classes of compounds in the cardiovascular context.

Keywords: SMuRFless; atherosclerosis; coronary artery disease; drug screening; endothelial colony forming cells; endothelial dysfunction; mitochondrial dysfunction.

Figure 1

Oxidative phosphorylation and mitochondrial ROS (mROS) production. Nutrient oxidation in the TCA cycle releases free energy as reduced cofactors NADH and FADH₂. Electrons from NADH and FADH₂ are transported across Complexes I–IV, forming the ETC. Through a series of redox reactions, the transport of electrons is coupled with the translocation of protons (H⁺) across the inner mitochondrial membrane and into the intermembrane space. This process generates the proton motive force (PMF), driving ATP synthesis as H⁺ re-enters the mitochondrial matrix through Complex V (ATP synthase). Thus, nutrient oxidation is coupled with ATP production. mROS are produced from the leakage of e- at Complex I and III to form superoxide (O₂^•−). O₂^•− is generated in the mitochondrial matrix at Complex I while O₂^•− is released to both the mitochondrial matrix and intermembrane space at Complex III. Once formed, O₂^•− undergoes dismutation by either SOD1 (in the intermembrane) or SOD2 (in the mitochondrial matrix) into H₂O₂. Created with BioRender.com (accessed on 7 June 2023).

Figure 2

Progression of atherosclerosis. (a) Atherogenic factors such as elevated and modified low-density lipoprotein (LDL) and reactive oxygen species (ROS) cause endothelial dysfunction. Circulating LDL accumulates in the intima of coronary vessels and is oxidised by factors such as ROS, nitric oxide (NO), and macrophages. ROS also directly damages the endothelium and creates a perpetuating cycle. (b) Oxidized LDL activates the endothelium, attracting monocytes to the intima that differentiate into macrophages. Oxidized LDL is phagocytosed by macrophages, becoming foam cells that later form fatty streaks. Fatty streaks attract smooth muscle cells (SMCs) to the lesion site and produce extracellular matrix. (c) The atherosclerotic plaque then forms through the accumulation of large amounts of extracellular matrix, leading to the thickening of the arterial intima. (d) The plaque forms a fibrous cap around the lipid core, which builds up and narrows the arteries, eventually leading to complications or myocardial infarction (MI). Created with BioRender.com (accessed on 7 June 2023).

Figure 3

Protonophoric mitochondrial uncoupling mechanism. Mitochondrial uncoupling occurs when protons re−enter the mitochondrial matrix by bypassing ATP synthase (Complex V) without producing ATP. Protonophoric uncouplers aid the transport of protons (H⁺) across the inner mitochondrial membrane, dissipating the PMF. These protonophores bind to H⁺ in the intermembrane space, translocating them into the mitochondrial matrix. When protonophores are deprotonated, they can diffuse across the inner mitochondrial membrane and repeat the process. A decrease in the PMF leads to increased energy expenditure as the mitochondria need to increase nutrient oxidation in order to maintain ATP synthesis. Created with BioRender.com (accessed on 7 June 2023).