Roles of mitochondrial dynamics and mitophagy in diabetic myocardial microvascular injury

Abstract

Myocardial microvessels are composed of a monolayer of endothelial cells, which play a crucial role in maintaining vascular barrier function, luminal latency, vascular tone, and myocardial perfusion. Endothelial dysfunction is a key factor in the development of cardiac microvascular injury and diabetic cardiomyopathy. In addition to their role in glucose oxidation and energy metabolism, mitochondria also participate in non-metabolic processes such as apoptosis, intracellular ion handling, and redox balancing. Mitochondrial dynamics and mitophagy are responsible for regulating the quality and quantity of mitochondria in response to hyperglycemia. However, these endogenous homeostatic mechanisms can both preserve and/or disrupt non-metabolic mitochondrial functions during diabetic endothelial damage and cardiac microvascular injury. This review provides an overview of the molecular features and regulatory mechanisms of mitochondrial dynamics and mitophagy. Furthermore, we summarize findings from various investigations that suggest abnormal mitochondrial dynamics and defective mitophagy contribute to the development of diabetic endothelial dysfunction and myocardial microvascular injury. Finally, we discuss different therapeutic strategies aimed at improving endothelial homeostasis and cardiac microvascular function through the enhancement of mitochondrial dynamics and mitophagy.

Keywords: Cardiac microvascular injury; Diabetes; Endothelial cells; Mitochondrial dynamics; Mitophagy.

Fig. 1

Pathological effects of diabetes on the endothelium. Diabetes reduces the number and function of endothelial progenitor cells. These deficits contribute to the pathophysiology of macrovascular disease, microvascular disease (retinopathy, neuropathy, and nephropathy), and cardiomyopathy

Fig. 2

Multiple functions of the endothelium. Endothelial cells demonstrate vascular-specific heterogeneity of function. The endothelium not only performs its well-established barrier function and regulates cell permeability, but also performs autocrine, paracrine, and endocrine functions, and regulates blood flow and blood pressure by generating numerous vasoactive factors. Important among these vasoactive molecules are NO, prostacyclin (PGI2), C-type natriuretic peptide (CNP), endothelin-1 (ET-1), and angiotensin converting enzyme (ACE), the latter of which converts angiotensin 1 to the vasoconstrictor angiotensin II. The endothelium also contributes to blood hemostasis and fluidity by supplying NO and PGI2 (inhibitors of platelet activation) and von Willebrand factor (an anchor for proteins such as factor VIII). Moreover, the endothelium regulates platelet adhesion and fibrinolysis by releasing tissue-type plasminogen activator (tPA) and its inhibitor, plasminogen activator inhibitor-1 (PAI-1). Endothelial cells are also key participants in immune and inflammatory responses. Endothelial cell permeability is determined by endothelial cell-specific adhesion molecules that regulate leukocyte extravasation into tissues (diapedesis). These adhesion molecules include E-selectin (also known as endothelial-leukocyte adhesion molecule 1, ELAM-1), intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and platelet endothelial cell adhesion molecule 1 (PECAM1, also known as cluster of differentiation 31, CD31). Endothelial cells are of prime importance for vessel formation during embryonic development (vasculogenesis), new blood vessel formation (angiogenesis), remodeling during the formation of new blood vessels from preexisting vasculature (angiogenesis), and vessel differentiation and remodeling (arteriogenesis)

Fig. 3

Conceptual illustration of mitochondrial dynamics. Mitochondria undergo cycles of fusion to form elongated mitochondrial networks, and fission into smaller individual organelles. Fusion is conducted by Mfn1, Mfn2, and Opa1, while fission is performed by Drp1 and Fis1. During their normal lifespan and in the setting of increased oxidative stress, mitochondrial components accumulate damage. Fission allows damaged components to be isolated for elimination

Fig. 4

Schematic representation of different approaches to enhance mitochondrial function in diabetes