Mitochondria and endothelial function

Abstract

In contrast to their role in cell types with higher energy demands, mitochondria in endothelial cells primarily function in signaling cellular responses to environmental cues. This article provides an overview of key aspects of mitochondrial biology in endothelial cells, including subcellular location, biogenesis, dynamics, autophagy, reactive oxygen species production and signaling, calcium homeostasis, regulated cell death, and heme biosynthesis. In each section, we introduce key concepts and then review studies showing the importance of that mechanism to endothelial control of vasomotor tone, angiogenesis, and/or inflammatory activation. We particularly highlight the small number of clinical and translational studies that have investigated each mechanism in human subjects. Finally, we review interventions that target different aspects of mitochondrial function and their effects on endothelial function. The ultimate goal of such research is the identification of new approaches for therapy. The reviewed studies make it clear that mitochondria are important in endothelial physiology and pathophysiology. A great deal of work will be needed, however, before mitochondria-directed therapies are available for the prevention and treatment of cardiovascular disease.

Figure 1

Conceptual illustration of the mitochondrial life cycle and the contribution of mitochondrial dynamics and mitophagy to quality control. Biogenesis is regulated by PGC-1α which activates NRF-1,2 and TFAM and TFBM. Mitochondria undergo cycles of fusion to form elongated mitochondrial networks and fission into smaller individual organelles. Fusion is mediated by MFN1, MFN2, and OPA1. Fission is mediated by DRP1 and FIS1. During their normal lifespan and in the setting of increased oxidative stress, damage to mitochondrial components accumulates. Fission provides a mechanism to isolate damaged components for elimination. Mitophagy involves mitochondrial depolarization, retention PINK1 in the mitochondrial membrane and recruitment of Parkin, which targets the mitochondria to autophagosome. P62 also plays a role in targeting cargo to the autophagosome and is subsequently degraded during active autophagy. Assembly of the phagosome involves Beclin-1 and conjugation of LC3 onto phosphatidylethanolamine to form of LC3-II. (Illustration Credit: Ben Smith).

Figure 2

Illustration of mitochondrial membrane components in endothelial cells related to ROS generation. I, II, III, IV, V = Complexes I–V of the electron transport chain; ABC-me = ATP-binding cassette-mitochondrial erythroid; ALA = amino levulinic acid; AMPK = AMP activated protein kinase; CoQ = coenzyme Q10/ ubiquinone; Cx43 = connexin 43; CytC = cytochrome C; OMM = outer mitochondrial membrane; IMM = inner mitochondrial membrane; IM space = inter membrane space; MAO = monamine oxidase; mV = millivolts; mitoKATP = mitochondrial ATP-sensitive potassium channel; MnSOD = manganese superoxide dismutase; mtDNA = mitochondrial DNA; NO = nitric oxide; NT = neurotransmitter; PGC-1α = peroxisome proliferator-activated receptor gamma coactivator-1α; ROS = reactive oxygen species; UCP2 = uncoupling protein-2; VEGF = vascular endothelial growth factor.