Mitochondrial Contact Sites in Inflammation-Induced Cardiovascular Disease

Abstract

The mitochondrion, the ATP-producing center, is both physically and functionally associated with almost all other organelles in the cell. Mitochondrial-associated membranes (MAMs) are involved in a variety of biological processes, such as lipid exchange, protein transport, mitochondrial fission, mitophagy, and inflammation. Several inflammation-related diseases in the cardiovascular system involve several intracellular events including mitochondrial dysfunction as well as disruption of MAMs. Therefore, an in-depth exploration of the function of MAMs will be of great significance for us to understand the initiation, progression, and clinical complications of cardiovascular disease (CVD). In this review, we summarize the recent advances in our knowledge of MAM regulation and function in CVD-related cells. We discuss the potential roles of MAMs in activating inflammation to influence the development of CVD.

Keywords: autophagy; cardiovascular disease; inflammasome; inflammation; mitochondria; mitochondrial-associated membranes.

FIGURE 1

Overview of the formation and autophagic clearance of inflammasomes. MAMs form in macrophages when they are stimulated by LPS and exposed to NLRP3 agonists (such as ATP, Alum, and Nigericin). Under these conditions, mitochondria usually become unstable, and then ASC and NLRP3 will be recruited at the MAM, which forms a positive-feedback loop. In Crohn’s Disease, serving as a compensatory mechanism, IRGM promotes selective autophagy to suppress the formation of NLRP3 inflammasomes to limit inflammation.

FIGURE 2

The role of inflammasomes and MAMs in atherosclerosis. (A) In macrophages, cholesterol crystals, free fatty acids, and LDL increase the progression of atherosclerosis by activating caspase-1 and NLRP3 inflammasome formation, followed by release of secreted factors. (B) In T-cells, HHcy increases ER-mitochondria coupling, which attenuates IFN-γ secretion and suppresses Treg cells to accelerate atherosclerosis.

FIGURE 3

Three factors influence diabetic cardiomyopathy. Metformin ameliorates diabetic cardiomyopathy via activation of AMPK, which inhibits mTOR and promotes autophagy. Rosuvastatin improves diabetic cardiomyopathy by repressing NLRP3-inflammasomes. FUNDC1 down-regulates Ca²⁺ flux and subsequently improves diabetic cardiomyopathy.

FIGURE 4

The role of inflammasomes and MAMs in heart failure (HF). Under high blood pressure, cardiomyocytes (CMs) activate CaMKIIδ, trigger inflammatory gene expression and activate NLRP3 inflammasomes. This leads to macrophage recruitment, fibrosis, and myocardial dysfunction, which finally induces heart failure. Noradrenaline, BNIP3 and RYR2 channels influence SR-to-mitochondria Ca²⁺ transfer and also alter cardiac metabolism. These factors all contribute to HF.

FIGURE 5

MAMs and the development of obesity. In obesity, liver cells have excessive MAMs, high mtROS, and Ca²⁺-overloaded mitochondria. These are all significantly relieved when IR3R1 and PACS2 are expressed at a lower level.

FIGURE 6

The integrity of MAMs in diabetes. Absence of CypD decreases the quantity of MAMs and damages their integrity, while Metformin reverses this effect and leads to recovery of insulin sensitivity.

FIGURE 7

The mechanism by which MAMs repress cigarette smoke-induced proliferation of endothelial cells. Bak is enriched at the ER following Bik-dependent dissociation of the Bak/Bcl-2 complex. Bak interacts with DPAK1 on the ER to increase the abundance of MAMs and Ca²⁺ flow from the ER to mitochondria, which suppresses the proliferation of endothelial cells induced by cigarette smoke.

FIGURE 8

The role of MAMs in hypertension. 1. Under extracellular stresses, PACS-2-associated MAM contacts are formed in VSMCs, which mediate mitophagy (autophagic degradation of mitochondria). 2. Depletion of PACS-2 decreases both mitophagy activity and the abundance of MAMs. This induces apoptosis and stimulates the formation of atherosclerotic plaques. 3. NgBR affects cell proliferation and migration by interacting with its ligand Nogo-B. Low expression of NgBR reduces the enrichment of MAMs and promotes pAkt-IP3R3 signaling, which enhances the proliferation of VSMCs and causes clinical symptoms.

FIGURE 9

MAMs in the development of atherosclerosis. MAMs are involved in signal transduction of macrophages during hypercholesteremia-induced chronic inflammation of the vascular wall.