Molecular Dysfunctions of Mitochondria-Associated Endoplasmic Reticulum Contacts in Atherosclerosis

Abstract

Atherosclerosis is a chronic lipid-driven inflammatory disease that results in the formation of lipid-rich and immune cell-rich plaques in the arterial wall, which has high morbidity and mortality in the world. The mechanism of atherosclerosis is still unclear now. Potential hypotheses involved in atherosclerosis are chronic inflammation theory, lipid percolation theory, mononuclear-macrophage theory, endothelial cell (EC) injury theory, and smooth muscle cell (SMC) mutation theory. Changes of phospholipids, glucose, critical proteins, etc. on mitochondria-associated endoplasmic reticulum membrane (MAM) can cause the progress of atherosclerosis. This review describes the structural and functional interaction between mitochondria and endoplasmic reticulum (ER) and explains the role of critical molecules in the structure of MAM during atherosclerosis.

Figure 1

Convergence of signal transduction and metabolism at the MAM. The signal pathways that play the main biological functions on MAM including (1) calcium signaling (IP3R-Grp75-VDAC1 and SERCA-Ca²⁺) maintain the homeostasis of intracellular Ca²⁺and regulate the mitochondria and ER functions; (2) mitochondria and ER dynamics (MFNs and BAP31-Fis1-Drp1) regulate the fission and fusion of mitochondria thus regulating their functions; (3) MAM is the main place for the synthesis and transport of a variety of lipids; (4) molecular chaperones (VAPB-PTPIP51 and Sig1R-GRP78) participate in the secretion, folding, transport, and activation of proteins; (5) signal pathways such as PACS2-PSS1 can play other roles such as sorting and translocation.