Mitochondria-associated endoplasmic reticulum membranes and cardiac hypertrophy: Molecular mechanisms and therapeutic targets

Abstract

Cardiac hypertrophy has been shown to compensate for cardiac performance and improve ventricular wall tension as well as oxygen consumption. This compensatory response results in several heart diseases, which include ischemia disease, hypertension, heart failure, and valvular disease. Although the pathogenesis of cardiac hypertrophy remains complicated, previous data show that dysfunction of the mitochondria and endoplasmic reticulum (ER) mediates the progression of cardiac hypertrophy. The interaction between the mitochondria and ER is mediated by mitochondria-associated ER membranes (MAMs), which play an important role in the pathology of cardiac hypertrophy. The function of MAMs has mainly been associated with calcium transfer, lipid synthesis, autophagy, and reactive oxygen species (ROS). In this review, we discuss key MAMs-associated proteins and their functions in cardiovascular system and define their roles in the progression of cardiac hypertrophy. In addition, we demonstrate that MAMs is a potential therapeutic target in the treatment of cardiac hypertrophy.

Mitochondria-associated endoplasmic reticulum membranes as a therapeutic target for cardiovascular diseases

“…It is worth noting that while the majority of enzymes involved in lipid synthesis are located in the membranes of the ER, there are also some present in mitochondrial membranes ( Rowland and Voeltz, 2012 ; Petrungaro and Kornmann, 2019 ; Dong et al, 2024 ). MAMs are enriched with proteins related to lipid metabolisms, such as phosphatidylserine synthase 1/2 (PSS1/2), phosphatidylethanolamine N-methyltransferase (PEMT) 2, fatty acid CoA ligase 4, phosphatidylserine decarboxylase (PSD), caveolin-1 (CAV1), diacylglycerol O-acyltransferase, and Acyl-coenzyme A: cholesterol acyltransferase/sterol O-acyltransferase (ACAT/SOAT) ( Luan et al, 2022 ; Wang et al, 2021 ; Zhang et al, 2023 ). The regulation of common cellular phospholipids, including phosphatidylcholine (PC), phosphatidylethanolamine (PE), and PS, is co-regulated by multiple proteins on MAMs.…”

“…Several proteins located in MAMs are involved in mitochondrial fission, including Drp1, Fis1, mitochondrial fission factor, and mitochondrial dynamics protein of 49 and 51 kDa, which form a protein complex that tightens mitochondria and initiates fission. Additionally, FUNDC1, inverted formin 2, syntaxin 17 (STX17), and ras analog in brain 32 are also involved ( Ji et al, 2017 ; Luan et al, 2022 ).…”

Broadening Horizons: Exploring mtDAMPs as a Mechanism and Potential Intervention Target in Cardiovascular Diseases

“…Cardiac hypertrophy is characterized by enlarged cardiomyocytes and fibrosis, eventually leading to heart failure [29]. Recent evidence suggests that immune cells and inflammatory signaling are crucial in nonischemic heart injuries, including cardiac hypertrophy [30].…”

Unique original endocrine findings: the endoplasmic reticulum-mitochondrial unit in steroid producing cells

“…These MAMs play a crucial role in various cellular functions ranging from lipid metabolism, to calcium signalling and cell death and classical steroidogenesis [3]. Dysregulation of ER-MIT interaction by MAMs has been implicated in insulin resistance, neurodegeneration, cardiac hypertrophy, and cancer [3][4][5][6][7].…”

“…Furthermore, stress triggers mitochondrial biogenesis. All markers of mitochondrial biogenesis including transcription factors, related kinases, and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PPARGC1A) protein, the master regulator of mitochondrial biogenesis are upregulated by stress stimuli [4]. Thus, stress and mitochondrial biogenesis, and morphology are intimately linked allowing a fine-tuning and feedback mechanism of steroid-dependent hormone-regulation.…”