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Review
. 2020 Nov 9:8:604240.
doi: 10.3389/fcell.2020.604240. eCollection 2020.

Mitochondria-Associated Endoplasmic Reticulum Membranes in Cardiovascular Diseases

Peng Gao  1 , Zhencheng Yan  1 , Zhiming Zhu  1
Affiliations
Review

Mitochondria-Associated Endoplasmic Reticulum Membranes in Cardiovascular Diseases

Peng Gao et al. Front Cell Dev Biol. .

Abstract

The endoplasmic reticulum (ER) and mitochondria are physically connected to form dedicated structural domains known as mitochondria-associated ER membranes (MAMs), which participate in fundamental biological processes, including lipid and calcium (Ca2+) homeostasis, mitochondrial dynamics and other related cellular behaviors such as autophagy, ER stress, inflammation and apoptosis. Many studies have proved the importance of MAMs in maintaining the normal function of both organelles, and the abnormal amount, structure or function of MAMs is related to the occurrence of cardiovascular diseases. Here, we review the knowledge regarding the components of MAMs according to their different functions and the specific roles of MAMs in cardiovascular physiology and pathophysiology, focusing on some highly prevalent cardiovascular diseases, including ischemia-reperfusion, diabetic cardiomyopathy, heart failure, pulmonary arterial hypertension and systemic vascular diseases. Finally, we summarize the possible mechanisms of MAM in cardiovascular diseases and put forward some obstacles in the understanding of MAM function we may encounter.

Keywords: SR-mitochondrial contact; cardiovascular diseases; metabolic transition; mitochondria-associated ER membrane; mitochondrial bioenergetics.

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Figures

FIGURE 1
FIGURE 1
Mitochondria-associated ER membranes and cell physiology. (A) Lipid synthesis and transfer. The MAMs account for PS generation through PSS, and PS synthesized in ER is then transferred to mitochondria by ORP5 and ORP8 for further conversion to PE. In addition, caveolin-1 inserted into the ER participates in ER-mitochondrial cholesterol transfer. (B) Ca2+ transfer and apoptosis. Ca2+ transfer from ER to mitochondria is mediated by a protein complex consisting IP3R1 in ER or RYR in SR, GRP75, and VDAC1 in OMM, then Ca2+ is transported into mitochondrial matrix via MCU. Excessive mitochondrial Ca2+ uptake triggers opening of mPTP to initiate apoptosis. Activation of caspase 8 activates downstream caspases and induces NOGO B cleavage, which is inhibited by cFLIPL. Some proteins are located on MAM govern the apoptotic pathway by preserving intraorganellar Ca2+ transfer, such as PML, BCL-XL, or PTEN. (C) Mitochondrial dynamics. The recruitment of main mitochondrial fission protein DRP1 to MAM is regulated by Mff, Fis1 and Syntaxin-17. And mitochondrial fusion is controlled by MFN2 on OMM and OPA1 on IMM. (D) Autophagy. At rest, Syntaxin-17 binds to DRP1, but in the absence of nutrients, DRP1 is replaced by pre-autophagosome marker ATG14L, which promotes the enrichment of mTORC2 and AKT to initiate the formation of autophagosome. The anchor sets formed by VAPB in ER and RMDB3 on OMM regulate autophagy by maintaining MAMs. (E) ROS generation and ER stress. Oxidative condition induces ser36 phosphorylation of p66Shc, resulting in p66Shc transfer to MAMs and produce ROS, which stimulates ER stress via IRE1 and PERK. Sigma-1R located on MAMs could stabilize IRE1. (F) Inflammation. Upon stimulation, NLRP3 is transferred from ER to MAMs where it interacts with its adaptor ASC and TXNIP to initiate inflammasome formation. AKT, serine/threonine kinase; ASC, apoptosis-associated speck-like protein; ATG14L, autophagy-related 14-like; BCL-XL, B cell lymphoma extra-large; cFLIPL, FADD-like apoptosis regulators; DRP1, dynamin-related protein 1; ER, endoplasmic reticulum; Fis1, fission 1 protein; GRP75, chaperone 75 kDa glucose-regulated protein; IP3R1, inositol-1,4,5-triphosphate receptor type 1; IMM, inner mitochondrial membrane; IRE1, inositol-requiring enzyme 1; MAM, mitochondria-associated ER membrane; Mff, mitochondrion fission factor; MCU, mitochondrial calcium uniporter; MFN2, mitofusin 2; mTORC2, mammalian target of rapamycin complex 2; NOGO B, neurite outgrowth inhibitor B; NLRP3, pyrin domain-containing 3 protein; OPA1, optic atrophy protein 1; ORP5, oxysterol-binding protein-related protein 5; OMM, outer mitochondrial membrane; PE, phosphatidylethanolamine; PERK, protein kinase-like ER kinase; PML, promyelocytic leukemia protein; PS, phosphatidylserine; PSS, PS synthase; PTEN, phosphatase and tensin homolog; RMDB3, regulator of microtubule dynamics 3; ROS, reactive oxygen species; RYR, ryanodine receptor; TXNIP, thioredoxin interacting protein; VAMP, vesicle associated membrane protein; VAPB, VAMP-associated protein B; VDAC1, voltage-dependent anion-selective channel protein 1.
FIGURE 2
FIGURE 2
Mitochondria-associated ER membranes and pathogenesis of cardiovascular diseases. Under normal conditions, glucose is taken up into cytoplasm via GLUT4, where it is divided into two molecules of pyruvate through glycolysis. PDH converts pyruvate derived from glycolysis into mitochondrial Ac-CoA, which enters into TCA cycle to generate substrates required for electron transfer of oxidative phosphorylation chain located on IMM. Both glycolysis and mitochondrial oxidative phosphorylation produce ATP but the efficiency of mitochondria is much higher than glycolysis. Ca2+ transferred from ER to mitochondria via IP3R (or RYR in VSMCs and cardiomyocytes)/VDAC1 complex acts as stimulants of main enzymes in TCA cycle to enhance the ability of mitochondrial bioenergetics. Under pathological stimulants, such as hypoxia, high glucose or ox-LDL, the formation of MAMs increases and lead to excessive mitochondrial Ca2+ uptake, which opens the mPTP to initiate apoptosis and mitochondrial fragmentation, the early steps of atherogenesis, I/R injury and diabetic cardiomyocyte damage. On the other hand, under TAC or NE stimulation, the formation of MAMs is reduced, with increased gap between ER and mitochondria, resulting in lowered mitochondrial Ca2+ level and elevated cytosolic Ca2+. The insufficient mitochondrial Ca2+ lowers the activity of oxidative phosphorylation, initiates metabolic switch to glycolysis to generate ATP, resulting in increased lactate production and mitochondrial fission. Inhibition of mitochondrial energy production evokes phenotype switch of VSMCs or cardiomyocytes from contractile to synthetic, a major step for developing hypertrophy-associated diseases, such as HF, PAH, and systemic vascular diseases. Mitochondrial dynamics participates in both processes as either inhibition of DRP1 or activation of MFN2 or OPA1 exerts beneficial effects on cardiovascular diseases. Ac-CoA, acetyl-coenzyme A; DRP1 dynamin-related protein 1; ER, endoplasmic reticulum; FUNDC1, FUN14 domain-containing protein 1; GLUT4, glucose transporter type 4; GSK3β, glycogen synthase kinase 3β; IMM, inner mitochondrial membrane; IP3R, inositol-1,4,5-triphosphate receptor; I/R, ischemia-reperfusion; MAMs, mitochondria-associated ER membranes; MCU, mitochondrial calcium uniporter; MFN2, mitofusin 2; mPTP, mitochondrial permeability transition pore; NE, norepinephrine; OPA1, optic atrophy protein 1; ox-LDL, oxidative low-density lipoprotein; PDH, pyruvate dehydrogenase complex; RYR, ryanodine receptor; TAC, thoracic aortic constriction; TCA, tricarboxylic acid; VDAC1, voltage-dependent anion-selective channel protein 1; VSMC, vascular smooth muscle cell.
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