Compositions and Functions of Mitochondria-Associated Endoplasmic Reticulum Membranes and Their Contribution to Cardioprotection by Exercise Preconditioning

Abstract

Mitochondria-associated endoplasmic reticulum membranes (MAMs) are important components of intracellular signaling and contribute to the regulation of intracellular Ca²⁺/lipid homeostasis, mitochondrial dynamics, autophagy/mitophagy, apoptosis, and inflammation. Multiple studies have shown that proteins located on MAMs mediate cardioprotection. Exercise preconditioning (EP) has been shown to protect the myocardium from adverse stimuli, but these mechanisms are still being explored. Recently, a growing body of evidence points to MAMs, suggesting that exercise or EP may be involved in cardioprotection by modulating proteins on MAMs and subsequently affecting MAMs. In this review, we summarize the latest findings on MAMs, analyzing the structure and function of MAMs and the role of MAM-related proteins in cardioprotection. We focused on the possible mechanisms by which exercise or EP can modulate the involvement of MAMs in cardioprotection. We found that EP may affect MAMs by regulating changes in MFN2, MFN1, AMPK, FUNDC1, BECN1, VDAC1, GRP75, IP3R, CYPD, GSK3β, AKT, NLRP3, GRP78, and LC3, thus playing a cardioprotective role. We also provided direction for future studies that may be of interest so that more in-depth studies can be conducted to elucidate the relationship between EP and cardioprotection.

Keywords: cardioprotection; exercise; exercise preconditioning; heart; mitochondria-associated endoplasmic reticulum membranes; preconditioning.

FIGURE 1

Composition and structure of MAMs. Abbreviations: MITO, mitochondria; MAMs, mitochondria-associated endoplasmic reticulum membranes; ER/SR, endoplasmic/sarcoplasmic reticulum; OMM, outer mitochondrial membrane; IMM, inner mitochondrial membrane; MCU, mitochondrial Ca²⁺ uniporter; NCX, Na⁺ Ca²⁺ exchanger; RYR, ryanodine receptor; NLRP3, NOD-like receptor protein 3; VDAC, voltage-dependent anion channel; FUNDC1, FUN14 domain containing 1; IP3R, inositol-1,4, 5-triphosphate receptor; PTPIP51, protein tyrosine phosphatase-interacting protein 51; VAPB, vesicle-associated membrane-protein-associated protein B; GSK3β, glycogen synthase kinase-3 beta; CYPD, cyclophilin D; ANT, adenine nucleotide transporter; mPTP, mitochondrial permeability transition pore; GRP75/78, glucose-regulated protein 75/78; SIG1R, sigma-1 receptor; PERK, PRK-like ER kinase; FIS1, fission 1; BAP31, B cell receptor-associated protein 31; TOM40, outer mitochondrial membrane 40; PDZD8, PDZ domain-containing protein 8; ORP5/8, oxysterol-binding protein-related protein 5/8; PS, phosphatidylserine; ATAD3, ATPase family AAA domain-containing protein 3; WASF3, Wiskoff-Aldrich syndrome protein family member 3; MFN1/2, mitofusin 1/2; AMPK, AMP-activated protein kinase; CNX, Calnexin; SERCA, Sarco/ER Ca²⁺ ATPase; TMX1, thioredoxin-related transmembrane protein 1; PACS-2, phosphofurin acidic cluster sorting protein 2; AKT, protein kinase B; mTORC2, mammalian TOR complex 2.

FIGURE 2

EP regulates MAM-related proteins to promote cardioprotection. Abbreviations: EP, exercise preconditioning; MAMs, mitochondria-associated endoplasmic reticulum membranes; VDAC1, voltage-dependent anion channel 1; GRP78, glucose-regulated protein 78; AKT, protein kinase B; BECN1, beclin1; MFN1/2, mitofusin 1/2; NLRP3, NOD-like receptor protein 3; GSK3β, glycogen synthase kinase-3 beta; LC3, microtubule-associated protein 1 light chain 3; AMPK, AMP-activated protein kinase; FUNDC1, FUN14 domain containing 1.