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. 2022 May 27;13(5):504. doi: 10.1038/s41419-022-04942-2

Table 1.

Components of MAMs participated in cardiovascular diseases.

Proteins Relevant functions in MAMs Functions in CVD
IP3Rs Ca2+ outflow channels located on the ER surface mediating Ca2+ transfer in MAMs. IP3Rs downregulation alleviates mitochondrial Ca2+ overload, myocardial cell death and infarct area in I/R hearts [24, 25, 102].
GRP75 Bridges IP3Rs to VDACs to sustain MAMs structure. Mitochondrial Ca2+ overload and H/R injury in myocardial cells [27, 28, 100].
VDACs Ion channels on OMM regulate movement of metabolites and ions across mitochondria. Level of VDACs elevates in myocardial infarction [26].
Fis1 Regulates ER-mitochondria tethering, apoptosis, and mitochondrial dynamics. Disruption of Fis1-mediated signaling results in heart diseases [29, 33, 34].
Mfn2 Modulator of MAMs structure by forming hetero- or homodimers with Mfn1/2. Responds to ER stress. Mfn2 decreases in cardiac hypertrophy. High Mfn2 inhibits cardiac hypertrophy and phenotypic switching in PASMCs [35, 36, 39, 134].
Mfn1 Tethering mitochondria to ER through connection with ER-located Mfn2 Mfn1 knockout is effective in relieving cardiac hypertrophy and I/R injury [35, 36, 107].
VAPB Physically/functionally interacts ER to mitochondria through OMM-resident PTPIP51. Modulates mitochondrial Ca2+ level. Downregulation of VAPB elicits myocardial damage during cardiac I/R [41, 42, 45, 46].
PTPIP51 Physically/functionally interacts mitochondria to ER via connecting to ER-resident VAPB. Modulates mitochondrial Ca2+ level. Overtly elevated PTPIP51 in cardiomyocytes following I/R [41, 42, 44].
Sig-1R Reduces IP3Rs degradation under ER stress and boosts Ca2+ transmission to mitochondria. Sig-1R inhibition promotes autophagy in cardiomyocytes under oxidative stress whereas its stimulation represses hypertrophy and myocardial cell injury [65, 115, 116].
FUNDC1 Facilitates mitochondrial fission and mitophagy. Regulates mitochondrial Ca2+ level. FUNDC1 decreases in HF. Heart-specific FUNDC1 ablation exhibits interstitial fibrosis, compromised cardiac function and elevated apoptosis [67, 85, 112114].
mPTP Promotes Ca2+-dependent apoptosis. Mediator of cardiomyocyte death during reperfusion damage [20, 5557].
PACS2 Favors ER-mitochondria coupling and controls Bid-mediated apoptosis. PACS2 silencing promotes VSMCs apoptosis and plaque rupture [70, 71, 137].
Drp1 Modulates mitochondrial dynamics, apoptosis and mitophagy. Drp1 overexpression evokes cardiac hypertrophy and phenotypic change in PASMCs [33, 34, 74, 75, 85, 123, 134].
CypD Regulates Ca2+ transfer from ER to mitochondria via IP3R. Inhibition of CypD-IP3R-GRP75-VDAC complex protects mitochondrial Ca2+ overload and H/R myocardial cells [97, 100].

Bid BH3-interacting domain death agonist, CVD cardiovascular diseases, CypD Cyclophilin D, Drp1 dynamin-related protein 1, ER endoplasmic reticulum, Fis1 fission protein 1 homolog, FUNDC1 FUN14 domain containing 1, GRP75 glucose-regulated protein 75, HF heart failure, H/R hypoxia/re-oxygenation, IP3R inositol 1,4,5-triphosphate receptors, I/R ischemia-reperfusion, MAMs mitochondria-associated membranes, Mfn1/2 mitofusin-1/−2, mPTP mitochondrial permeability transition pores, OMM outer mitochondrial membrane, PACS2 phosphofurin acidic cluster sorting protein 2, PASMCs pulmonary artery smooth muscle cells, PTPIP51 protein tyrosine phosphatase-interacting protein-51, Sig-1R sigma-1 receptor, VAPB vesicle-associated membrane protein-associated protein-B, VDACs voltage-dependent anion channels, VSMCs vascular smooth muscle cells.