Table 1.
Components of MAMs involved in cardiovascular disease.
| Proteins | Relevant function(s) in MAMs | Functions in CVD | Expression in cardiovascular system |
|---|---|---|---|
| Protethering proteins | |||
| GRP75 | Increased MAM formation and mitochondria Ca2+ uptake | Mitochondrial calcium overload and hypoxia/reoxygenation injury in cardiomyocytes | High |
| IP3Rs | Interacts with GRP75 and VDACs, modulates calcium in MAMs | Upregulation in cardiac hypertrophy. Modulates excitation-contraction coupling in ventricular and atrial cardiomyocytes | Low |
| VDACs | Interacts with GRP75 and IP3Rs, regulates intracellular Ca2+ level | Marked elevation of VDAC1 in myocardial infarction. VDAC1 inhibition alleviates excessive fibrosis in the atrial myocardium | Medium |
| MFN2 | Modulator of ER-mitochondria tethering and mitochondrial fusion | Downregulation in cardiac hypertrophy. MFN2 upregulation ameliorated the cardiac hypertrophy. | Medium |
| MFN1 | Tethering mitochondria to MAMs via interaction with ER-resident MFN2 | Represses cardiac hypertrophy and ischemia/reperfusion injury | Not detected |
| Fis1 | Modulates ER-mitochondria tethering and induces apoptosis. Induces mitophagy | Inhibition of the CREB/Fis1 pathway leads to heart disease | High |
| BECN1 | Enhances MAM formation and autophagosomes | Deregulation leads to heart diseases, through altered myocardial autophagy and apoptosis | Low |
| FUNDC1 | Promotes mitochondrial fission and mitophagy. Increases Ca2+ | Required for cardiac ischemia/reperfusion injury-activated mitophagy | Medium |
| Parkin | Mediates mitophagy. Increases the ER-mitochondria contacts and induces Ca2+ transfer and ATP synthesis | Upregulated during I/R injury | Low |
| IP3Rs/GRP75/VDAC complex-modulated proteins | |||
| Sig-1R | Prolongs Ca2+ signaling; Sig-1R increase represses ER stress response, whereas Sig-1R decrease induces apoptosis | Sig-1R activation represses hypertrophy and cardiomyocyte injury. Sig-1R KO displays cardiac remodeling | High |
| CypD | Regulates Ca2+ transfer from the ER to mitochondria through IP3R1 | The CypD/GRP75/IP3R/VDAC complex inhibition improved hypoxia/reoxygenation injury in cardiomyocytes | NA |
| GSK3β | Inhibition of GSK3β results in decreased ER Ca2+ release as well as sensitivity to apoptosis | GSK3β inhibition reduced infarct size in reperfused hearts | Not detected |
| Antitethering proteins | |||
| CAV1 | Negatively regulates the formation of MAMs and impairs Ca2+ transfer | CAV1 ablation aggravates cardiac dysfunction and decreases survival in myocardial ischemia | Medium |
| Upstream regulators of the formation of MAMs | |||
| p38 MAPK | Phosphorylation of Gp78 at S538 by p38 MAPK inhibits MAM formation and mitochondrial fusion by promoting degradation of MFN1/2 | p38 MAPK has been implicated in cardiomyocyte dysfunction and apoptosis | Medium |
| FOXO1 | Augments MAM formation by inducing PDK4 and promotes mitochondrial Ca2+ accumulation, mitochondrial dysfunction, and ER stress | FOXO1 protein is associated with ischemic heart disease (IHD) | Not detected |