The AMPK-MFN2 axis regulates MAM dynamics and autophagy induced by energy stresses

Mitochondria-Associated Endoplasmic Reticulum Membranes in Cardiovascular Diseases

“…In contrast, we recently observed a negative role of AMPK on MAM formation by reducing the expression of FUNDC1 (Wei et al, 2020). Also, under energy stress, considerable amounts of AMPK translocate from cytosol to the MAM and the mitochondrion as mitochondrial fission occurs, where they interact directly with MFN2 to initiate autophagy (Hu Y. et al, 2020). These findings suggest that the cardiovascular benefits of metformin may depend on its regulation of MAM formation.…”

Mitochondria-Associated Endoplasmic Reticulum Membranes (MAMs) and Their Prospective Roles in Kidney Disease

“…A core subset of proteins that tether mitochondria to the ER in mammalian cells has been identified; these proteins either play a direct role in the physical connection of MAMs or modulate the tethering complexes in MAMs ( Figure 1 ). The well-established proteins include (1) the protethering complexes or factors: (i) the phosphor acidic cluster sorting protein 2 (PACS2) [ 15 ], (ii) glucose-regulated protein 75 (Grp75) bridging inositol triphosphate receptor (IP3R) to voltage-dependent anion channel 1 (VDAC1) [ 25 ], (iii) mitofusin 2 (Mfn2) on the ER that bridges the two organelles by engaging in homotypic and heterotypic complexes with Mfn 1 or 2 on the outer mitochondrial membrane (OMM) [ 26 ], (iv) the mitochondrial fission 1 protein- (Fis1-) B cell receptor-associated protein 31 (BAP31) complex (ARCosome) [ 27 ], (v) the complex formed by vesicle-associated membrane protein-associated protein B (VAPB) and protein tyrosine phosphatase interacting protein 51 (PTPIP51) [ 28 , 29 ], (vi) the FUN14 domain containing 1- (FUNDC1-) IP3R2 complex [ 30 ], (vii) PDZD8 [ 31 ], (viii) Beclin1 (BECN1) [ 13 ], and (ix) MITOL, Parkin, and AMPK α , which regulate MAMs formation by directly interacting with mfn2 on the OMM side [ 32 , 33 ]; (2) the proteins that modulate IP3Rs/Grp75/VDAC complexes: Sigma-1 receptor (Sig-1R) [ 34 ], cyclophilin D (CypD) [ 35 ], thymocyte-expressed, positive selection-associated gene 1 (Tespa1) [ 36 ], reticulon 1C (RTN-1C) [ 37 ], glycogen synthase kinase-3 β (GSK3 β ) [ 38 ], disrupted-in-schizophrenia 1 (DISC1) [ 39 ], mitochondrial translocase of the outer membrane 70 (TOM70) [ 40 ], transglutaminase type 2 (TGM2) [ 41 ], Wolfram syndrome 1 (WFS1) [ 42 ], pyruvate dehydrogenase kinases 4 (PDK4) [ 43 ], and etoposide-induced protein 2.4 (EI24) [ 44 ]; (3) antitethering factors: (i) trichoplein/mitostatin (TpMs) that negatively regulates MAMs tethering via Mfn2 [ 45 ], (ii) FATE1 uncoupling MAMs by interacting with ER chaperones and emerin (EMD) and the mitofilin [ 46 ], and (iii) Caveolin-1 [ 47 ]; 4) Upstream regulators of MAMs formation: (i) glycogen synthase kinase-3 β (GSK3 β ) [ 28 ], (ii) p38 MAPK [ 48 ], (iii) cGMP-dependent protein kinase (PKG) [ 49 ], (iv) FOXO1 [ 43 ], (v) cAMP-dependent protein kinase (PKA) [ 47 ], and (vi) AMPK α [ 32 , 50 ]. The functional roles and relative protein expression of MAMs-resident proteins listed in this text are summar...…”

Mitochondrial destiny in type 2 diabetes: the effects of oxidative stress on the dynamics and biogenesis of mitochondria

“…Thus, the balance between fusion and fission of mitochondria plays a vital role in the regulation of mitochondrial energy (Hu et al, 2020).…”