Role of Mitochondria-Associated Endoplasmic Reticulum Membrane in Inflammation-Mediated Metabolic Diseases

Figure 2

Mitochondria-associated ER membrane as an inflammatory signaling hub. Close contact between the endoplasmic reticulum (ER) and mitochondria via mitochondria-associated ER membrane (MAM) formation allows the ER calcium channel IP3R to funnel calcium into mitochondria by forming a complex with the chaperone protein GRP75 and the mitochondrial outer membrane calcium channel VDAC. Then, the inner mitochondrial membrane calcium channel MCU injects calcium into the mitochondrial matrix. Under pathological conditions, elevated ER-mitochondrial interaction promotes calcium accumulation via proteins present at the MAM interface. The MAM-resident proteins PML and p53 control ER calcium release by physically interacting with IP3R. In addition, p66sh amplifies mitochondrial ROS production. Increased cellular ROS activates NF-κB, a master regulator of inflammation, resulting in increased expression of genes encoding numerous proinflammatory cytokines. PERK plays a dual role by tethering ER and mitochondria and detecting ROS production, which triggers its ER stress signaling cascade. In response to ER stress, activated IRE1 promotes NLRP3 through a TXNIP-dependent mechanism. NLRP3 detects mitochondrial ROS generation and recruits caspase-2 (Casp2) to mitochondria to cleave BID, forming c-BID, which in turn promotes BAX/BAK-mediated mtDAMP release. NLRP3 activation also promotes recruitment of ASC to MAM, where inflammasome complexes are assembled. Finally, inflammasomes activate caspase-1 (Casp1), which cleaves pro-IL-1β to generate mature IL-1β. Foreign pathogen-associated dsDNA is detected by RIG-1, resulting in activation of MAVS and therefore promotion of its downstream inflammatory response. MAVS can also recruit NLRP3 onto mitochondria and promote inflammasome formation, which specifically induces IL-1β production. Other MAM-resident proteins such as presenilins (PS) and α-synuclein (α-Syn) play a crucial role in the pathogenesis of Alzheimer’s disease and Parkinson’s disease, respectively. IP3R: inositol 1,4,5-trisphosphate receptor; MCU: mitochondrial calcium uniporter; GRP75: 75 kDa glucose-regulated protein; VDAC: voltage-dependent anion channel; PERK: pancreatic ER kinase; PML: promyelocytic leukemia protein; p53: tumor protein p53; p66sh: 66 kDa isoform of the growth factor adapter Shc; NF-kB: nuclear factor-kappa B; eIF2α: eukaryotic initiation factor 2 alpha; CHOP: CCAAT-enhancer-binding protein homologous protein; IRE1: inositol-requiring enzyme 1; NLRP3: NACHT, LRR, and PYD domain-containing protein 3; ASC: apoptosis-associated speck-like protein containing a CARD; TXNIP: thioredoxin-interacting protein; IL-1β: interleukin-1 beta; BID: BH3 interacting-domain death agonist; ROS: reactive oxygen species; BAX: Bcl-2-associated X protein; BAK: Bcl-2 homologous antagonist/killer; MAVS: mitochondrial antiviral-signaling protein; RIG-1: retinoic acid-inducible gene-1 protein; mtDAMPs: mitochondrial damage-associated molecular patterns.