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

Figure 3

A hypothetical model of mitochondrial DAMP induction through mitochondria-associated ER membrane (MAM). Cellular metabolic dysfunction mediated by infection, hypoxia, obesity, and diabetes triggers abnormal association of endoplasmic reticulum (ER) and mitochondria. This increase in MAM formation induces mitochondrial calcium overload and exacerbates mitochondrial ROS generation, leading to mitochondrial permeability transition pore (mPTP) opening. The mitochondrial matrix protein CypD mediates mitochondrial calcium accumulation by physically interacting with the IP3R, GRP75, and VDAC complex at the MAM interface and modulates mPTP pore opening directly. mPTP opening facilitates release of mitochondrial components such as ATP, ROS, cytochrome C, mtDNA, cardiolipin, succinate, and N-formyl peptides into the cytosol, where they serve as mtDAMPS to activate the inflammasome. Subsequently, inflammasomes activate caspase-1 (Casp1) to induce cleavage and maturation of the proinflammatory cytokines IL-1β and IL-18. CypD: cyclophilin D; IP3R: inositol 1,4,5-trisphosphate receptor; GRP75: 75 kDa glucose-regulated protein; VDAC: voltage-dependent anion channel; mtDNA: mitochondrial DNA; IL-1β: interleukin-1 beta; IL-18: interleukin-18; ATP: adenosine triphosphate; ROS: reactive oxygen species; mtDAMPs: mitochondrial damage-associated molecular patterns.