Pattern recognition receptors for mitochondrial damage-associated molecular patterns (mDAMP-PRRs)

Mitochondrial damage-associated molecular patterns (mDAMPs) are endogenous molecules released from damaged or stressed mitochondria that activate the innate immune system. This group of receptors, excluding TLR2, includes Toll-like receptor 9 (TLR9), which senses unmethylated CpG motifs in mitochondrial DNA (mtDNA) within endosomes (Zhang et al., 2010, Nature). In the cytoplasm, the enzyme cyclic GMP-AMP synthase (cGAS) detects mtDNA, triggering the STING pathway to produce type I interferons (West & Shadel, 2017, Nature Reviews Immunology). The NLRP3 inflammasome also acts as a sensor for mitochondrial signals such as reactive oxygen species (ROS), cardiolipin, and mtDNA, leading to the secretion of pro-inflammatory cytokines like IL-1β (Zhou et al., 2011, Nature). Additionally, formyl peptide receptor 1 (FPR1) recognizes N-formylmethionyl peptides released from the mitochondrial matrix, promoting neutrophil activation and chemotaxis (Rabiet et al., 2005, Journal of Leukocyte Biology). These pathways are central to sterile inflammation in conditions such as trauma, myocardial infarction, and neurodegenerative diseases (Grazioli & Pugin, 2018, Frontiers in Immunology). Pharmacological modulation of these receptors, including the use of TLR9 antagonists like hydroxychloroquine or NLRP3 inhibitors like MCC950, represents a significant therapeutic strategy for managing chronic inflammatory and autoimmune disorders.

Other names

Mitochondrial DAMP sensorsmtDNA receptorsCytosolic DNA sensorsFormyl peptide receptorsNLRP3 inflammasomecGAS-STING pathwayToll-like receptor 9

Inhibition of endosomal Toll-like receptor 9 signaling, blockade of NLRP3 inflammasome assembly and activation, inhibition of cyclic GMP-AMP synthase (cGAS) enzymatic activity, and antagonism of formyl peptide receptor 1 (FPR1) binding.