Aryl hydrocarbon receptor-induced activation of AIM2 inflammasome is mediated by MOMP and MPT: A vital therapeutic pathway for inflammation.

Understanding how mitochondrial dysfunction (MD) triggers damage-associated molecular pattern (DAMP) signaling could advance therapies for inflammatory diseases. While aryl hydrocarbon receptor (AHR) is implicated in MD-related inflammation, its mechanistic role remains unclear. 8:2 fluorotelomer alcohol (8:2 FTOH), a per- and polyfluoroalkyl substance compound, was identified as an exogenous ligand for AHR. We demonstrate that AHR ligands drive mitochondrial outer membrane permeabilization (MOMP) and mitochondrial permeability transition (MPT) via transcriptional and non-transcriptional activation of AHR, promoting mitochondrial DNA (mtDNA) leakage and AIM2 inflammasome activation-the key mechanism of 8:2 FTOH-induced inflammation. Mechanistically, the F1F0ATP synthase/ATPase activity inhibition and B-cell lymphoma-2 (BCL-2)-associated X and BCL-2 antagonist/killer expression increase, with crosstalk between MOMP and MPT amplifying the mtDNA release. Inhibition of AHR/AIM2 alleviates the 8:2 FTOH-caused inflammation. Our findings establish AHR as a central regulator of mitochondrial DAMP signaling, and we propose therapeutic strategies for inflammatory diseases linked to environmental AHR activation.