Mitophagy at the crossroads of oxidative stress and autoimmune thyroiditis

Our recent study reveals how mitochondrial oxidative stress activates protective mitophagy in autoimmune thyroiditis. In thyroid epithelial cells, mitochondrial reactive oxygen species (mtROS) activate ATM serine/threonine kinase (ATM)-checkpoint kinase 2 (CHEK2) signaling. CHEK2 directly phosphorylates Tax1 binding protein 1 (TAX1BP1) at serine 722, enhancing its binding to lysine 63 (K63)-linked ubiquitin chains and promoting mitochondrial clearance. The nonphosphorylatable serine 722-to-alanine (S722A) mutant impairs mitophagy and increases cytosolic mitochondrial DNA (mtDNA) and stimulator of interferon genes (STING1) pathway activity. Deletion of either PTEN induced kinase 1 (Pink1) or parkin RBR E3 ubiquitin protein ligase (Prkn) aggravates thyroiditis in mice, whereas STING1 inhibition with C-176 reduces inflammation and thyroid autoantibody responses in both knockout models.