Mitophagy defects exacerbate inflammation and aberrant proliferation in lymphocytic thyroiditis

Abstract

Abstract Background Mitochondrial dysfunction of the thyroid due to defective mitophagy has been observed in lymphocytic thyroiditis (LT). However, the effect of impaired mitophagy on the pathogenesis of LT has not been elucidated. Results We investigated the molecular pathological effect of mitophagy defects in thyroid glands through bioinformatics and histological approach using human and mouse thyroids and human thyroid cells. In this current study, it is showed that PINK1, a key regulator of mitophagy, is compromised in human thyroids with LT, and inflammatory responses and nodular hyperplasia are induced in the thyroids of PINK1-deficient mice. We found that mitophagy defects trigger pro-inflammatory cytokine production in thyroid cells and immune cell recruitment. Additionally, mitochondrial reactive oxygen species-driven hypoxia depletes CREB, a transcriptional repressor of amphiregulin (AREG), resulting in aberrant thyroid cell proliferation by AREG-mediated epidermal growth factor receptor signaling activation. Conclusions This signaling pathway could be a potential therapeutic target for thyroid goitrous changes in patients with LT. Our findings reveal the mitophagy defects in the thyroid that may be involved in LT pathogenesis and progression.