Mitophagy Defects Exacerbate Inflammation and Aberrant Proliferation in Lymphocytic Thyroiditis

Area of Science:

• Endocrinology
• Cell Biology
• Immunology

Background:

• Mitochondrial dysfunction and defective mitophagy are observed in lymphocytic thyroiditis (LT).
• The precise role of impaired mitophagy in LT pathogenesis remains unclear.

Purpose of the Study:

• To investigate the role of mitophagy dysregulation in thyroid gland pathogenesis.
• To elucidate the mechanisms linking mitophagy defects to inflammation and hyperplasia in LT.

Main Methods:

• Analysis of RNA sequencing data from human thyroids (GTEx) and Pink1-deficient mice.
• Histopathological evaluation of human and mouse thyroid tissues.
• Assessment of cell proliferation, ROS production, and cytokine secretion in human thyroid cells treated with PINK1 siRNA or mitophagy inhibitors.

Main Results:

• Reduced PINK1 expression in human LT thyroids.
• Pink1 deficiency in mice led to thyroid inflammation and hyperplasia.
• Mitophagy defects increased ROS, pro-inflammatory cytokines, and immune cell recruitment.
• Increased amphiregulin (AREG) secretion and decreased CREB expression in thyroid cells with mitophagy defects.
• EGFR inhibition with cetuximab reduced aberrant cell proliferation.

Conclusions:

• Thyroid mitophagy defects exacerbate inflammation via ROS, cytokines, and immune cell recruitment.
• Mitophagy defects contribute to thyroid hyperplasia through the EGFR pathway by upregulating AREG.
• Targeting the EGFR pathway may offer therapeutic potential for LT-associated hyperplasia.