Reduced Circulating MOTS-c Levels in Hashimoto's Thyroiditis Reflect Integrated Autoimmune and Metabolic...

Background: Hashimoto's thyroiditis (HT) is a common autoimmune disorder characterized by chronic inflammation and metabolic alterations. Mitochondria-derived peptides (MDPs), particularly mitochondrial open-reading frame of the 12S rRNA-c (MOTS-c), have emerged as key regulators of cellular metabolism, insulin sensitivity, oxidative stress, and inflammatory responses. This study aimed to investigate the association between circulating MOTS-c levels and HT and to explore its potential role in thyroid autoimmunity and metabolic regulation. Methods: In this cross-sectional study, patients diagnosed with HT (n: 90) were compared with age- and sex-matched healthy controls (n: 90). Results: A total of 180 participants were included, comprising 90 patients with HT and 90 age- and sex-matched healthy controls. Circulating MOTS-c levels were significantly lower in patients with HT compared to controls (p < 0.001). MOTS-c levels demonstrated significant inverse correlations with body mass index, fasting glucose, HbA1c, HOMA-IR, thyroid-stimulating hormone, C-reactive protein, and thyroid autoantibody levels (all p < 0.05). In subgroup analyses, these associations remained significant within the HT cohort, particularly for HOMA-IR and thyroid autoantibodies. Multivariable regression analysis identified HT (β = -30.04, p < 0.001) and HOMA-IR (β = -0.85, p < 0.001) as independent determinants of reduced circulating MOTS-c levels. Levothyroxine (LT4) use was not associated with significant differences in MOTS-c concentrations. Conclusions: Circulating MOTS-c levels are markedly reduced in patients with HT and are independently associated with insulin resistance and autoimmune burden. These findings suggest that impaired mitochondrial signaling may play a role in the pathophysiology of thyroid autoimmunity and highlight MOTS-c as a promising biomarker linking metabolic dysfunction and immune dysregulation.