Lower Circulating MOTS-c Found in Hashimoto's Thyroiditis, New Study Reports

Most of the published research on MOTS-c comes from rodent models examining AMPK signaling and metabolic stress response. A study published in the Journal of Clinical Medicine (May 2026) takes a different angle: it measures circulating MOTS-c directly in people with Hashimoto’s thyroiditis, an autoimmune condition affecting the thyroid, and asks whether levels of this mitochondrial-derived peptide track with disease markers. It’s a cross-sectional, observational design, not an intervention study, but it adds a comparatively rare human clinical data point to a research literature that has been thin on that front.

What the researchers did

The study, led by a group at Health Sciences University in Istanbul, compared 90 patients diagnosed with Hashimoto’s thyroiditis against 90 age- and sex-matched healthy controls. Researchers measured circulating MOTS-c levels alongside a panel of metabolic and immune markers: body mass index, fasting glucose, HbA1c, HOMA-IR (a standard insulin-resistance index), thyroid-stimulating hormone, C-reactive protein, and thyroid autoantibody titers.

What they found

Circulating MOTS-c was significantly lower in the Hashimoto’s group than in controls. Within the patient group, lower MOTS-c correlated with higher BMI, higher fasting glucose and HbA1c, greater insulin resistance (HOMA-IR), higher C-reactive protein, and higher thyroid autoantibody levels — meaning the MOTS-c deficit tracked most closely with patients who had more pronounced metabolic and autoimmune disturbance, not just a Hashimoto’s diagnosis in isolation. In statistical modeling that adjusted for other variables, both the Hashimoto’s diagnosis itself and the degree of insulin resistance independently predicted lower MOTS-c. Whether patients were on levothyroxine (standard thyroid hormone replacement) made no measurable difference to MOTS-c levels.

Why this is a useful data point

MOTS-c’s core research narrative — a mitochondrially encoded peptide that activates AMPK signaling under metabolic stress — has mostly been built from cell culture and mouse studies. This paper doesn’t test a mechanism; it’s an association study in humans, and its main contribution is showing that the metabolic dysregulation researchers have flagged in animal models has a measurable, correlating counterpart in a specific autoimmune patient population. The consistent link to insulin resistance specifically (rather than just to the autoimmune diagnosis broadly) is the detail most relevant to MOTS-c’s existing research framing as a metabolic-signaling peptide, since it lines up with the pathway the preclinical literature already points to.

What it doesn’t show

This is a cross-sectional, observational study — it establishes a correlation, not a causal or mechanistic relationship, and it did not administer MOTS-c to any participant. It cannot say whether lower MOTS-c is a contributor to the metabolic and autoimmune disturbance seen in Hashimoto’s, a downstream consequence of it, or a marker of some shared upstream process. The authors themselves frame MOTS-c here as a candidate biomarker worth further study, not as a demonstrated therapeutic target. Replication in other cohorts and longitudinal designs (tracking the same patients over time) would be needed to move this from association toward mechanism.

Further reading

Sonay HO, Duran EN, Algemi M, et al. “Reduced Circulating MOTS-c Levels in Hashimoto’s Thyroiditis Reflect Integrated Autoimmune and Metabolic Dysregulation: A Cross-Sectional Study.” Journal of Clinical Medicine, 15(11), 4002 (2026). pubmed.ncbi.nlm.nih.gov/42278864 · doi.org/10.3390/jcm15114002