MOTS-c

MOTS-c (Mitochondrial Open Reading frame of the 12S rRNA-c) is a 16-amino-acid peptide encoded by the mitochondrial genome, distinguishing it from virtually every other peptide in human pharmacology, which are nuclear-encoded. It was discovered by Pinchas Cohen's lab at USC in 2015 and is one of a growing class of mitochondrial-derived peptides (MDPs).

Peppudex card: see the mechanism + evidence-grade summary at [Peppudex / MOTS-c](https://peppudex.com/peptides/mots-c).

Overview

Published assays have detected MOTS-c in human plasma with concentrations varying widely depending on the method (ELISA vs mass spec) and the population studied. Reported ranges in healthy adults span roughly tens to a few hundred ng/mL across different studies; the precise reference range is still under active investigation. MOTS-c is studied primarily for its role in glucose homeostasis, AMPK activation, and exercise-mimicry pathways, with the strongest evidence in rodent models.

Mechanism

MOTS-c translocates to the cell nucleus under metabolic stress (glucose deprivation, oxidative stress, exercise), where it modulates nuclear gene expression in response to mitochondrial state. Downstream effects:

• AMPK activation · master switch for catabolic energy programs
• Enhanced glucose uptake in skeletal muscle independent of insulin
• Improved insulin sensitivity in diet-induced obese rodent models
• Activation of antioxidant and mitochondrial biogenesis pathways

See: AMPK, Mitochondrial-derived_peptides, Insulin_sensitivity.

Evidence

• Diet-induced obese mice · MOTS-c reversed insulin resistance and reduced body-fat percentage (Lee et al., 2015, PMID 25738459)
• Aged mice · MOTS-c improved physical performance on treadmill and grip strength (Reynolds et al., 2021, PMID 33473109)
• Plasma MOTS-c levels have been reported to decline with age in human cohort studies (see Du et al. 2018, J Mol Med; Lu et al. 2019, Free Radic Biol Med). The exact magnitude and trajectory of the age-related decline varies by assay and population.

Human clinical evidence is early-stage. Several small studies on insulin-resistance populations are listed on ClinicalTrials.gov but no phase III completions exist.

Dosing literature

Animal studies used 0.5–10 mg/kg via intraperitoneal injection. Community-reported research dose range is 5–10 mg per administration, 2–3 times per week, subcutaneous. Cycling protocols of 4–8 weeks are common.

Storage

Lyophilized: 4 °C 24 months, –20 °C indefinite. Reconstituted: 2–8 °C, use within 28 days. See Reconstitution.

Regulatory status

• United States. Research use only. Not FDA-approved.
• WADA. Not currently on the prohibited list.

See also

• AMPK · core downstream target
• Mitochondrial-derived_peptides · class overview
• Humanin · related MDP
• [Peppudex card · MOTS-c](https://peppudex.com/peptides/mots-c) · mechanism, evidence grades A-F, FAQs, peer-reviewed sources

References

• Lee C, et al. "The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance." Cell Metab. 2015;21(3):443-54. PMID 25738459.
• Reynolds JC, et al. "MOTS-c is an exercise-induced mitochondrial-encoded regulator of age-dependent physical decline and muscle homeostasis." Nat Commun. 2021;12(1):470. PMID 33473109.
• Du C, Zhang C, Wu W, et al. "Circulating MOTS-c levels are decreased in obese male children and adolescents and associated with insulin resistance." Pediatr Diabetes. 2018.