MOTS-c (Mitochondrial Open Reading Frame of the 12S rRNA-c) is a 16-amino-acid mitochondrial-derived peptide (MDP) encoded within the mitochondrial 12S rRNA gene (MT-RNR1). Discovered in 2015 by Lee et al. at USC, it acts as a metabolic regulator primarily through AMPK activation. In mouse models, MOTS-c prevents diet-induced obesity and insulin resistance, enhances exercise capacity (old mice ran 2x longer on treadmill tests), and reduces age-related metabolic decline. A modified analog (CB4211) showed good tolerability in a Phase 1 human trial. No clinical trials of native MOTS-c in humans have been completed.
Category: Metabolic / Mitochondrial. Evidence rating: D (animal/preclinical only).
Clinical status: Research-only / No human clinical trials completed (Phase 1 of analog CB4211 only)
MOTS-c activates AMPK by inhibiting the folate cycle, causing accumulation of AICAR (an AMP analog). Activated AMPK shifts cells into energy-efficient mode: enhancing glucose uptake, fatty-acid oxidation, and mitochondrial respiration while downregulating fat storage and gluconeogenesis. Under…
Research base: 4 registered clinical trials and 112 indexed publications reference MOTS-c.
Safety considerations: No adverse effects reported in preclinical animal studies; Human tolerability is completely unknown for native MOTS-c (no completed human trials); Modified analog CB4211 showed good tolerability in Phase 1.
Reviewed by the PeptideAtlas Editorial Team. Last reviewed: 2026-08-12.
Related peptides: SS-31, Humanin.
Compare: MOTS-c vs SS-31, MOTS-c vs Humanin.
No. While called an "exercise mimetic" based on rodent studies (old mice ran 2x longer), there is no human evidence that MOTS-c can replicate the complex benefits of physical exercise. MOTS-c is naturally released during exercise, suggesting it is one of many mediators of exercise benefits.
No. Both are mitochondrial-derived peptides, but they are encoded by different genes. MOTS-c is encoded by the 12S rRNA gene (MT-RNR1), while humanin and SHLPs 1-6 are encoded by the 16S rRNA gene. They have different mechanisms and targets.
Native MOTS-c has not completed human clinical trials. A modified analog (CB4211) showed good tolerability in Phase 1. Human dosing, safety, and efficacy remain unknown.
MOTS-c activates AMPK (the cell's energy sensor) by inhibiting the folate cycle. This shifts cells into energy-efficient mode. Under stress, it also moves from mitochondria to the nucleus to upregulate protective genes -- a unique retrograde signaling mechanism.
WADA prohibits peptide hormones and their releasing factors not approved for therapeutic use, which would include MOTS-c.