MITOCHONDRIAL OPEN READING FRAME (MOTS-C)

Mechanism of Action
MOTS-c is a 16–amino acid peptide encoded by a small open reading frame (ORF) in mitochondrial DNA (the 12S rRNA gene). It functions as a metabolic regulator by activating AMP-activated protein kinase (AMPK) in peripheral cells, which stimulates glucose uptake and glycolysis. It also improves insulin sensitivity in skeletal muscle and counteracts diet-induced weight gain and insulin resistance in high-fat diet models. A distinctive feature of MOTS-c is its ability to translocate to the cell nucleus under metabolic stress: in such conditions, the peptide migrates from the mitochondria to the nucleus in an AMPK-dependent process, where it binds to transcription factors associated with antioxidant response elements (AREs), modulating gene expression to enhance cellular stress resistance. In summary, MOTS-c acts as a mitochondrial signal with endocrine-metabolic effects, integrating mitochondrial activity with nuclear gene regulation to maintain energy homeostasis.
 
Clinical or Therapeutic Uses
MOTS-c is being studied as a potential therapy for metabolic disorders. In animal models, it has shown antidiabetic and anti-obesity effects: administration improves glucose utilization, increases insulin sensitivity, and prevents obesity and hyperglycemia in mice fed a high-calorie diet. Because it can mimic some effects of exercise, MOTS-c has been described as an “exercise mimetic,” potentially benefiting individuals with limited mobility. For example, aged or obese mice treated with MOTS-c demonstrated a significant increase in physical endurance—approximately doubling treadmill running distance and time compared with controls.
In the context of aging, endogenous MOTS-c levels decline with age, and certain genetic variants of MOTS-c have been associated with increased human longevity. Supplementation has been proposed as a means to attenuate age-related metabolic decline; in cellular and animal models, MOTS-c reversed features of metabolic aging by improving mitochondrial function and reducing inflammation.
Regarding cardiovascular health, preclinical studies suggest that MOTS-c exerts cardioprotective effects similar to exercise, improving cardiac function and preventing pathological remodeling in heart failure via AMPK activation and pro-survival pathways. A synthetic analogue, CB4211 (developed by CohBar), reduced liver fat and body weight in obese mice and is currently being evaluated in a phase 1b clinical trial for patients with non-alcoholic fatty liver disease (NAFLD). Overall, MOTS-c is viewed as a promising candidate for the treatment of metabolic syndrome, type 2 diabetes, obesity, cardiovascular disease, and age-related frailty, although it remains in the research stage.
 
Side Effects or Associated Risks
Available data suggest good short-term tolerability. In a preliminary study involving young men, MOTS-c administered for 7 days was safe and well tolerated, with no evidence of toxicity. Reported adverse effects were limited mainly to mild injection-site reactions (local redness or discomfort). Because MOTS-c activates AMPK (similarly to metformin), it may share some effects with that drug (such as mild gastrointestinal discomfort), although this has not been clearly documented to date.