MOTS-c: Mitochondrial-Derived Peptide Profile

MOTS-c is a 16-amino-acid peptide encoded in mitochondrial DNA, discovered in 2015 by Lee, Cohen, and colleagues at USC. Along with humanin and SHLPs 1-6, it showed that mitochondria also send circulating "mitokine" signals, not only make ATP-machinery proteins. At rest it stays with mitochondria; under metabolic stress it enters the nucleus and helps turn on protective genes. Muscle is the main target; it also circulates in blood. ## Mechanism It first disrupts the folate-methionine cycle, lowering 5-Me-THF and methionine while raising homocysteine. That raises AICAR and activates AMPK, increasing fat oxidation and GLUT4-mediated muscle glucose uptake. AMPK knockdown removes only part of the effect. Nuclear entry is AMPK-dependent. MOTS-c binds antioxidant response element promoters and works alongside NRF2. ## Main findings High-fat-diet mice given daily injections for 8 weeks did not become obese despite equal caloric intake. Old mice roughly doubled treadmill distance, and late-life intermittent dosing improved strength and gait. In people, exercise raised muscle MOTS-c roughly 12-fold and plasma levels about 50%. Levels fall with age, and replacement reversed muscle insulin resistance in older mice. People with type 2 diabetes had lower circulating MOTS-c. A Northeast Asian genetic variant binds a key kinase much more weakly, and diabetes risk rose specifically in inactive men carrying it. Other mouse work points to heart protection, reduced immobilization atrophy, and possible neuroprotection after traumatic brain injury — cancer-related effects remain unsettled. ## Human data There is no completed trial of native MOTS-c. An analog compound was tested over 28 days in obese patients with fatty liver disease: no serious adverse events, meaningful liver enzyme improvement, and lower glucose versus placebo, though liver fat itself fell equally in both arms and persistent injection-site nodules were reported. The program was later discontinued. ## Dose, safety, and legal status No human dosing data exist. Animal studies used injected doses only — oral administration is not considered viable. Long-term safety, drug interactions, and effects of supra-physiologic use are unknown. MOTS-c is not FDA-approved, not a dietary supplement, and not eligible for compounding. It has been banned by WADA at all times since 2024 as an AMPK activator, with no therapeutic-use exemption available. ## Bottom line The preclinical biology is strong and the exercise link is well established. It is not a proven human therapy. The only evidence-backed way to raise MOTS-c today remains exercise itself.