MOTS-c and the Strange Story of Mitochondrial-Derived Peptides
It isn't encoded in your nuclear DNA at all — MOTS-c comes from a gene hiding inside mitochondrial DNA, a genome most people don't know produces proteins.
Almost every peptide covered on this site is encoded by a gene in nuclear DNA — the chromosomes in the cell's nucleus. MOTS-c is different: it's encoded within the mitochondrial genome, the small separate loop of DNA carried inside mitochondria themselves, best known for encoding parts of the cell's energy-production machinery rather than signaling peptides. MOTS-c was one of the first "mitochondrial-derived peptides" identified, a class discovered only within the last couple of decades.
That origin is directly tied to its proposed function. Mitochondria are the cell's energy-production centers, and MOTS-c is studied as a signal that communicates the mitochondria's metabolic state to the rest of the cell — activating AMPK, a master regulator of cellular energy balance that's also the target of drugs like metformin. This is the mechanistic basis for its association with insulin sensitivity and exercise-capacity research: it's acting on the same energy-sensing pathway the body already uses during exercise and caloric stress.
That link to exercise is also why community protocols dose it around training sessions rather than on a fixed daily schedule — the hypothesis is that MOTS-c's effect is most relevant when the cell is already under the kind of metabolic demand that naturally triggers AMPK activity, not as a standing baseline signal.
Because the mitochondrial-derived peptide class is so recently discovered, the human literature is thinner than for peptides that have been studied for decades — most of what's known comes from animal models and mechanistic cell-culture work, which is worth keeping in mind relative to how confidently its effects get described elsewhere.