For most of the twentieth century the mitochondrial genome was understood as a small, functionally narrow remnant encoding components of the respiratory chain. The identification of open reading frames producing short bioactive peptides changed that picture, and MOTS-c is the most extensively characterised of them.
Encoded where you would not expect
MOTS-c is a sixteen amino acid peptide encoded within the mitochondrial 12S ribosomal RNA gene — a sequence whose primary function is structural. That a coding sequence should be nested inside a structural RNA gene is unusual enough that the finding took time to be accepted, and it remains one of the more striking results in the field.
The proposed mechanism
Published work describes MOTS-c as inhibiting the folate cycle, causing AICAR to accumulate, which in turn activates AMP-activated protein kinase — the cell's principal energy sensor. Under metabolic stress the peptide is reported to translocate to the nucleus and associate with stress-response transcription factors, which is the observation that positions it as a signal between the two genomes rather than simply a metabolic effector.
The interesting claim is not that a mitochondrial peptide affects metabolism. It is that the mitochondrion appears to be reporting its own state to the nucleus in a language the nucleus reads.
Distinguishing signal from substrate
This is why MOTS-c and NAD+ are frequently studied together and frequently confused. NAD+ is a substrate — consumed stoichiometrically by sirtuins, PARPs and CD38, with the free pool set by the balance of synthesis and consumption. MOTS-c is a signal. Measured only downstream, substrate limitation and signalling change can look identical, and separating them is the reason the two appear in the same experimental designs.
What remains open
The receptor question, principally. The mechanism by which an intracellularly generated peptide exerts effects consistent with extracellular signalling is not fully resolved, and the literature is candid about it. This is an active area rather than a settled one, and results should be read accordingly.
