MOTS-c

MOTS-c is a sixteen-residue peptide encoded in mitochondrial DNA rather than the nuclear genome, which is unusual enough to be the reason it is studied at all. It is modelled as an alpha helix in the PepXtide structural library.

The coding sequence is a short open reading frame of 51 base pairs lying within MT-RNR1, the mitochondrial 12S ribosomal RNA gene, and the peptide was described in 2015 by a group at the University of Southern California. It has two better-known relatives from the same class of mitochondrially encoded short peptides: humanin, encoded within the 16S gene, and the small humanin-like peptides.

One point about its biosynthesis is routinely reported incorrectly and is worth getting right. Although the gene is mitochondrial, translation of the peptide takes place in the cytoplasm using the standard genetic code. The discovery paper states this explicitly and gives the reason: read with the mitochondria-specific genetic code, the reading frame yields tandem start and stop codons. The transcript is polyadenylated and exported from the mitochondrion. A description of this peptide as translated with the mitochondrial genetic code is a citable error.

The chain itself is entirely unmodified: sixteen residues, Met-Arg-Trp-Gln-Glu-Met-Gly-Tyr-Ile-Phe-Tyr-Pro-Arg-Lys-Leu-Arg, with free termini, no amidation, no lipidation, no bridge and no cysteine. The absence of cysteine does not make it chemically inert, however, because it contains two methionines and a tryptophan, all three of which are oxidation-prone, and oxidation products have been reported in validated bioanalytical work. Among the peptides in this catalogue it is one of the more oxidation-sensitive.

The described mechanism is metabolic rather than receptor-mediated, and no validated cell-surface receptor exists for it. Published work places its action on the methionine-folate cycle and the de novo purine biosynthesis pathway tethered to it, with accumulation of the intermediate AICAR and consequent phosphorylation of AMP-activated protein kinase at threonine 172. A second, nuclear arm has been reported, in which the peptide translocates to the nucleus under metabolic stress in an AMPK-dependent manner and participates in the regulation of antioxidant-response-element genes alongside NRF2. Several transcription factors named in that work were identified by motif enrichment rather than demonstrated binding, and should be read as inferences.

Analytical work on the peptide is well developed. A plasma LC-MS/MS method validated to international laboratory standards reports a detection limit around 100 picograms per millilitre and identifies four metabolites plus two oxidation products. Worth knowing before designing an experiment: a commercial immunoassay for this peptide gave concentrations that could not be confirmed by mass spectrometry, so quantitation should rest on a chromatographic method.