MOTS-c

Molecular identity

Sequence

Met-Arg-Trp-Gln-Glu-Met-Gly-Tyr-Ile-Phe-Tyr-Pro-Arg-Lys-Leu-Arg

Formula

C101H152N28O22S2

Molecular weight

2174.6 g/mol

CAS

1627580-64-6

PubChem CID

146675088

What it acts on

• Folate one-carbon cycle and the de novo purine biosynthesis tethered to it — the primary paper reports that the peptide inhibits this route, with AMPK activation as the consequence; the intervening AICAR step is named by a 2023 review, not by the primary paper.
• AMPK — a 2023 review names the AICAR–AMPK axis as the main route of the peptide's metabolic effects, with activation following disruption of the folate–methionine cycle; no receptor-mediated step is described anywhere in the cited work.
• Adaptive nuclear gene expression — under metabolic stress the peptide is described as translocating from mitochondria to the nucleus and regulating transcription directly; GLUT4, STAT3 and IL-10 are named as regulated genes in one 2023 review.
• Skeletal-muscle glucose handling — the cited work names skeletal muscle as the apparent primary target organ and reports improved glucose-metabolism readouts there.

What the studies report

Each item below summarises the paper it is numbered to, written from that paper's own abstract. The badge says how the evidence was produced.

1. 1.
   reviewFront Endocrinol (Lausanne) (2023)

   A 2023 review of the peptide's discovery, physiology and proposed applications across aging, cardiovascular disease, insulin resistance and inflammation. It records that the peptide is co-expressed with mitochondria in different tissues, is present in plasma, that its plasma level decreases with age, and that it translocates to the nucleus under metabolic stress to direct nuclear gene expression. It also records that the peptide has been shown to improve glucose metabolism in skeletal muscle; the review does not rank its evidence. The authors state plainly that the peptide has been used only sparingly in treating disease and that no effective method of applying it in the clinic has been developed.

2. 2.
   reviewMetabolites (2023)

   A 2023 review assembling the genes and pathways associated with the peptide, which the authors treat as a peptide hormone of the mitochondrial-derived family. The mechanism they summarise is disruption of the folate–methionine cycle and consequent activation of AICAR–AMPK signalling, with GLUT4, STAT3 and IL-10 among the downstream genes named. The authors state that no prior article had summarised these genes and pathways — that is, the paper compiles scattered findings rather than reporting new data, and frames diagnostic and therapeutic use explicitly as a future prospect.

3. 3.
   animal modelCell Metab (2015)

   The primary report that identified the peptide. The authors describe a short open reading frame within the mitochondrial 12S rRNA encoding a 16-amino-acid peptide, and trace its cellular action to inhibition of the folate cycle and the de novo purine biosynthesis tethered to it, with AMPK activation as the consequence. Skeletal muscle is named as the apparent primary target organ. In mice, administration is reported to have prevented age-dependent and high-fat-diet-induced insulin resistance as well as diet-induced obesity. The study is confined to rodents and cells; the paper presents no human data.

4. 4.
   reviewBioessays (2019)

   A 2019 conceptual review on mitochondria–nucleus communication. It notes that many nuclear-encoded proteins are known to regulate mitochondrial gene expression while, conversely, no mitochondrial-encoded factor was known to actively regulate nuclear genes — and positions MOTS-c as the first candidate: on metabolic stress such as glucose restriction or oxidative stress, the peptide translocates to the nucleus and directly regulates adaptive nuclear gene expression. The authors label the broader framework — coevolved mitonuclear genomes operating as one bipartite system — as an explicit hypothesis, not an established mechanism.

Used in research on