August 26, 2026 · 2 min read

MOTS-c: a peptide encoded in mitochondrial DNA and its metabolic research

MOTS-c is a 16-amino-acid peptide encoded by mitochondrial DNA. A research overview of the discovery paper, its AMPK mechanism, and open questions.

Most proteins are encoded in the nucleus. MOTS-c, the mitochondrial open reading frame of the 12S rRNA type-c, is not. It is a 16-amino-acid peptide encoded by a short open reading frame inside mitochondrial DNA, which makes it a signaling molecule that the mitochondrion makes for the rest of the cell and the body.

The MOTS-c sequence

Sequence: Methionine, Arginine, Tryptophan, Glutamine, Glutamic acid, Methionine, Glycine, Tyrosine, Isoleucine, Phenylalanine, Tyrosine, Proline, Arginine, Lysine, Leucine, Arginine.

  • Hydrophobic
  • Positively charged
  • Polar
  • Negatively charged
  • Glycine or proline
Length
16 amino acids
Average mass
2,174.6 Da
Formula
C101H152N28O22S2
Met-Arg-Trp-Gln-Glu-Met-Gly-Tyr-Ile-Phe-Tyr-Pro-Arg-Lys-Leu-Arg, encoded in the mitochondrial 12S rRNA gene. The mass calculated from this sequence matches PubChem (CID 146675088).

The 2015 discovery paper

The Cell Metabolism paper from 2015 described MOTS-c and reported that treating mice prevented age-dependent and high-fat-diet-induced insulin resistance, and prevented diet-induced obesity. The authors concluded that mitochondria may actively regulate metabolism at the cellular and organismal level through peptides encoded in their own genome.

How MOTS-c is proposed to work

  1. 1

    Encoded in mtDNA

    A short open reading frame in the 12S rRNA gene encodes a 16-amino-acid peptide.

  2. 2

    Skeletal muscle

    Its primary target organ appears to be skeletal muscle.

  3. 3

    Folate cycle

    It inhibits the folate cycle and de novo purine biosynthesis.

  4. 4

    AMPK

    That leads to AMPK activation, a central energy sensor.

From Lee et al., Cell Metabolism 2015, in cells and mice.

What a later review adds

A 2023 review in Frontiers in Endocrinology adds that MOTS-c travels to the nucleus during metabolic stress and that its plasma level falls with age. It also says plainly that no effective method of applying MOTS-c in the clinic has been developed. Other groups have reported effects in models of gestational diabetes and ovarian cancer, and a 2022 review covers it in human aging and age-related disease.

Points from the 2023 review

  1. Nuclear translocation

    Moves to the nucleus during metabolic stress and directs expression of nuclear genes.

  2. Declines with age

    Plasma levels decrease with age.

  3. Clinical gap

    Used less often in treating disease, and no effective clinical delivery method has been developed.

From Zheng et al., Front Endocrinol 2023. A summary of the review's description of MOTS-c biology and its limits.

Reading it carefully

The foundational result is a mouse study, and much of what followed is cell or animal work. Mechanistic claims that run through AMPK are plausible but come from a limited set of systems. As with other mitochondrial peptides, a result depends on the exact sequence and purity of the material used.

References

  1. Lee C et al. The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance. Cell Metab 2015.
  2. Zheng Y et al. MOTS-c: A promising mitochondrial-derived peptide for therapeutic exploitation. Front Endocrinol 2023.
  3. Mohtashami Z et al. MOTS-c, the Most Recent Mitochondrial Derived Peptide in Human Aging and Age-Related Diseases. Int J Mol Sci 2022.

Related research notes