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Mitochondrial-derived peptide (MDP); AMPK activator / exercise mimetic

MOTS-c

Prohibitedaka Mitochondrial ORF of the 12S rRNA type-c, MOTS-c peptide

Identified by Lee and colleagues (2015, Cell Metabolism) as a mitochondrial-to-nucleus signalling peptide regulating metabolism. It has been investigated for obesity, insulin resistance and age-related decline, but only in laboratory and animal models; it is not an approved drug or recognized therapy.

Mechanism

In plain terms it is a signal made by mitochondria that shifts cells toward burning fuel more efficiently, mimicking some effects of exercise. Technically, under metabolic stress MOTS-c translocates from mitochondria to the nucleus; it inhibits the folate cycle and tethered de novo purine biosynthesis, raising AICAR levels, which activates AMP-activated protein kinase (AMPK). AMPK activation upregulates GLUT4 and glucose uptake in skeletal muscle, alters fatty-acid metabolism, and MOTS-c further modulates stress-adaptive nuclear gene expression (Lee et al., 2015; Reynolds et al., 2021).

Regulatory Status by Region

  • United States (FDA)Not approved for any indication; an experimental peptide with no FDA-approved therapeutic use, and not an approved/compoundable drug substance.
  • Australia (TGA)Not on the ARTG; an unapproved experimental substance with no approved indication.
  • European Union (EMA)No EMA marketing authorization; not an approved medicine in the EU.
  • WADAProhibited at all times under Section S4.4 (Metabolic Modulators), 4.4.1 Activators of AMP-activated protein kinase (AMPK); MOTS-c is explicitly named. No therapeutic use exemption is available because there is no approved therapeutic use.

Key Studies

  • The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance (Lee C, Zeng J, Drew BG, et al. Cell Metab. 2015;21(3):443-454. PMID 25738459 (preclinical: mice/cell models))
  • MOTS-c is an exercise-induced mitochondrial-encoded regulator of age-dependent physical decline and muscle homeostasis (Reynolds JC, Lai RW, Woodhead JST, et al. Nat Commun. 2021;12(1):470. PMID 33473109 (mouse studies; human exercise observational data))

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