Mitochondrial-derived peptide · research peptide

MOTS-c

Studied for: metabolic regulation, insulin sensitivity, glucose uptake, mitochondrial stress response (preclinical)

MOTS-c is a 16-amino-acid mitochondrial-derived peptide (MDP) encoded within the 12S rRNA region of the mitochondrial genome. First reported in 2015, it has been studied in preclinical models for regulation of insulin sensitivity, glucose uptake, and stress response through AMPK-dependent signaling. It is not FDA-approved.

Class
Mitochondrial-derived peptide (MDP)
Length
16 amino acids[1]
Genomic origin
Encoded in 12S rRNA region of mtDNA[1]
Primary signaling
AMPK · SIRT1 · PGC-1α[2][3]
Plasma half-life
Short; specific value not well established[2]
Oral bioavailability
Low[2]
FDA status
Not approved
Educational reference only. MOTS-c has no approved human clinical use. This page summarizes published preclinical mechanism research and documents reconstitution math for lyophilized research vials. It does not recommend a dose, an indication, or a source.

Last reviewed April 22, 2026 by the Enhanced Health Editorial Team. Reviewed for source alignment, FDA-status language, and medical-claim boundaries. See the editorial policy.

What MOTS-c is

MOTS-c (Mitochondrial Open Reading frame of the 12S rRNA-c) is a 16-residue peptide encoded within the mitochondrial genome — specifically within an open reading frame embedded in the 12S ribosomal RNA gene. It was identified in 2015 as one of the earliest members of a family of mitochondrial-derived peptides (MDPs) that includes humanin and SHLPs.[1] MDPs are hypothesized to serve as signaling molecules connecting mitochondrial state to nuclear gene expression.

Mechanism

MOTS-c's metabolic effects cluster around AMPK activation:[2][3]

  • Folate cycle and AICAR. MOTS-c regulates the folate cycle and de novo purine biosynthesis pathway, increasing intracellular AICAR (5-aminoimidazole-4-carboxamide ribonucleotide). AICAR phosphorylates and activates AMPK.
  • AMPK → SIRT1 / PGC-1α. Activated AMPK regulates energy homeostasis and engages the SIRT1 and PGC-1α axis, which drives mitochondrial biogenesis and anti-inflammatory signaling.
  • Glucose uptake. Through AMPK, MOTS-c promotes glucose entry into skeletal muscle and improves insulin sensitivity, inhibiting weight gain and insulin resistance in high-fat-diet rodent models.
  • Nuclear translocation under stress. Under metabolic stress, MOTS-c can translocate from the cytosol to the nucleus in an AMPK-dependent manner and bind transcription factors regulated by antioxidant response elements (ARE), improving cellular stress resistance.[4]

Pharmacokinetics

  • Bioavailability. Mitochondrial-derived peptides including MOTS-c have low bioavailability and poor stability, limiting straightforward therapeutic development.[2]
  • Half-life. Plasma half-life is reported as short in the literature. A specific, peer-reviewed human half-life value is not yet well summarized in the published record.
  • Human PK. Published rigorous human pharmacokinetic characterization for injectable MOTS-c is limited; claims of specific hour values should be sourced carefully.

Storage and stability

  • Lyophilized powder. Store sealed per the supplier's certificate of analysis — typically refrigerated at 2–8 °C or frozen at −20 °C.
  • After reconstitution. Store refrigerated at 2–8 °C. Bacteriostatic water (0.9% benzyl alcohol) is preferred for multi-draw use; sterile water is used for single-draw preparations.
  • Handling. Swirl to mix. Avoid freeze–thaw. Discard cloudy or discolored solutions.

Reconstitution math

Math only — no dose recommendation. Concentration after reconstitution determines how many insulin-syringe units equal a given amount.

Example 1 · 10 mg vial + 2 mL bac water concentration = 10 mg / 2 mL = 5 mg/mL = 5000 mcg/mL
1 unit = 0.01 mL = 50 mcg
→ 1 mg = 20 units
→ 2 mg = 40 units
→ 5 mg = 100 units (full syringe)
Example 2 · 10 mg vial + 1 mL bac water concentration = 10 mg / 1 mL = 10 mg/mL = 10,000 mcg/mL
1 unit = 0.01 mL = 100 mcg = 0.1 mg
→ 1 mg = 10 units
→ 5 mg = 50 units
→ 10 mg = 100 units (full syringe)
Example 3 · 10 mg vial + 3 mL bac water concentration = 10 mg / 3 mL ≈ 3.333 mg/mL ≈ 3333 mcg/mL
1 unit ≈ 33.3 mcg
→ 1 mg ≈ 30 units
→ 3.33 mg ≈ 100 units (full syringe)

Frequently asked questions

What is MOTS-c?

A 16-amino-acid mitochondrial-derived peptide encoded in the 12S rRNA region of mtDNA. First described 2015. Not FDA-approved.[1]

How does it work?

Increases AICAR → activates AMPK → engages SIRT1 / PGC-1α. Also translocates to the nucleus under metabolic stress. Promotes glucose uptake in preclinical models.[2][3][4]

What is the half-life?

Short; specific peer-reviewed value not well summarized in published literature. Low oral bioavailability.[2]

How do I reconstitute a 10 mg vial?

Typical: 10 mg + 2 mL bac water = 5 mg/mL → 1 unit = 50 mcg; 1 mg = 20 units. Using 1 mL gives 10 mg/mL (100 mcg per unit).

Is it FDA-approved?

No. Research peptide; no Phase 3 trials as of April 2026.

How is it stored after reconstitution?

Refrigerated at 2–8 °C. Bacteriostatic water for multi-draw use; sterile water for single-draw. Avoid freeze–thaw and vigorous shaking.

Primary references

  1. Lee C, Zeng J, Drew BG, et al. The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance. Cell Metab, 2015;21:443–454 (PubMed 25738459). PubMed 25738459
  2. Kim KH, Son JM, Benayoun BA, Lee C. Mitochondria-derived peptide MOTS-c: effects and mechanisms related to stress, metabolism, and aging. Protein Cell, 2023 review (PMC9854231). PMC9854231
  3. Merry TL, et al. MOTS-c: a promising mitochondrial-derived peptide for therapeutic exploitation. Review, 2023 (PMC9905433). PMC9905433
  4. Kim KH, Son JM, Benayoun BA, Lee C. The mitochondrial-encoded peptide MOTS-c translocates to the nucleus to regulate nuclear gene expression in response to metabolic stress. Cell Metab, 2018 (PubMed 29983246). PubMed 29983246

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