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Research-onlyVendors pendingFacts verified · 2026-05-25

MOTS-c

Also known as mitochondrial-derived peptide, mt-rnr1 orf peptide, mitochondrial open reading frame of the 12S rRNA-c, MDP · Wikipedia

MOTS-c (Mitochondrial Open Reading frame of the Twelve S rRNA type-c) is a 16-amino-acid peptide encoded within a short open reading frame inside the mitochondrial 12S rRNA (MT-RNR1) region of mtDNA, first reported by Lee et al. (Cell Metabolism, 2015). It is the most extensively studied of the mitochondrial-derived peptides (MDPs) and functions as a metabolic signaling molecule that activates AMP-activated protein kinase (AMPK), promotes glucose uptake and fatty-acid oxidation, and regulates nuclear gene expression in response to metabolic stress (Kim et al., Cell Metabolism 2018). Circulating MOTS-c declines with age and after high-fat diet exposure. Preclinical studies link exogenous MOTS-c administration to improved insulin sensitivity, enhanced physical performance, and protection against age-related metabolic decline. No human clinical trials have been completed to date; MOTS-c is sold and used as a research chemical.

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Mechanism of action

MOTS-c is a 16-amino-acid peptide encoded within a short open reading frame in the mitochondrial 12S rRNA (MT-RNR1) gene. Mechanistically, MOTS-c targets the folate cycle and inhibits de novo purine biosynthesis, causing accumulation of AICAR (5-aminoimidazole-4-carboxamide ribonucleotide), a potent endogenous activator of AMP-activated protein kinase (AMPK) (Lee et al.

MOTS-c is a 16-amino-acid peptide encoded within a short open reading frame in the mitochondrial 12S rRNA (MT-RNR1) gene. Mechanistically, MOTS-c targets the folate cycle and inhibits de novo purine biosynthesis, causing accumulation of AICAR (5-aminoimidazole-4-carboxamide ribonucleotide), a potent endogenous activator of AMP-activated protein kinase (AMPK) (Lee et al., Cell Metabolism 2015). AMPK activation in skeletal muscle and other tissues promotes GLUT4-dependent glucose uptake, increases mitochondrial biogenesis via PGC-1α signaling, enhances fatty-acid oxidation, and improves insulin sensitivity. Under metabolic stress, MOTS-c translocates from mitochondria to the nucleus and regulates nuclear gene expression through interactions with stress-responsive transcription factors (Kim et al., Cell Metabolism 2018). Endogenous MOTS-c is induced by exercise in human skeletal muscle and plasma and is considered an exercise-mimetic candidate; intermittent administration in middle-aged and aged mice improved physical performance, muscle homeostasis, and healthspan (Reynolds et al., Nature Communications 2021). Circulating levels decline with age, and the K14Q variant has been associated with metabolic phenotypes in human population studies.

Pharmacokinetic properties

Half-life

Short in plasma (minutes to ~1 hour for unmodified peptide); precise human PK not established

Routes

subcutaneous · intramuscular

Bioavailability

Not orally bioavailable; parenteral administration required. Endogenous circulating levels decline with age and after high-fat-diet exposure. No formal human PK studies published.

Amino-acid sequence

Met-Arg-Trp-Gln-Glu-Met-Gly-Tyr-Ile-Phe-Tyr-Pro-Arg-Lys-Leu-Arg (16 aa)

Use & research dosing

Metabolic SupportEnergyInsulin SensitivityExercise Performance

No human clinical dosing has been established. Preclinical rodent studies used intraperitoneal doses in the 0.5-15 mg/kg/day range (Lee et al., 2015; Reynolds et al., 2021). Allometric scaling to human equivalents is highly speculative for unmodified peptides with short half-lives. Self-experimentation protocols commonly reported online use 5-10 mg subcutaneous 2-3 times per week in 4-12 week cycles, but these doses are not derived from validated human pharmacokinetic studies. There is no FDA-approved label and no validated dose-response or safety window in humans. Material purity from research-grade vendors is highly variable.

Research-use framing only. SavePeptides sells nothing for human consumption. Doses above reflect reported research / self-experimentation ranges, not clinical recommendations.

Editorial perspective

MOTS-c was the first identified mitochondrial-derived peptide of major metabolic interest (Lee et al., Cell Metabolism 2015) and remains the prototype for the MDP field, alongside humanin and the SHLPs. The K14Q variant (a single amino acid polymorphism) has been enriched in some Japanese male centenarian cohorts, supporting a longevity-relevant role. Despite a decade of preclinical research, there are no completed human clinical trials and no clinical-stage pharmaceutical development program for MOTS-c specifically; commercial development has been limited by the peptide's short half-life and lack of clear regulatory indication. Researchers continue to explore exercise-mimetic, anti-obesity, and anti-aging applications. All current human use is self-experimentation with research-grade material.

— SavePeptides editorial desk · last updated 2026-05-25

Cautions & contraindications

Before researching this compound, note:

  • No completed human clinical trials; no validated safety profile in humans
  • Unknown long-term effects of chronic AMPK activation outside of physiologic exercise
  • Theoretical concern in active malignancy: AMPK can be tumor-suppressive in some contexts but supports survival of metabolically stressed cancer cells in others
  • Unknown interaction with metformin, berberine, and other AMPK activators (additive effects possible)
  • Unknown interaction with insulin and sulfonylureas (theoretical hypoglycemia risk)
  • Injection-site reactions
  • Research-grade material purity highly variable between vendors; endotoxin contamination is a known issue
  • Avoid in pregnancy and breastfeeding (no safety data)
  • Not characterized in renal or hepatic impairment
  • No data on immunogenicity with chronic administration

Research foundation

The papers behind the page.

  1. [01]https://pubmed.ncbi.nlm.nih.gov/25738459/
  2. [02]https://www.cell.com/cell-metabolism/fulltext/S1550-4131(18)30390-5
  3. [03]https://www.nature.com/articles/s41467-020-20790-0
  4. [04]https://pubmed.ncbi.nlm.nih.gov/36233287/
  5. [05]https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9854231/

Facts verified

2026-05-25

Confidence

medium

What this means

  • no completed human clinical trials
  • human dosing based on extrapolation and self-experimentation only
  • research-grade material purity highly variable
  • amino acid sequence in input file appears inconsistent with primary literature; canonical 16-aa sequence used

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