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The Peptide Effect
preclinicalLongevity & Metabolism

MOTS-c

Also known as: Mitochondrial Open reading frame of the Twelve S rRNA type-c, Mitochondrial-Derived Peptide MOTS-c

MOTS-c is a 16-amino acid peptide encoded in the mitochondrial DNA, making it one of the first identified mitochondrial-derived peptides (MDPs). It acts as an exercise mimetic by activating the AMPK pathway, a master regulator of cellular energy homeostasis. MOTS-c bridges the gap between mitochondrial signaling and nuclear gene regulation, representing a novel form of retrograde communication from mitochondria to the nucleus.

Key Facts

Mechanism
MOTS-c is encoded in the 12S rRNA gene of mitochondrial DNA. Under metabolic stress, it translocates from mitochondria to the cell nucleus, where it regulates nuclear gene expression — a process known as mitonuclear communication. Its primary metabolic effects are mediated through activation of the AMPK (AMP-activated protein kinase) pathway, which promotes glucose uptake, fatty acid oxidation, and mitochondrial biogenesis. MOTS-c also inhibits the folate-methionine cycle, leading to AICAR accumulation, which further activates AMPK. This cascade mimics many of the metabolic adaptations seen with physical exercise.
Research Status
preclinical
Half-Life
Not well established in humans
Molecular Formula
C₁₀₁H₁₅₂N₂₈O₂₅S₂
Primary Use
Longevity & Metabolism
Table of Contents

Benefits

  • Exercise mimetic — activates AMPK and promotes metabolic adaptations similar to physical exercisemoderate
  • Improves insulin sensitivity and glucose homeostasis in diet-induced obesity modelsmoderate
  • Promotes fat metabolism and reduces body weight in animal studiespreliminary
  • May slow age-related metabolic decline — endogenous MOTS-c levels decrease with agepreliminary
  • Improved physical performance and exercise capacity in aged micepreliminary
  • Potential role in regulating skeletal muscle metabolism during agingpreliminary

Dosage Protocols

RouteDosage RangeFrequencyNotes
Subcutaneous injection5–10 mg2–3× per weekMost commonly reported protocol in community use
Subcutaneous injection (loading)10 mgDaily for 2–4 weeksLoading phase sometimes used before transitioning to maintenance dosing
Subcutaneous injection (maintenance)5 mg2× per weekLower maintenance dose following an initial loading phase

Medical disclaimer

Dosage information is provided for educational reference only. Always follow your prescriber's instructions and consult a qualified healthcare provider before starting any peptide protocol.

Side Effects

  • Injection site irritation (redness, minor swelling)common
  • Transient fatigue after initial dosescommon
  • Mild nausearare
  • Extremely limited human safety data — long-term effects unknownserious
  • Potential interaction with diabetes medications due to glucose-lowering effectsserious

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Frequently Asked Questions

Can MOTS-c replace exercise?
No. While MOTS-c is described as an "exercise mimetic" because it activates AMPK and triggers some of the same metabolic pathways as exercise, it cannot replicate all the benefits of physical activity. Exercise produces cardiovascular adaptations, neuromuscular improvements, bone density maintenance, and psychological benefits that no peptide can fully replace. MOTS-c may be valuable as a supplement to exercise or for individuals with physical limitations that prevent regular activity, but it should not be viewed as an exercise replacement.
What are mitochondrial-derived peptides (MDPs)?
Mitochondrial-derived peptides are small bioactive peptides encoded within the mitochondrial genome. They were only recently discovered — Humanin in 2001 and MOTS-c in 2015. These peptides represent a new form of cellular signaling where mitochondria communicate with other parts of the cell and even other organs. MDPs play roles in metabolism, stress response, and aging. MOTS-c and Humanin are the best-studied MDPs, with MOTS-c being unique in its ability to translocate to the nucleus and directly regulate gene expression.
How does MOTS-c activate AMPK?
MOTS-c activates AMPK through an indirect mechanism. It inhibits the folate-methionine cycle in cells, which leads to the accumulation of AICAR (5-aminoimidazole-4-carboxamide ribonucleotide), a well-known endogenous activator of AMPK. AMPK activation then triggers a cascade of metabolic effects including increased glucose uptake, enhanced fatty acid oxidation, improved mitochondrial function, and inhibition of lipogenesis. This pathway is similar to what occurs during exercise-induced energy depletion.
Does MOTS-c decline with age?
Yes. Circulating MOTS-c levels have been shown to decline with age in both rodents and humans. This age-related decline correlates with decreased metabolic function and increased susceptibility to metabolic diseases. Some researchers hypothesize that restoring MOTS-c levels to youthful concentrations could help prevent or reverse age-related metabolic dysfunction, though this remains an active area of investigation.
What is the current status of MOTS-c research?
MOTS-c research is still in the preclinical stage. The peptide was first identified in 2015 by Dr. Changhan David Lee's group at the University of Southern California. Most data comes from cell culture and rodent studies. There are no published Phase I clinical trials in humans as of 2026. The peptide is available through research chemical suppliers but is not approved for human use by any regulatory agency.

References

  1. 1
    The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance(2015)PubMed ↗
  2. 2
    MOTS-c is an exercise-induced mitochondrial-encoded regulator of age-dependent physical decline and muscle homeostasis(2019)PubMed ↗
  3. 3
    Mitochondrial-derived peptides in energy metabolism(2019)PubMed ↗
  4. 4
    Nuclear-encoded mitochondrial-derived peptide MOTS-c translocates to the nucleus in response to metabolic stress(2018)PubMed ↗

Last updated: 2026-02-14