MOTS-c (Mitochondrial Open Reading Frame of the 12S rRNA-c)

Mitochondrial-Derived Peptide | Metabolic Regulator

Weight: 2,174.6 Da
Half-life: ~30 minutes
Chain: 16 amino acids
5 studies
2022 latest
3 recent
Well Studied
Dose Start 5mg daily, increase to 10-15mg based on goals
Frequency Daily for metabolic support, or 3x weekly for anti-aging
Cycle 4-12 weeks depending on goals
Storage Refrigerate reconstituted solution at 2-8°C, use within 14 days
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MOTS-c is a mitochondrial-derived peptide that operates as a mitohormone through the Folate-AICAR-AMPK pathway. Under metabolic stress, it translocates to the nucleus to bind stress-response transcription factors (NRF2, ATF1/ATF7), regulating genes involved in metabolism and cellular adaptation.

Mechanism of Action

Inhibits the folate cycle leading to AMPK activation. Under metabolic stress, translocates to nucleus to bind stress-response transcription factors, regulating genes involved in metabolism, insulin sensitivity, and cellular adaptation.

01 Enhanced insulin sensitivity (~30% improvement)
02 Improved glucose metabolism and tolerance
03 AMPK pathway activation
04 Mitochondrial function optimization
05 Exercise performance enhancement (12-15% improvement)
06 Potential lifespan extension (6.4% median increase in mice)

Molecular Data

Molecular Weight
2,174.6 Da
Chain Length
16 amino acids
Type
Mitochondrial-derived peptide (MDP)
Amino Acid Sequence
One-letter: MRWQEMGYIFYPRKLR
H₂N
M 1
O ‖ C
N
R 2
O ‖ C
N
W 3
O ‖ C
N
Q 4
O ‖ C
N
E 5
O ‖ C
N
M 6
O ‖ C
N
H
G 7
O ‖ C
N
Y 8
O ‖ C
N
I 9
O ‖ C
N
F 10
O ‖ C
N
Y 11
O ‖ C
N
P 12
O ‖ C
N
R 13
O ‖ C
N
K 14
O ‖ C
N
L 15
O ‖ C
N
R 16
COOH
Met
1

Methionine

Position 1

Arg
2

Arginine

Position 2

Trp
3

Tryptophan

Position 3

Gln
4

Glutamine

Position 4

Glu
5

Glutamic Acid

Position 5

Met
6

Methionine

Position 6

Gly
7

Glycine

Position 7

Tyr
8

Tyrosine

Position 8

Ile
9

Isoleucine

Position 9

Phe
10

Phenylalanine

Position 10

Tyr
11

Tyrosine

Position 11

Pro
12

Proline

Position 12

Arg
13

Arginine

Position 13

Lys
14

Lysine

Position 14

Leu
15

Leucine

Position 15

Arg
16

Arginine

Position 16

N-terminus C-terminus
Hydrophobic
Polar
Positive (+)
Negative (-)
Modified
Peak 0.0 mcg
Trough 0.0 mcg
SS Peak 0.0 mcg
SS Trough 0.0 mcg

Research Indications

Metabolic
Insulin Resistance most effective

Improves insulin sensitivity by ~30% in animal studies through AMPK activation.

Type 2 Diabetes Support most effective

Restores metabolic function via insulin receptor sensitization.

Obesity Prevention effective

Promotes fatty acid oxidation despite identical caloric intake.

Anti-Aging
Age-Related Decline Reversal effective

Reverses age-dependent physical decline in animal models.

Mitochondrial Biogenesis effective

Enhances mitochondrial function via PGC-1α activation.

Lifespan Extension effective

6.4% median lifespan extension observed in mice studies.

Exercise Performance
Running Performance moderate

12-15% improvement in running performance from single dose in studies.

Muscle Homeostasis moderate

Exercise induced 11.9-fold increase in skeletal muscle MOTS-c.

Recovery Support moderate

Supports muscle recovery and adaptation to exercise.

Dosing Protocols

Subcutaneous injection is the primary route. Optimal administration is morning before exercise. AMPK activation occurs within 30 minutes.

GoalDoseFrequencyRoute
Metabolic health5-10mgOnce dailySubQ
Anti-aging protocol15mg3x weeklySubQ
Exercise performance10-15mgPre-workoutSubQ
Conservative start5mgOnce dailySubQ

Reconstitution Instructions

Materials Needed:
  • MOTS-c lyophilized powder
  • Bacteriostatic water
  • Insulin syringes
  • Alcohol swabs
  1. 1 Allow vial to reach room temperature (15-20 minutes)
  2. 2 Calculate required bacteriostatic water volume
  3. 3 Draw BAC water into insulin syringe
  4. 4 Inject slowly down vial side (not directly onto powder)
  5. 5 Gently swirl until dissolved (never shake vigorously)
  6. 6 Store at 2-8°C; use within 14 days

Interactions

~
Metformin
Both activate AMPK; monitor for additive hypoglycemic effects.
monitor
++
NAD+ Precursors
Complementary mitochondrial enhancement through different pathways.
synergistic
+
Growth Hormone Peptides
Different mechanisms allow safe combination.
compatible
~
Berberine
Both are AMPK activators; monitor for additive effects.
monitor
++
Resveratrol
Complementary SIRT1/AMPK activation pathways.
synergistic
~
Diabetes Medications
May require dose adjustments to prevent hypoglycemia.
monitor

What to Expect

Week 1-2
AMPK pathway activation; initial glucose tolerance improvements
Week 2-4
Enhanced exercise capacity; improved insulin sensitivity
Week 4-8
Sustained metabolic benefits; potential body composition changes
Week 8-12
Maximum mitochondrial function enhancement; metabolic flexibility

Side Effects & Safety

Common Side Effects

  • Generally well-tolerated in animal studies with minimal side effects
  • Mild injection site reactions (redness, swelling)

Stop Signs - Discontinue if:

  • Severe allergic reactions or anaphylaxis
  • Recurrent hypoglycemia (<50 mg/dL)
  • Persistent severe injection site reactions
  • Unexplained weight loss >10% of baseline

Contraindications

  • Pregnancy or breastfeeding
  • WADA prohibited substance (banned for athletic competition)
  • Limited long-term human safety data

Quality Checklist

Good Signs

  • White to off-white powder with uniform appearance indicating proper storage
  • Clear, colorless solution without particles after reconstitution
  • Sequence verification (MRWQEMGYIFYPRKLR) with CoA >95% purity by RP-HPLC

Warning Signs

  • Limited human clinical data - start conservatively
  • WADA banned substance - not for competitive athletes

Bad Signs

  • Discolored powder or solution
  • Cloudy solution after reconstitution
  • No certificate of analysis available

References

  • The Mitochondrial-Derived Peptide MOTS-c Promotes Metabolic Homeostasis and Reduces Obesity and Insulin Resistance
    Lee, C., et al.
    Cell Metabolism (2015)

    Landmark discovery paper identifying MOTS-c as a 16-amino-acid peptide encoded by mitochondrial DNA. Prevented age-dependent and high-fat-diet-induced insulin resistance and obesity in mice via AMPK activation in skeletal muscle.

  • The Mitochondrial-Encoded Peptide MOTS-c Translocates to the Nucleus to Regulate Nuclear Gene Expression in Response to Metabolic Stress
    Kim, S.J., et al.
    Cell Metabolism (2018)

    MOTS-c rapidly translocates to the nucleus within 30 minutes under metabolic stress in an AMPK-dependent manner, where it interacts with stress-responsive transcription factors including NRF2 and ATF7 to regulate nuclear gene expression.

  • MOTS-c Is an Exercise-Induced Mitochondrial-Encoded Regulator of Age-Dependent Physical Decline and Muscle Homeostasis
    Reynolds, J.C., et al.
    Nature Communications (2021)

    Exercise induced an 11.9-fold increase in skeletal muscle MOTS-c. MOTS-c enhanced physical performance across age groups and improved muscle homeostasis in aging mice.

  • MOTS-c Increases in Skeletal Muscle Following Long-Term Physical Activity and Improves Acute Exercise Performance After a Single Dose
    Hyatt, J.K.
    Physiological Reports (2022)

    4-8 weeks of voluntary running increased MOTS-c protein expression ~1.5-5-fold in rodent skeletal muscles, sustained for 4-6 weeks of detraining. Single dose improved acute exercise performance.

  • The Mitochondrial-Derived Peptide MOTS-c Relieves Hyperglycemia and Insulin Resistance in Gestational Diabetes Mellitus
    Yin, Y., et al.
    Pharmacological Research (2022)

    MOTS-c significantly alleviated hyperglycemia, improved insulin sensitivity and glucose tolerance, and reduced birth weight and offspring death in a gestational diabetes mouse model.

Disclaimer

This information is for educational and research purposes only. Consult a healthcare professional before use.