Disclaimer: Information provided is for research and educational purposes only. MOTS-c is not approved by the FDA or any regulatory agency for therapeutic or cosmetic use.

Introduction:

MOTS-c (short for mitochondrial open reading frame of the 12S rRNA-c) is a 16-amino-acid peptide encoded by mitochondrial DNA. Discovered in 2015, it helps cells adapt to metabolic stress by optimizing energy use, improving insulin sensitivity, and maintaining mitochondria function.¹

Unlike most peptides (encoded in nuclear DNA), MOTS-c originates inside mitochondria and can even move to the nucleus to influence gene expression—an unusual form of mitochondria-to-nucleus signaling.²

Early research suggests MOTS-C may play a role in energy regulation, insulin sensitivity, exercise performance, and healthy aging. ³

MOTS-c Fast Facts

• Source: Encoded within the mitochondrial 12S rRNA gene (mtDNA).¹
  
• Length: 16 amino acids.
  
• Core actions: Activates AMPK, enhances glucose uptake, supports mitochondrial quality control, and regulates nuclear genes under stress.¹²
  
• Where it shows up: Skeletal muscle (notably during/after exercise), liver, and circulation.¹³
  
• Research interests: Insulin resistance and metabolic health, exercise physiology, aging biology.¹³⁴

Chemical Structure

MOTS-c is a 16-amino-acid peptide encoded by the mitochondrial 12S rRNA gene. Its short, stable sequence allows it to act rapidly during energy stress, such as exercise or fasting, when cells need to rebalance fuel use and protect mitochondria.

MOTS-c Chemical Structure

How MOTS-c Works (In Brief)

When the body experiences energy stress — such as during exercise, fasting, or low nutrient availability — MOTS-c levels rise. It activates AMPK, the cell’s energy sensor, shifting metabolism toward fat oxidation and improved glucose control.¹

Uniquely, MOTS-c can also enter the nucleus and activate protective stress-response genes, demonstrating that mitochondria don’t just generate energy — they can also direct cellular adaptation.²

Discovery & Research Milestones

Direct links to all these studies can be found at the bottom of the article

Year	Study & Source	Key Finding
2015	Lee et al.¹	Discovery of MOTS-c as a mitochondrial-encoded peptide that improves insulin sensitivity and protects against diet-induced obesity.
2016	Lee et al.¹²	Follow-up work framed MOTS-c as a master regulator of cellular metabolism through AMPK activation and energy-balance pathways
2018	Kim et al.²	Found that MOTS-c can enter the nucleus to turn on stress-response genes.
2019	Benayoun & Lee¹¹	Framed MOTS-c as a messenger between mitochondria and the nucleus.
2020	D’Souza et al⁴	Showed MOTS-c levels decline with age in blood but rise in muscle.
2021	Reynolds et al.³	Identified MOTS-c as exercise-induced, improving endurance and strength.
2021	Yu et al.⁵	Demonstrated MOTS-c supports mitochondrial health via AMPK activation.
2021	Yang et al.¹⁰	Found MOTS-c and exercise work synergistically to enhance glucose control.
2022-2023	Mohtashami 2022⁸; Wan 2023⁶; Zheng 2023⁷; Kong 2023⁷	Recent reviews position MOTS-c as a promising link between metabolism, aging, and exercise physiology.

A Closer Look: What Research Shows

1. Metabolism & insulin sensitivity
   In mouse models of diet-induced obesity, MOTS-c improves glucose tolerance and prevents insulin resistance, partly via AMPK.¹
   
2. Exercise and Endurance
   MOTS-c rises with exercise; giving MOTS-c in animal studies boosts endurance and supports muscle adaptation across ages.³
   
3. Mitochondrial health
   In human stem-cell models, MOTS-c improves mitochondrial homeostasis (in turn linked to higher energy levels) and reduces ROS while activating AMPK and rebalancing mTORC1.⁵
   
4. Aging signals
   In humans, plasma MOTS-c tends to decline with age, while muscle MOTS-c can increase—hinting at a compensatory response.⁴

Summary

MOTS-c is a mitochondrial-encoded peptide that helps cells balance energy use, resist metabolic stress, and coordinate mitochondrial and nuclear responses. By activating AMPK, enhancing glucose control, and influencing gene expression, MOTS-c bridges the gap between energy metabolism, exercise physiology, and aging biology.While evidence is strongest in animal and cellular models, early human findings make MOTS-c a leading target in metabolism and longevity research.¹–¹²

FAQs About MOTS-C

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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(3):443-454. https://pubmed.ncbi.nlm.nih.gov/25738459
   
2. 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;28(4):516-524.e7. https://pubmed.ncbi.nlm.nih.gov/29983246/
   
3. Reynolds JC, Mazzucco AE, Chen CY, et al. MOTS-c is an exercise-induced mitochondrial-encoded regulator of age-dependent physical decline and muscle homeostasis. Nat Commun. 2021;12:470. https://pubmed.ncbi.nlm.nih.gov/33473109
   
4. D’Souza RF, Woodhead JST, Zeng N, et al. Increased expression of the mitochondrial derived peptide, MOTS-c, in skeletal muscle of healthy aging men is associated with myofiber composition. Aging (Albany NY). 2020;12(6):5244-5265. https://pubmed.ncbi.nlm.nih.gov/32182209
   
5. Yu WD, Wang HB, Teng L, et al. MOTS-c promotes mitochondrial homeostasis in human placenta-derived mesenchymal stem cells via AMPK activation and mTORC1 inhibition. J Tissue Eng Regen Med. 2021;15(3):254-267. https://pubmed.ncbi.nlm.nih.gov/33639272
   
6. Wan W, Zhang Z, Wang Y, et al. Mitochondria-derived peptide MOTS-c: effects and mechanisms. Front Endocrinol (Lausanne). 2023;14:1094815. https://pmc.ncbi.nlm.nih.gov/articles/PMC9854231
   
7. Zheng Y, Fu X, Ge J. MOTS-c: A promising mitochondrial-derived peptide for therapeutic use. Int J Mol Sci. 2023;24(3):2655. https://pmc.ncbi.nlm.nih.gov/articles/PMC9905433
   
8. Mohtashami Z, Roy BD, Mahmoodzadeh A, et al. MOTS-c, the most recent mitochondrial derived peptide in human health and disease. Endocr Metab Immune Disord Drug Targets. 2022;22(9):931-939. https://pubmed.ncbi.nlm.nih.gov/36233287/ (Open access summary: https://pmc.ncbi.nlm.nih.gov/articles/PMC9570330/) PubMed+1
   
9. Kong BS, Park SY. Mitochondrial-encoded peptide MOTS-c, diabetes, and the mitochondrial–nuclear axis. Diabetes Metab J. 2023;47(3):368-383. https://pmc.ncbi.nlm.nih.gov/articles/PMC10244198
   
10. Yang B, Yu Q, Chang B, et al. MOTS-c interacts synergistically with exercise to attenuate insulin resistance and enhance glucose metabolism via AMPK–PGC-1α signaling (mouse). Biochim Biophys Acta Mol Basis Dis. 2021;1867(6):166126. https://pubmed.ncbi.nlm.nih.gov/33722744
    
11. Benayoun BA, Lee C. MOTS-c: a mitochondrial-encoded regulator of the nucleus. Trends Endocrinol Metab. 2019;30(11):882-884. https://pubmed.ncbi.nlm.nih.gov/31378979/ (Open access: https://pmc.ncbi.nlm.nih.gov/articles/PMC8224472/) PubMed+1
    
12. Lee C, Kim KH, Cohen P. MOTS-c: a novel mitochondrial-derived peptide regulating metabolism. Am J Physiol Endocrinol Metab. 2016;310(8):E728-E735. https://pubmed.ncbi.nlm.nih.gov/27216708/ (Open access: https://pmc.ncbi.nlm.nih.gov/articles/PMC5116416/