MOTS-c

Key Benefits#

• Improves insulin sensitivity and glucose metabolism
• Enhances exercise capacity and endurance
• Reduces age-related metabolic decline
• Activates AMPK — the master metabolic regulator
• Promotes fat oxidation
• Anti-inflammatory effects
• May extend healthspan via mitochondrial optimization
• Increases energy and reduces fatigue

Mechanism of Action#

MOTS-c is encoded in the 12S ribosomal RNA region of mitochondrial DNA and is released from mitochondria in response to metabolic stress. It translocates to the cell nucleus where it activates AMPK signaling pathways, regulating glucose metabolism, folate cycle, and nucleotide synthesis. It promotes fat oxidation over glucose utilization and enhances mitochondrial function. In animal studies, injections into aged mice significantly improved exercise capacity and reversed metabolic aging phenotypes.

Dosing Protocols#

Side Effects#

• Injection site irritation
• Fatigue during initial adaptation
• Unknown long-term profile (limited human data)

Contraindications#

Pregnancy or breastfeeding. Limited human safety data.

Storage#

Lyophilized powder: store at −20°C. Reconstituted: refrigerate at 2–8°C, use within 14 days.

Featured In Stacks#

1. 1.
   Mitochondrial-derived peptides MOTS-c and humanin attenuate dexamethasone-induced atrophy in human skeletal muscle cells

   Elhusseiny R, Ihsan M, Bellefroid T, Farooq A, Racinais S, Deldicque L · Physiological reports · 2026PubMed Verified

2. 2.
   Aerobic exercise and MOTS-c attenuate diabetic myocardial fibrosis via inhibition of the THBS1/TGF-β signaling pathway

   Li Z, Wang T, Fu Y, Chen F, Li S · Frontiers in endocrinology · 2026PubMed Verified

3. 3.
   Therapeutic Effects of MOTS-c in the Valproic Acid-Induced Autism Model in Rats: Role of Tetrahydrobiopterin and Brain-Derived Neurotrophic Factor

   Güvenir Seven S, Sahin H, Erkanlı Şentürk G, Uysal N, Uzun H, Ekici O et al. · Molecular neurobiology · 2026PubMed Verified

4. 4.
   Reduced serum and skeletal muscle MOTS c levels in women with polycystic ovary syndrome are associated with mitochondrial dysfunction

   Kutuk IS, Akin S, Demirel H, Mumusoglu S, Ciftci T, Yildiz BO · Scientific reports · 2026PubMed Verified

5. 5.
   MOTS-c attenuates cardiac dysfunction following high altitude exposure by promoting mitophagy

   Feng Z, Xing Y, Lou J, Li H, Zhang Z, Li M et al. · Free radical biology & medicine · 2026PubMed Verified

6. 6.
   Exogenous MOTS-c mitigates myocardial ischemia-reperfusion injury: experimental and in silico evidence from rat heart models

   Santhanam SS, Jayaraman S, Kurian GA · Naunyn-Schmiedeberg's archives of pharmacology · 2026PubMed Verified

7. 7.
   Next-generation therapies for hepatocellular carcinoma: CAR-T cell and anticancer peptide synergy

   Kannan HT, Pan I · International journal of biological macromolecules · 2026ReviewPubMed Verified

8. 8.
   Mitochondrial-derived microproteins in lung disease: insights and implications

   Behan M, Yen K, Cohen P, Kliment CR · American journal of physiology. Lung cellular and molecular physiology · 2026ReviewPubMed Verified

9. 9.
   Systemic MOTS-c levels are increased in adults with obesity in association with metabolic dysregulation and remain unchanged after weight loss

   Yoon SH, Yuan F, Zhu X, Tang H, Abdurakhimoova D, Krier J et al. · Journal of clinical & translational endocrinology · 2026PubMed Verified

10. 10.
    Mitochondria-derived peptides in liver disease: Emerging regulators of hepatic metabolism and therapeutic targets

    Thoudam T, Zeng G, Gao H, Jiang Y, Huda N, Yang Z et al. · Hepatology communications · 2026ReviewPubMed Verified

11. 11.
    MOTS-c improves intrinsic muscle mitochondrial bioenergetic health and efficiency in a PGC-1α/AMPK-dependent manner

    Gudiksen A, Hansen CC, van der Stede T, Daugaard AH, Schmidt JH, Ringholm S et al. · Free radical biology & medicine · 2026PubMed Verified

12. 12.
    Serum Mitochondrial Open Reading Frame of the 12S rRNA-c (MOTS-c) Dynamics as a Complementary Marker of Treatment Response in Newly Diagnosed Multiple Myeloma: A Prospective Analysis

    Erol V, Avci E, Kabukcu Hacioglu S, Guler N, Akgun Cagliyan G, Ünver Koluman B et al. · Cureus · 2025PubMed Verified

13. 13.
    Mitochondrial-derived microproteins in cancer and neurodegeneration: A new era of cross-disease mechanistic insights

    Hu S, Hu C, Tong M · Pathology, research and practice · 2026ReviewPubMed Verified

14. 14.
    Muscle-Targeted Nanocomposite Therapy Alleviates Age-Related Sarcopenia via Antioxidant and Metabolic Reprogramming

    Liu Z, Shen Z, Lu H, Lu B, Zhang P, Chen W et al. · ACS nano · 2026PubMed Verified

15. 15.
    Circulating Mitochondrial Open Reading Frame of the 12S Ribosomal RNA Type-c Is Higher in Acute Coronary Syndrome and Is a Prognostic Biomarker for Major Cardiac Events in Patients With Acute Myocardial Infarction: A Case-Control Study

    Cao P, Wang B, Zhang N, Yang J, Tong Q, Gong Z · Journal of the American Heart Association · 2025PubMed Verified

16. 16.
    Insights into the Biomarker Potential of Humanin and Mots-c Expression and Telomere Length in Alzheimer's Disease

    Rodríguez-Esparragón F, Cazorla-Rivero SE, Torrealba E, Cánovas-Molina Á, González-Hernández AN, Martín-Alfaro R et al. · International journal of molecular sciences · 2025PubMed Verified

17. 17.
    MOTS‑c protects against placental injury via Nrf2 activation in hypoxia‑induced intrauterine growth restriction mice

    Chen D, Zhao HM, Sun XL, Xing ZX, Li SP, Li SC et al. · International journal of molecular medicine · 2026PubMed Verified

18. 18.
    MOTS-c in type 2 diabetes mellitus: From risk factors to cardiac complications and potential treatment

    Fang T, Han JC, Taberner A, Pham T · Life sciences · 2025ReviewPubMed Verified

19. 19.
    MOTS-c attenuates mitochondrial dysfunction induces pyroptosis and cartilage degradation in osteoarthritis via an Nrf2-Dependent Mechanism

    Li K, Yang T, Chen F, Lou C, Chen Y, Chen Z et al. · Free radical biology & medicine · 2025PubMed Verified

20. 20.
    MOTS-C levels ın ındividuals with and without obesity and ıts association with ınflammation, insulin resistance and endothelial dysfunction

    Ozkaya DY, Haymana C, Demirci I, Duman UG, Küpçük E, Koç GE et al. · Archives of endocrinology and metabolism · 2025PubMed Verified

21. 21.
    Exercise-Induced Muscle-Fat Crosstalk: Molecular Mediators and Their Pharmacological Modulation for the Maintenance of Metabolic Flexibility in Aging

    Tero-Vescan A, Degens H, Matsakas A, Ștefănescu R, Ősz BE, Slevin M · Pharmaceuticals (Basel, Switzerland) · 2025ReviewPubMed Verified

22. 22.
    Mitochondrial-encoded peptide MOTS-c prevents pancreatic islet cell senescence to delay diabetes

    Kong BS, Lee H, L'Yi S, Hong S, Cho YM · Experimental & molecular medicine · 2025PubMed Verified

23. 23.
    Retrospective study on the value of serum angiopoietin 2 and cystatin C levels in the early diagnosis of acute coronary syndrome

    Zou Q, Huang Y, Peng Y, Lu X, Ye F, Xu J et al. · Medicine · 2025PubMed Verified

24. 24.
    Characterization of the Avian Mitochondrial-Derived Peptide MOTS-c and Its Potential Role as a Metabolic Regulator

    Shu X, Liu J, Xu B, Wang H, Liu L, Zheng X et al. · Animals : an open access journal from MDPI · 2025PubMed Verified

25. 25.
    Diagnostic relevance of Humanin, GAS5 and miR-21/miR-103 in prostate disease risk stratification

    Coradduzza D, Cruciani S, Sibono L, Tedde A, Zinellu A, Maioli M et al. · Clinical and experimental medicine · 2025PubMed Verified

26. 26.
    A mitochondrial-derived peptide MOTS-c contributes to the protective effect against brain injury associated with LPS-induced sepsis by strengthening the blood-brain barrier's ultrastructure

    Bai Y, Wu H, Wang X, Guo Y, Gong B, Dong B et al. · The International journal of neuroscience · 2026PubMed Verified

27. 27.
    Mitochondrial-Derived Peptides: Implication in the Therapy of Neurodegenerative Diseases

    Thakur R, Chauhan A, Moudgil H, Singh S, Devi R · Molecular neurobiology · 2025ReviewPubMed Verified

28. 28.
    The unexplored Nexus: Mitochondria derived microproteins and Parkinson's disease

    Patel K, Soni R, Shah J · Pathology, research and practice · 2025ReviewPubMed Verified

29. 29.
    Repeated Heat Stress Modulates the Levels of the Mitokines MOTS-C and FGF21 in Active Men during Calf Muscle Immobilization

    Elhusseiny R, Ihsan M, Labidi M, Alhammoud M, Mtibaa K, Nader N et al. · Medicine and science in sports and exercise · 2025RCTPubMed Verified

30. 30.
    Mitochondria-derived peptide MOTS-c restores mitochondrial respiration in type 2 diabetic heart

    Pham T, Taberner A, Hickey A, Han JC · Frontiers in physiology · 2025PubMed Verified

31. 31.
    The impact of mitokine MOTS-c administration on the soleus muscle of rats subjected to a 7-day hindlimb suspension

    Sidorenko DA, Lvova ID, Tyganov SA, Shenkman BS, Sharlo KA · Journal of muscle research and cell motility · 2025PubMed Verified

32. 32.
    Mitochondrial-Derived Peptides as Therapeutics and Biomarkers for Combating Vascular Aging and Associated Cardiovascular Diseases

    Sivakumar R, Senghor KAA, Vinodhini VM, Kumar J · Current cardiology reviews · 2025PubMed Verified

33. 33.
    Reduced serum levels of mitochondria-derived peptide MOTS-c in patients with obstructive sleep apnea

    Luo Z, Ji R, Ye R, Shi Y, Pang Q, Yin M · Sleep and biological rhythms · 2025PubMed Verified

34. 34.
    Mitochondria-derived peptide MOTS-c and its role in OSA pathogenesis: a potential therapeutic target?

    Edwards BA, Joosten SA, Landry SA · Sleep and biological rhythms · 2025PubMed Verified

35. 35.
    MOTS-c-modified functional self-assembly peptide hydrogels enhance the activity of nucleus pulposus-derived mesenchymal stem cells of intervertebral disc degeneration

    Lin Y, Yang RY, Li J, Shao SZ, Shi XQ, Huang ZW et al. · Materials today. Bio · 2025PubMed Verified

36. 36.
    Mitochondrial dysfunction characterises the multigenerational effects of maternal obesity on MASLD

    Heldens A, Antwi M, Onghena L, Meese T, Gansemans Y, Smet J et al. · JHEP reports : innovation in hepatology · 2025PubMed Verified

37. 37.
    MOTS-c modulates pancreatic islet function in rats and pigs in vitro

    Bień J, Pruszynska-Oszmalek E, Kolodziejski P, Leciejewska N, Szczepankiewicz D, Grzęda E et al. · Histochemistry and cell biology · 2025PubMed Verified

38. 38.
    MOTS-c attenuates airway barrier dysfunction in allergic asthma by inhibiting epithelial apoptosis via Nrf2 pathway

    Zhang W, Li S, Zhang Y, Wu Y, Chen D, Pang Q et al. · International immunopharmacology · 2025PubMed Verified

39. 39.
    Circulating mitochondrial biomarkers in acute coronary syndrome

    Iboleon-Jimenez A, Sánchez-Quintero MJ, Carmona-Segovia ADM, Sojo B, Fernández-Ramos AM, García-Rodríguez L et al. · Frontiers in medicine · 2025PubMed Verified

40. 40.
    MOTS-c mimics exercise to combat diabetic liver fibrosis by targeting Keap1-Nrf2-Smad2/3

    Chen F, Li Z, Wang T, Fu Y, Lyu L, Xing C et al. · Scientific reports · 2025PubMed Verified

41. 41.
    MOTS-c attenuates lung ischemia-reperfusion injury via MYH9-Dependent nuclear translocation and transcriptional activation of antioxidant genes

    Li X, Zhan F, Qiu G, Lu P, Shen Z, Qi Y et al. · Redox biology · 2025PubMed Verified

42. 42.
    MOTS-c as a Potential Diagnostic-prognostic Biomarker for Myocardial Infarction

    Cakmak A, Yazgan B · Cardiovascular & hematological agents in medicinal chemistry · 2025PubMed Verified

43. 43.
    Corrigendum to "MOTS-c mimics remote ischemic preconditioning in protecting against lung ischemia-reperfusion injury by alleviating endothelial barrier dysfunction" [Free Radic Biol Med. 229 (2025) 127-138]

    Wang DD, Xu B, Sun JJ, Sui M, Li SP, Chen YJ et al. · Free radical biology & medicine · 2025PubMed Verified

44. 44.
    MOTS-c: Magical Molecule for Diabetic Cardiomyopathy?

    Yerra VG, Connelly KA · Cardiovascular drugs and therapy · 2025PubMed Verified

45. 45.
    Circulating PGC-1α and MOTS-c Peptide as Potential Mitochondrial Biomarkers in Patients Undergoing Aortic Valve Replacement

    Sánchez-Quintero MJ, Iboleón A, Martín Chaves L, Pozo Vilumbrales B, Carmona-Segovia ADM, Martínez López P et al. · Biologics : targets & therapy · 2025PubMed Verified

46. 46.
    Mitochondria‑derived peptides: Promising microproteins in cardiovascular diseases (Review)

    Ran Y, Guo Z, Zhang L, Li H, Zhang X, Guan X et al. · Molecular medicine reports · 2025ReviewPubMed Verified

47. 47.
    A Mighty Mitochondrial Microprotein: The Protective Role of MOTS-c in Acute Lung Injury

    Kliment C · American journal of respiratory cell and molecular biology · 2025PubMed Verified

48. 48.
    MOTS-c Promotes Glycolysis via AMPK-HIF-1α-PFKFB3 Pathway to Ameliorate Cardiopulmonary Bypass-induced Lung Injury

    Shen Z, Lu P, Jin W, Wen Z, Qi Y, Li X et al. · American journal of respiratory cell and molecular biology · 2025PubMed Verified

49. 49.
    Effects of Glucagon-Like Peptide-1 Receptor Agonists, Sodium-Glucose Cotransporter-2 Inhibitors, and Their Combination on Neurohumoral and Mitochondrial Activation in Patients With Diabetes

    Ikonomidis I, Pavlidis G, Pliouta L, Katogiannis K, Maratou E, Thymis J et al. · Journal of the American Heart Association · 2025PubMed Verified

50. 50.
    MOTS-c Levels and Sarcopenia Risk in Chronic Peritoneal Dialysis Patients: A Pilot Study

    Zicarelli M, Greco M, Roumeliotis S, Lo Vasco ME, Dragone F, Kourtidou C et al. · Medicina (Kaunas, Lithuania) · 2025PubMed Verified