Product description
What is MOTS-c?
MOTS-c (Mitochondrial Open Reading Frame of the 12S rRNA-c) is a unique, naturally occurring peptide consisting of 16 amino acids (MRWQEMGYIFYPRKLR), which was discovered in 2015 by Dr. Pinchas Cohen's team at the University of Southern California. It is the first signal peptide encoded by mitochondrial DNA (mtDNA) rather than nuclear DNA.
This peptide belongs to a newly discovered class of biologically active molecules called peptides of mitochondrial origin (MDPs - Mitochondrial-Derived Peptides), which also includes humanin. MOTS-c is encoded by a short open reading frame (sORF) located within the mitochondrial 12S rRNA gene.
The discovery of MOTS-c changed the paradigm of perceiving mitochondria - from "final" organelles responsible only for energy production to active regulators of metabolic processes communicating with the cell nucleus and other tissues of the body.
The concentration of MOTS-c in plasma and tissues (especially skeletal muscle) decreases with age. In young people, blood levels are 11-21% higher than in middle-aged and older people.
Mechanism of action
MOTS-c's mechanism of action is based on unique mito-nuclear communication and activation of key metabolic pathways:
AMPK pathway activation – MOTS-c inhibits the folate cycle and the related de novo purine biosynthesis, which leads to the accumulation of AICAR (ribonucleotide 5-aminoimidazole-4-carboxamide) – an endogenous activator of the kinase AMP-activated protein (AMPK). AMPK is the main regulator of cellular energy homeostasis, controlling glucose uptake, fatty acid oxidation and mitochondrial biogenesis.
Translocation to the nucleus – Under conditions of metabolic stress (e.g., during physical exercise, caloric restriction, hyperglycemia), MOTS-c is translocated from the mitochondria to the cell nucleus in an AMPK-dependent manner. In the nucleus, the peptide regulates gene expression by binding to ARE-related transcription factors (Antioxidant Response Elements), including NRF2.
Regulation of gene expression – MOTS-c affects the transcription of over 1,000 genes related to metabolism, proteostasis, stress response and antioxidant defense. The peptide activates the expression of mitochondrial protective genes and inhibits pro-inflammatory genes.
Endocrine-like action – MOTS-c functions not only intracellularly, but also as a signaling factor acting in a paracrine and endocrine manner. The peptide is detectable in blood plasma and its levels increase after exercise in humans.
Tissue-specific interaction – A 2024 study showed that MOTS-c binds directly to the protein kinase CK2α with opposite effects in different tissues: activation in skeletal muscle (promotion of muscle function) and inhibition in adipose tissue (reduction of lipid accumulation).
Directions of scientific research
MOTS-c is the subject of intensive preclinical research as a potential exercise mimetic and anti-aging intervention.
Research on glucose metabolism and insulin resistance
Fundamental research by Cohen's team showed that MOTS-c prevents insulin resistance associated with age and a high-fat diet in mice. Administration of the peptide (5 mg/kg/day) for 7 days improved insulin sensitivity of the entire body (GIR index in the euglycemic-hyperinsulinemic clamp), especially in skeletal muscles (IS-GDR). In aged mice (12 months), MOTS-c restored insulin sensitivity to levels seen in young mice (3 months).
Research on physical performance and muscle aging
A landmark 2021 study (Reynolds et al., Nature Communications) showed that MOTS-c significantly increased physical performance in young (2 months), middle-aged (12 months), and old (22 months) mice. Intermittent administration of MOTS-c (3x a week) started even at an advanced age (23.5 months) improved grip strength, gait parameters, walking test performance and glycemic control. Studies have shown that in humans, exercise induces endogenous MOTS-c expression in skeletal muscle and circulation.
Obesity research
In high-fat diet-induced obesity models (60% calories from fat), 8-week administration of MOTS-c (0.5 mg/kg/day) prevented weight gain and adipose tissue accumulation. The mechanism involved AMPK activation and improved fatty acid oxidation.
Research on age-related metabolic diseases
MOTS-c is being studied in the context of a number of diseases associated with aging: type 2 diabetes, cardiovascular diseases (protection of cardiomyocytes against ischemia), osteoporosis, postmenopausal obesity and neurodegenerative diseases (including Alzheimer's disease). Polymorphisms of the gene encoding MOTS-c have been associated with longevity in human populations.
Research on fibrosis and lung diseases
The latest research (2025) showed that MOTS-c prevents diabetes-induced liver fibrosis through the Keap1-Nrf2-Smad2/3 pathway. The peptide is also being studied in the context of fibroblast dysfunction in age-related chronic obstructive pulmonary disease (COPD).
Clinical trials
CohBar Inc. developed a more stable MOTS-c analog (CB4211) that has undergone Phase Ia/Ib clinical trials in non-alcoholic steatohepatitis (NASH) and obesity. The preparation showed a favorable safety profile and preliminary signals of effectiveness in reducing fat content in the liver.
Scientific context
MOTS-c represents a new paradigm in mitochondrial biology and intercellular communication. The discovery that mitochondria - which have their own, separate genome - encode active signal peptides that regulate metabolic processes throughout the body opens new directions in research on aging and metabolic diseases.
The peptide is referred to as an "exercise mimetic" because its metabolic effects (activation of AMPK, improvement of insulin sensitivity, stimulation of mitochondrial biogenesis) resemble the adaptations induced by regular physical activity. Furthermore, exercise itself induces the release of endogenous MOTS-c.
The decline in MOTS-c levels with age correlates with the development of insulin resistance, sarcopenia and other age-related metabolic dysfunctions. This suggests that mtDNA mutations accumulating during aging may lead to reduced production of protective peptides, including MOTS-c and humanin.
Research safety profile
In preclinical studies, MOTS-c demonstrated a favorable safety profile with no toxic effects observed over a wide dose range. The peptide is a natural component of the body, which potentially reduces the risk of immunogenicity.
No serious adverse events were reported in Phase I clinical trials of the CB4211 analogue. However, the long-term safety profile of exogenous MOTS-c administration in humans requires further study.
MOTS-c is on the list of substances monitored by USADA (U.S. Anti-Doping Agency) due to its potential to improve physical performance.
Bibliography - latest scientific research
- 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. PubMed
- Reynolds JC, Lai RW, Woodhead JST, et al. MOTS-c is an exercise-induced mitochondrial-encoded regulator of age-dependent physical decline and muscle homeostasis. Nat Commun. 2021;12:470. PubMed
- 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(3):516-524. PubMed
- Zheng Y, Wei Z, Wang T. MOTS-c: A promising mitochondrial-derived peptide for therapeutic exploitation. Front Endocrinol. 2023;14:1120533. PMC
- Wan W, Zhang L, Lin Y, et al. Mitochondria-derived peptide MOTS-c: effects and mechanisms related to stress, metabolism and aging. J Transl Med. 2023;21(1):36. PMC
- Mohtashami Z, Singh MK, Salimiaghdam N, et al. MOTS-c, the Most Recent Mitochondrial Derived Peptide in Human Aging and Age-Related Diseases. Int J Mol Sci. 2022;23(19):11991. PubMed
- Kal S, Mahata S, Jati S, Mahata SK. Mitochondrial-derived peptides: Antidiabetic functions and evolutionary perspectives. Peptides. 2024;172:171147. PubMed
- Chen F, Li Z, Wang T, et al. MOTS-c mimics exercise to combat diabetic liver fibrosis by targeting Keap1-Nrf2-Smad2/3. Sci Rep 2025;15:12456. PubMed
- Lu Z, Chen Y, Liu D, et al. MOTS-c modulates skeletal muscle function by directly binding and regulating CK2α in a tissue-specific manner. iScience. 2024;27(6):110012. PubMed
- Zhang B, Chang JY, Lee MH, et al. Mitochondrial Stress and Mitokines: Therapeutic Perspectives for the Treatment of Metabolic Diseases. Diabetes Metab J 2024;48(1):1-17. PMC
