Product description
What is MOTS-c?
MOTS-c (Mitochondrial Open Reading Frame of the 12S rRNA-c) is a unique, naturally occurring peptide composed of 16 amino acids (MRWQEMGYIFYPRKLR), which was discovered in 2015 by the team of Dr. Pinchas Cohen at the University of Southern California. It is the first signaling peptide encoded by mitochondrial DNA (mtDNA), rather than nuclear DNA.
This peptide belongs to a newly discovered class of biologically active molecules known as mitochondrial-derived peptides (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 how mitochondria are viewed – from „terminal” organelles responsible solely for energy production to active regulators of metabolic processes that communicate 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, the blood level is 11-21% higher than in middle-aged and older individuals.
Mechanism of action
The mechanism of action of MOTS-c is based on unique mito-nuclear communication and activation of key metabolic pathways:
Activation of the AMPK pathway – MOTS-c inhibits the folate cycle and the associated de novo purine biosynthesis, leading to accumulation of AICAR (5-aminoimidazole-4-carboxamide ribonucleotide) – an endogenous activator of AMP-activated protein kinase (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 exertion, caloric restriction, hyperglycemia), MOTS-c translocates from the mitochondria to the cell nucleus in an AMPK-dependent manner. In the nucleus, the peptide regulates gene expression by binding to transcription factors associated with ARE (Antioxidant Response Elements), including NRF2.
Regulation of gene expression – MOTS-c affects the transcription of more than 1,000 genes related to metabolism, proteostasis, stress response and antioxidant defense. The peptide activates the expression of protective mitochondrial 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 level increases after physical exercise in humans.
Tissue-specific interaction – Studies from 2024 showed that MOTS-c directly binds to the CK2α protein kinase 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.
Studies on glucose metabolism and insulin resistance
Fundamental studies by Cohen's team showed that MOTS-c prevents age- and high-fat-diet-related insulin resistance in mice. Administration of the peptide (5 mg/kg/day) for 7 days improved whole-body insulin sensitivity (the GIR index in the euglycemic-hyperinsulinemic clamp), especially in skeletal muscle (IS-GDR). In older mice (12 months), MOTS-c restored insulin sensitivity to levels observed in young animals (3 months).
Studies on physical performance and muscle aging
In a breakthrough 2021 study (Reynolds et al., Nature Communications), MOTS-c was shown to significantly increase physical performance in young (2 months), middle-aged (12 months) and old (22 months) mice. Intermittent administration of MOTS-c (3x per week), started even at an advanced age (23.5 months), improved grip strength, gait parameters, walking-test performance and glycemic control. Studies showed that in humans, physical exercise induces endogenous MOTS-c expression in skeletal muscle and circulation.
Studies on obesity
In models of obesity induced by a high-fat diet (60% of calories from fat), 8-week administration of MOTS-c (0.5 mg/kg/day) prevented body-weight gain and adipose tissue accumulation. The mechanism involved AMPK activation and improved fatty acid oxidation.
Studies on age-related metabolic diseases
MOTS-c is being studied in the context of a range of age-related diseases: type 2 diabetes, cardiovascular diseases (protection of cardiomyocytes against ischemia), osteoporosis, postmenopausal obesity, and neurodegenerative diseases (including Alzheimer's disease). Polymorphisms in the gene encoding MOTS-c have been associated with longevity in human populations.
Studies on fibrosis and lung diseases
Recent studies (2025) showed that MOTS-c counteracts 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 studies
CohBar Inc. developed a more stable MOTS-c analog (CB4211), which underwent phase Ia/Ib clinical studies in nonalcoholic steatohepatitis (NASH) and obesity. The preparation demonstrated a favorable safety profile and preliminary signals of efficacy in reducing liver fat content.
Scientific context
MOTS-c represents a new paradigm in mitochondrial biology and intercellular communication. The discovery that mitochondria – which possess their own distinct genome – encode active signaling peptides that regulate the metabolic processes of the whole body opens new directions of research into aging and metabolic diseases.
The peptide is described as an „exercise mimetic”, because its metabolic effects (AMPK activation, improved insulin sensitivity, stimulation of mitochondrial biogenesis) resemble the adaptations induced by regular physical activity. Moreover, physical exercise itself induces the release of endogenous MOTS-c.
The age-related decline in MOTS-c levels 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.
Safety profile in studies
In preclinical studies, MOTS-c showed a favorable safety profile with no observed toxic effects across a wide dose range. The peptide is a natural component of the body, which potentially reduces the risk of immunogenicity.
In phase I clinical studies of the CB4211 analog, no serious adverse events were reported. However, the long-term safety profile of exogenous MOTS-c administration in humans requires further studies.
MOTS-c is on the list of substances monitored by USADA (U.S. Anti-Doping Agency) due to its potential performance-enhancing effect.
Bibliography – latest scientific studies
- 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
