# MOTS-C research guide MOTS-C is a 16-amino-acid mitochondrial-derived peptide (MDP) - one of a small family of peptides encoded inside mitochondrial DNA, in the 12S rRNA (MT-RNR1) region. First described in 2015, it's studied in cell and animal research for mitochondrial biology and the AMPK energy pathway. Form Labs materials are research reference materials, not the approved medicines; no Form Labs product is approved for human or veterinary use. - Identity: CAS 1627580-64-6 (database/catalog identifier), molecular formula C101H152N28O22S2, molecular weight 2174.6 g/mol (Form Labs catalogue record). - Full name: mitochondrial ORF of the 12S rRNA type-c (Form Labs catalogue record); this guide names humanin as another mitochondrial-derived peptide in the same small family. - Human-linked evidence: observational only; one cycling bout raised the body's own MOTS-C in 10 healthy men (Reynolds et al., Nature Communications, 2021). - Form Labs supplies MOTS-C as laboratory reference material, with a catalog lot record, for research use only. Matching current certification is unverified. 16: MOTS-C is a chain of 16 amino acids (sequence MRWQEMGYIFYPRKLR). An identity fact, not a product claim. (Lee et al., Cell Metabolism, 2015: https://doi.org/10.1016/j.cmet.2015.02.009) 16: MOTS-C is a chain of 16 amino acids (sequence MRWQEMGYIFYPRKLR). An identity fact, not a product claim. (Lee et al., Cell Metabolism, 2015: https://doi.org/10.1016/j.cmet.2015.02.009) 2015: The year MOTS-C was first described, as one of a small family of peptides encoded inside mitochondrial DNA. Research context, not a product claim. (Lee et al., Cell Metabolism, 2015: https://doi.org/10.1016/j.cmet.2015.02.009) AMPK: The cell's main energy-sensing pathway (AMP-activated protein kinase) - the pathway MOTS-C is most associated with across the research. Research context, not a product claim. (Lee et al., Cell Metabolism, 2015: https://doi.org/10.1016/j.cmet.2015.02.009) ## Why is MOTS-C studied? MOTS-C is studied because it is a 16-amino-acid mitochondrial-derived peptide (MDP) encoded inside mitochondrial DNA in the 12S rRNA (MT-RNR1) region rather than in the cell nucleus (Form Labs catalogue record). Lee and colleagues first described MOTS-C in 2015 (Lee et al., Cell Metabolism, 2015). Most of the research cited in this guide is cell-culture and rodent work on mitochondrial biology and the AMPK energy pathway, and none of it gave native MOTS-C to people. A peptide written in mitochondrial DNA. Nearly every protein the body makes is encoded in the DNA inside the cell's nucleus. MOTS-C is unusual because its gene sits inside mitochondrial DNA - the small, separate genome of the mitochondria themselves, the energy-handling structures inside the cell. That's what first drew researchers to it. It was first described in 2015 by Lee and colleagues, who identified it from a short open reading frame in the mitochondrial 12S rRNA gene (the MT-RNR1 region). That made it one of a small, newly recognised family of mitochondrial-derived peptides - humanin is another - and the field is still young. Most of what's been published since is cell-culture and rodent research into mitochondrial biology and the AMPK energy pathway. There are no large human trials of the native peptide, so this guide treats all of it as research context - not as anything the vial will do for a person. ## What laboratory observations have MOTS-C studies reported? Lee et al. (Cell Metabolism, 2015) reported AMPK-pathway and insulin-sensitivity observations for MOTS-C in cell and mouse models, with no human data. Kim et al. (Cell Metabolism, 2018) reported MOTS-C movement into the nucleus under glucose restriction in cultured human cells. Cell-culture findings remain distinct from a clinical study in people. MOTS-C laboratory observations ### Mitochondrial origin Lee et al. (Cell Metabolism, 2015) described MOTS-C as a mitochondrial-derived peptide in cell and mouse research. ### Cell and mouse models Lee et al. (Cell Metabolism, 2015) linked MOTS-C to the folate/one-carbon and AMPK pathways in cell and mouse models; the paper included no human data. ### Cultured human cells Kim et al. (Cell Metabolism, 2018) reported MOTS-C movement into the nucleus under glucose restriction in cultured human cells; this is a cell-culture finding. | | | | --- | --- | | Research code | MOTS-C / MT-RNR1 sORF | | Class | Mitochondrial-derived peptide (MDP) - a small peptide encoded inside mitochondrial DNA rather than the cell nucleus. | | Molecule | A 16-amino-acid peptide, sequence MRWQEMGYIFYPRKLR, supplied as a freeze-dried powder. | | Reported half-life | This guide records no established clinical half-life for MOTS-C. | | Originator | First described by Lee and colleagues in 2015, from a short open reading frame in the mitochondrial 12S rRNA gene. Form Labs did not run the cited studies. | | Approval status | Laboratory research material only - not an approved medicine, and not evaluated by the TGA or any regulator for human use. | ## What has MOTS-C been studied for? MOTS-C research includes cell and mouse metabolism findings (Lee et al., Cell Metabolism, 2015), cultured-cell stress observations (Kim et al., Cell Metabolism, 2018), and exercise-related measurements in mice and healthy men (Reynolds et al., Nature Communications, 2021). The human observations measured endogenous MOTS-C rather than a clinical intervention with native MOTS-C. ### Metabolic homeostasis & AMPK Activation of the AMPK energy-sensing pathway via folate/one-carbon metabolism, and insulin sensitivity in mice. Lee et al., Cell Metabolism, 2015 (cells + mice) ### Mitonuclear stress signalling Movement of MOTS-C into the nucleus under glucose restriction to regulate stress-response genes. Kim et al., Cell Metabolism, 2018 (cells) ### Exercise & age-related physical decline Running capacity and physical performance in aged mice; one cycling bout raised endogenous MOTS-C in 10 healthy men. Reynolds et al., Nature Communications, 2021 (mice + human exercise) ### Muscle function & CK2 (genetic association) Binding and activation of CK2 in mice and cells, and a natural gene variant linked to sarcopenia and type-2-diabetes risk across three human cohorts. Kumagai et al., iScience, 2024 (mice + cells + human genetic) ### Circulating MOTS-C as a biomarker Blood levels of MOTS-C measured against obesity and insulin-resistance markers in young people. Du et al., Pediatric Diabetes, 2018 (human observational) ## Published studies ## What did the MOTS-C studies find? The five MOTS-C studies cited in this guide are mostly cell and mouse work, with human data that is observational. Lee et al. (Cell Metabolism, 2015) reported that MOTS-C activated AMPK and was associated with improved insulin sensitivity in mice, with no human data. Reynolds et al. (Nature Communications, 2021) found one cycling bout raised the body's own MOTS-C in 10 healthy men. Du et al. (Pediatric Diabetes, 2018) found circulating MOTS-C was lower in obese than non-obese children. ### The discovery paper - MOTS-C and the AMPK pathway Lee C, Zeng J, Drew BG, et al. - Cell Metabolism - 2015 Preclinical (cell cultures and mice) The paper that first identified MOTS-C, from a short open reading frame in mitochondrial DNA, and linked it to the AMPK energy pathway and insulin sensitivity in mice. | | | | --- | --- | | Studied in | Human cell lines (HEK293, HeLa, L6) and mice. | | Design | A discovery paper - lab cell work plus animal experiments that established the peptide and its main pathway. | | Measured | AMPK pathway activation, folate/one-carbon metabolism, and markers of insulin sensitivity in mice. | Lee et al. (Cell Metabolism, 2015) reported AMPK activation through the folate/one-carbon pathway in cells and increased insulin sensitivity in mice. The paper included no human data. https://doi.org/10.1016/j.cmet.2015.02.009 ### MOTS-C moves into the nucleus under glucose restriction Kim KH, Son JM, Benayoun BA, Lee C - Cell Metabolism - 2018 Preclinical (cell cultures only) This paper showed that under glucose restriction MOTS-C moves into the cell nucleus and helps regulate stress-response genes. | | | | --- | --- | | Studied in | Human cell lines (HEK293, HepG2) in culture. | | Design | A cell-culture study of where MOTS-C sits in the cell and which genes it touches under metabolic stress. | | Measured | Movement of MOTS-C into the nucleus and changes in stress- and antioxidant-response gene activity (NRF2/AMPK). | Under glucose restriction, MOTS-C moved from the cytoplasm into the nucleus of the cultured cells and helped regulate antioxidant and stress-response genes (Kim KH, Son JM, Benayoun BA, Lee C - Cell Metabolism - 2018). https://doi.org/10.1016/j.cmet.2018.06.008 ### Exercise, aging and physical performance in mice Reynolds JC, Lai RW, Woodhead JST, et al. - Nature Communications - 2021 Preclinical (mice) plus a small human endogenous measurement This paper reported that aged mice given MOTS-C had better physical performance, and that one bout of cycling raised the body's own MOTS-C in 10 healthy men. | | | | --- | --- | | Studied in | Aged mice, plus 10 healthy men for an endogenous (body's-own) measurement. | | Design | Animal experiments on running capacity, grip and stride, plus a small human exercise observation. No MOTS-C was given to the men. | | Measured | Running capacity, grip strength and stride in aged mice; endogenous MOTS-C levels after exercise in the men; and lifespan in mice. | Reynolds et al. (Nature Communications, 2021) reported running-capacity, grip and stride differences in aged mice. Separately, endogenous MOTS-C rose after cycling in 10 healthy men; the men did not receive MOTS-C. The mouse lifespan trend was non-significant (P=0.05). https://doi.org/10.1038/s41467-020-20790-0 ### The CK2 connection and a natural gene variant Kumagai H, Kim SJ, Miller B, et al. - iScience - 2024 Preclinical (mice and cells) plus human genetic association This paper reported that MOTS-C binds and activates a protein called CK2, and that a natural gene variant with weaker CK2 binding was linked to certain muscle and metabolic traits in large human cohorts. | | | | --- | --- | | Studied in | Mice and cell cultures, plus three human cohort datasets analysed for a genetic association. | | Design | Lab mechanistic work on CK2 binding plus a genetic-association analysis of a natural MOTS-C variant. Not a trial that gave MOTS-C to people. | | Measured | CK2 binding and activation in mice and cells; and statistical association of the K14Q variant with sarcopenia and type-2-diabetes risk across the cohorts. | MOTS-C bound and activated CK2 in mice and cells (Kumagai H, Kim SJ, Miller B, et al. - iScience - 2024). A natural MOTS-C gene variant (K14Q) with weaker CK2 binding was associated, across three human cohorts, with higher sarcopenia and type-2-diabetes risk (Kumagai H, Kim SJ, Miller B, et al. - iScience - 2024). This is a genetic association rather than a clinical outcome for native MOTS-C (Kumagai H, Kim SJ, Miller B, et al. - iScience - 2024). https://doi.org/10.1016/j.isci.2024.111212 ### Circulating MOTS-C measured against metabolic markers Du C, Zhang C, Wu W, et al. - Pediatric Diabetes - 2018 Human observational study This paper measured MOTS-C in the blood of young people and compared the levels across obesity and insulin-resistance groups. | | | | --- | --- | | Studied in | Children and adolescents, grouped by obesity status. | | Design | An observational biomarker study - measuring circulating MOTS-C and comparing it across groups. No MOTS-C was given to anyone. | | Measured | Blood levels of MOTS-C alongside insulin-resistance and related metabolic markers. | Circulating MOTS-C was lower in obese than non-obese children and adolescents (a human observational measurement), and tracked with insulin-resistance markers (Du C, Zhang C, Wu W, et al. - Pediatric Diabetes - 2018). It's an observational study in people, not a trial that gave MOTS-C to anyone - a correlation in a population, not evidence of what the peptide does to a person (Du C, Zhang C, Wu W, et al. - Pediatric Diabetes - 2018). https://doi.org/10.1111/pedi.12685 ## What has MOTS-C research not established? MOTS-C research cited in this guide has not included large human clinical trials: none of the cited studies gave native MOTS-C to people for any outcome. Human efficacy numbers are not established in the cited literature. The research cited in this guide gives no direction for use in or on people or animals, and describes the molecule in general, not what a specific batch does. - Large human clinical trials - there is no peer-reviewed trial giving native MOTS-C to people for any outcome. - Any use in or on people or animals - none of the research on this page is a use direction. - What a specific batch does - the studies are about the molecule in general, not this vial. ## Is MOTS-C approved, and where does the research stand? MOTS-C is described in this guide as laboratory research material only. This guide's timeline begins with Lee and colleagues' description of MOTS-C (Lee et al., Cell Metabolism, 2015), then nuclear movement under glucose restriction (Kim et al., Cell Metabolism, 2018), mouse and exercise data (Reynolds et al., Nature Communications, 2021) and CK2 binding (Kumagai et al., iScience, 2024). - 2015: MOTS-C is first described by Lee and colleagues, from a short open reading frame in mitochondrial DNA (Cell Metabolism). - 2018: Kim and colleagues report MOTS-C moving into the nucleus under glucose restriction to regulate stress-response genes (Cell Metabolism). - 2018: Du and colleagues measure circulating MOTS-C against obesity and insulin-resistance markers in young people (Pediatric Diabetes). - 2021: Reynolds and colleagues report better physical performance in aged mice given MOTS-C, and that exercise raises the body's own MOTS-C in 10 healthy men (Nature Communications). - 2024: Kumagai and colleagues map CK2 binding and activation, and a linked natural gene variant associated with muscle and metabolic traits (iScience). ## What does the MOTS-C research mean, and what does it not? The MOTS-C evidence comes from a young field: MOTS-C was first described in 2015 (Lee et al., Cell Metabolism, 2015), and the research cited in this guide is predominantly cell cultures and mice, which does not translate into claims about people. The human-linked findings are observational or endogenous, covering exercise raising the body's own MOTS-C, a gene variant associated with traits, and blood levels tracking markers. None gave MOTS-C to people as a treatment. ### It's a young field MOTS-C was first described in 2015, and mitochondrial-derived peptides as a family are still new. The evidence base is growing but small compared with longer-studied peptides. ### Most evidence is cells and rodents The published work is predominantly cell cultures and mice. Useful for understanding the molecule, but it doesn't translate into claims about people. ### The human evidence is observational only The human-linked findings are observational or endogenous - exercise raises the body's own MOTS-C (Reynolds), a gene variant is associated with traits (Kumagai), and blood levels track markers (Du). None gave MOTS-C to people as a treatment. ### The lab report is the authority for a batch Historical sample reports and these papers do not establish current lot identity, purity or release status. ## How is MOTS-C handled as reference material? MOTS-C is laboratory reference material, not for human consumption or veterinary use. Storage and lot checks follow the product label and any verified matching certificate of analysis (COA). This guide's catalogue record notes storage at 2-8 C and protection from light. Historical sample reports do not verify current lot identity, purity or release status. ### Research-use boundary MOTS-C is supplied strictly for laboratory research. It's not for human consumption, veterinary, medical, or cosmetic use. ### COA and label The historical report on file for MOTS-C is an independent lab assessment measuring peptide content at 11.15 mg; it prints no purity percentage. It covers its named sample, not the current catalog lot. Matching current certification is unverified. ### Storage Supplied freeze-dried. Store cold at 2-8 C (fridge-cold) and out of light, following the vial label, any verified matching lab report for the batch, and the receiving lab's own written procedures. ### Educational boundary This guide is a plain summary of third-party research that Form Labs did not run. It isn't medical advice or a product claim. ## Plain-English definitions. ### Mitochondrial-derived peptide (MDP) A small peptide encoded inside mitochondrial DNA rather than the cell's nuclear DNA. MOTS-C and humanin are examples. ### MT-RNR1 The mitochondrial gene region that codes for the 12S rRNA, where MOTS-C's short gene sits. ### 12S rRNA A type of ribosomal RNA encoded by mitochondrial DNA; produced by the MT-RNR1 gene. ### sORF Short open reading frame - a short genetic section that can code for a small peptide, like MOTS-C. ### AMPK AMP-activated protein kinase - the cell's central energy-sensing pathway, and the one MOTS-C is most associated with. ### Folate / one-carbon (AICAR) pathway A metabolic route the 2015 paper linked to MOTS-C's activation of AMPK. ### Mitonuclear Describing communication between the mitochondria and the cell nucleus - relevant to MOTS-C's move into the nucleus under stress. ### CK2 A protein kinase (enzyme) that MOTS-C binds and activates, as reported in 2024 lab work. ### GLUT4 A transport protein that moves glucose across cell membranes; named in MOTS-C study context. ### RUO Research use only - a lab-only boundary, not for human consumption, veterinary, medical, or cosmetic use. ### COA Certificate of analysis - the batch paperwork controlling identity, purity, appearance, and release. ## What are the most common questions about MOTS-C? MOTS-C is a 16-amino-acid mitochondrial-derived peptide with the sequence MRWQEMGYIFYPRKLR, encoded in the 12S rRNA (MT-RNR1) region of mitochondrial DNA (Form Labs catalogue record). The most common questions about MOTS-C cover what a mitochondrial-derived peptide is, what the discovery paper found (Lee et al., Cell Metabolism, 2015), whether human trials exist, how MOTS-C relates to AMPK, exercise and aging, and how it differs from humanin. Form Labs supplies research-use-only reference material. ### What is MOTS-C, in one line? MOTS-C is a 16-amino-acid mitochondrial-derived peptide (sequence MRWQEMGYIFYPRKLR) encoded within the 12S rRNA (MT-RNR1) region of mitochondrial DNA, studied in cell and animal research for mitochondrial biology and the AMPK energy pathway. ### What is an MDP, and how was MOTS-C discovered? A mitochondrial-derived peptide (MDP) is a small peptide encoded inside mitochondrial DNA rather than the cell nucleus. MOTS-C was first described in 2015 by Lee and colleagues in Cell Metabolism, from a short open reading frame in the mitochondrial 12S rRNA gene; it's one of a small MDP family that also includes humanin. ### What did the 2015 discovery paper find? Lee et al. (Cell Metabolism, 2015) reported AMPK-pathway observations in cells and increased insulin sensitivity in mice; the paper included no human data. ### Does MOTS-C have any human clinical trials? Reynolds et al. (Nature Communications, 2021) measured endogenous MOTS-C after cycling in 10 healthy men. Kumagai et al. (iScience, 2024) reported genetic associations, and Du et al. (Pediatric Diabetes, 2018) reported circulating MOTS-C measurements. These are observational or genetic records rather than clinical intervention results for native MOTS-C. ### How does MOTS-C relate to AMPK and metabolism? Lee et al. (Cell Metabolism, 2015) reported a link between MOTS-C, folate/one-carbon metabolism and AMPK in cell and mouse models; the study included no human data. ### What does research say about MOTS-C, exercise and aging? Reynolds et al. (Nature Communications, 2021) reported running-capacity and physical-performance differences in aged mice. In a separate observation, endogenous MOTS-C rose after cycling in 10 healthy men, who did not receive MOTS-C. The lifespan trend in mice was non-significant; the animal and human observations remain distinct. ### What is the "nuclear translocation" finding? Kim and colleagues (2018) reported that, under glucose restriction, MOTS-C moves from the cytoplasm into the cell nucleus and helps regulate stress- and antioxidant-response genes (via NRF2/AMPK). This was a cell-culture study in human cell lines, describing how the peptide behaves in cells under stress - not a human or animal outcome. ### Is MOTS-C the same as humanin or other MDPs? No. MOTS-C and humanin are both mitochondrial-derived peptides, but they're different molecules encoded by different parts of mitochondrial DNA (MOTS-C from the 12S rRNA / MT-RNR1 region) and studied for overlapping but distinct roles in metabolism and stress signalling. MOTS-C is a 16-amino-acid peptide, sequence MRWQEMGYIFYPRKLR. ### What does "for research use only" mean here? "For research use only" means MOTS-C is supplied strictly for laboratory research and is not for human or veterinary consumption, medical use, or cosmetic use. This guide is an educational summary of third-party published research that Form Labs did not conduct - not medical advice or a product claim. ### Is MOTS-C prohibited in sport? MOTS-C acts on the AMPK pathway, and the World Anti-Doping Agency (WADA) prohibits AMPK activators as metabolic modulators (category S4) at all times in sport. Athletes subject to anti-doping rules should confirm MOTS-C's current status directly with WADA. Form Labs supplies MOTS-C for laboratory research only, not for human use. ## References - The 2015 discovery paper identifying MOTS-C and linking it to the AMPK pathway and insulin sensitivity in mice. Lee C, Zeng J, Drew BG, et al. Cell Metabolism, 2015. DOI: 10.1016/j.cmet.2015.02.009 - Cell-culture study of MOTS-C moving into the nucleus under glucose restriction to regulate stress-response genes. Kim KH, Son JM, Benayoun BA, Lee C. Cell Metabolism, 2018. DOI: 10.1016/j.cmet.2018.06.008 - Mouse and small human exercise study of MOTS-C, physical performance and aging. Reynolds JC, Lai RW, Woodhead JST, et al. Nature Communications, 2021; 12: 470. DOI: 10.1038/s41467-020-20790-0 - Mouse, cell and human genetic-association study linking MOTS-C to CK2 binding and to muscle and metabolic traits. Kumagai H, Kim SJ, Miller B, et al. iScience, 2024; 27: 111212. DOI: 10.1016/j.isci.2024.111212 - Human observational study of circulating MOTS-C against obesity and insulin-resistance markers in young people. Du C, Zhang C, Wu W, et al. Pediatric Diabetes, 2018. DOI: 10.1111/pedi.12685 - Review of MOTS-C as a mitochondrial-derived peptide regulating muscle and fat metabolism. Lee C, Kim KH, Cohen P. Free Radical Biology and Medicine, 2016. DOI: 10.1016/j.freeradbiomed.2016.05.015 - Review of mitochondrial-derived peptides in aging and age-related disease. Kim et al. The Journal of Physiology, 2017. DOI: 10.1113/JP274472 - Review of MOTS-C as a candidate for metabolic disorders. Wan et al. Journal of Translational Medicine, 2023. DOI: 10.1186/s12967-023-03885-2 - Review of MOTS-C in metabolic homeostasis and longevity. Mohtashami et al. International Journal of Molecular Sciences, 2022. DOI: 10.3390/ijms231911991 - Review of the role of MOTS-C in metabolic diseases. Zheng et al. Frontiers in Endocrinology, 2023. DOI: 10.3389/fendo.2023.1120533 ![Two separate circles that do not touch, labelled Mitochondrial DNA and Cell nucleus. The diagram is not to scale.](/assets/content/rc-two-separate-genomes.png) MOTS-C is encoded inside mitochondrial DNA in the 12S rRNA (MT-RNR1) region rather than in the cell nucleus (Lee et al., Cell Metabolism, 2015), and under glucose restriction MOTS-C moves from the cytoplasm into the cell nucleus in human cell cultures (Kim et al., Cell Metabolism, 2018); the diagram shows mitochondrial DNA and the cell nucleus as two separate circles and is not to scale. --- Canonical page: https://www.formlaboratories.com/research/mots-c Form Laboratories - Perth-based research-use-only peptide supplier, shipping Australia-wide. - Site guide for agents: https://www.formlaboratories.com/llms.txt - Sitemap: https://www.formlaboratories.com/sitemap.xml - Full catalogue: https://www.formlaboratories.com/shop - Contact: hello@formlaboratories.com All materials are supplied for laboratory research use only - not for human or veterinary use, and nothing on this site is medical advice.