Also Known As: Mitochondrial Open Reading frame of the 12S rRNA-c, MT-RNR1-derived peptide, MRWQEMGYIFYPRKLR, MDP-1
MOTS-c (Mitochondrial Open Reading frame of the 12S rRNA-c) is a natural 16-amino-acid peptide (MRWQEMGYIFYPRKLR) encoded by a small open reading frame within the human MT-RNR1 gene (12S mitochondrial rRNA) on mitochondrial DNA — not nuclear DNA. It was the first member of the mitochondrial-derived peptide (MDP) class assigned a defined systemic metabolic role, alongside humanin and SHLP1–6 (both encoded on MT-RNR2 / 16S rRNA). Discovered in 2015 by Changhan Lee and Pinchas Cohen at the USC Leonard Davis School of Gerontology (Lee 2015, Cell Metabolism, PMID 25738459). Studies report that MOTS-c interferes with the folate / methionine cycle, raising intracellular AICAR and allosterically activating AMP-activated protein kinase (AMPK) in skeletal muscle; in exercise physiology, endogenous MOTS-c in human skeletal muscle rose nearly 12-fold after acute exercise (Reynolds 2021, Nat Commun, PMID 33473109 — a replication outside the original Cohen-discovery focus, with co-authorship from Auckland and Merry/Cameron-Smith independent groups). MOTS-c is not the same molecule as CB4211, the stabilized synthetic analog developed by CohBar Inc.: CB4211 is structurally related but distinct, and completed a Phase 1a/1b NAFLD study (NCT03998514, n = 88, completed April 2021); the CB4211 Phase 1 data do not transfer directly to the natural peptide. CohBar suspended IND-enabling work in 2022 due to formulation issues, merged with Morphogenesis in 2023, and now trades as TuHURA Biosciences (NASDAQ: HURA) with an immuno-oncology focus — the CB4211 NASH program is effectively dormant. MOTS-c is not approved by the FDA, EMA, or any other regulatory agency for any clinical indication and is on the WADA Prohibited List as of 2024 (Class S4, AMPK activators). Research use only.
Studies report that MOTS-c interferes with the folate / methionine cycle, raising intracellular AICAR and allosterically activating AMP-activated protein kinase (AMPK) — primarily in skeletal muscle. Secondarily, under metabolic or oxidative stress, MOTS-c translocates from the cytoplasm into the nucleus, where it modulates stress-responsive transcription. MOTS-c is positioned as a retrograde mitochondria-to-nucleus bioregulator coordinating cellular bioenergetics with whole-body glucose handling. Observed in research settings; for research use only.
MOTS-c was the first member of the MDP class to be assigned a defined systemic metabolic role. Its discovery established that mtDNA encodes bioactive peptides via small ORFs in the rRNA genes — MOTS-c on MT-RNR1 (12S rRNA), and humanin and SHLP1-6 on MT-RNR2 (16S rRNA) (Kim/Yen 2021, GeroScience, PMID 32910336). In the original discovery paper (Lee 2015, Cell Metab, PMID 25738459), intraperitoneal MOTS-c administration in mice prevented age-dependent and high-fat-diet-induced insulin resistance and diet-induced obesity, with improved glucose tolerance and reduced fat mass after high-fat feeding — mechanistically mapped to skeletal-muscle AMPK activation via folate-cycle inhibition. Studies report that under metabolic or oxidative stress, MOTS-c translocates from the cytoplasm into the nucleus, where it binds chromatin-associated factors and shifts transcriptional programs toward antioxidant defense and metabolic adaptation (Kim 2018, PMID 29983246). In skeletal muscle, MOTS-c acts as an exercise mimetic — endogenous expression rises after physical activity and exogenous administration improves metabolic flexibility and physical performance in mouse models (Reynolds 2021, PMID 33473109). Important editorial scoping: claims about human pharmacology rest predominantly on observational studies of endogenous MOTS-c (post-exercise plasma levels, allele variants); peer-reviewed human exposure data on **synthetic** MOTS-c administration as a research peptide does not exist, and the only in vivo human Phase 1 dataset is for **CB4211**, a stabilized analog (NCT03998514) — not the natural 16-aa peptide. Mechanism statements here are therefore intentionally hedged — studies report, observed in research settings — and never framed as established human pharmacology. For research use only.
The published evidence base combines the original in vivo mouse work on insulin resistance and glucose homeostasis (Lee 2015), an independent human exercise-physiology replication (Reynolds 2021, Auckland / USC), an Asian-specific allele study (Zempo / Fuku 2021), an MDP review (Kim/Yen 2021), and a NAFLD Phase 1 study of the **stabilized analog CB4211** (NCT03998514, CohBar) — no Phase 1/2/3 trial of the **natural 16-aa peptide** has been completed. Observed in research settings.
Studies report that intraperitoneal MOTS-c administration in mice prevented age-dependent and high-fat-diet-induced insulin resistance and diet-induced obesity, with improved glucose tolerance and reduced fat mass after high-fat feeding. Mechanism: skeletal-muscle AMPK activation and folate-cycle inhibition.
— Lee et al. 2015, Cell Metab 21(3):443–454 (PMID 25738459)
Studies report that endogenous skeletal-muscle MOTS-c levels increased nearly 12-fold after acute exercise in young men and remained partially elevated four hours post-exercise; circulating plasma MOTS-c rose ~50% during and after exercise. In aged mice (~22 months — comparable to humans 65+), exogenous MOTS-c approximately doubled treadmill running capacity. Observed in research settings.
— Reynolds et al. 2021, Nat Commun 12:470 (PMID 33473109)
Studies report in a meta-analysis of three Japanese cohorts (J-MICC, MEC, TMM; total n = 27,527) that male — but not female — C-allele carriers of the K14Q allele variant showed higher prevalence of type 2 diabetes; the association concentrated among men in the lowest tertile of physical activity (kinesio-genomic interaction, a population-genetic finding). In vivo, the K14Q allele variant failed to recapitulate the wild-type weight-loss and glucose-tolerance benefits in high-fat-fed male mice (allele-variant-specific loss of function, not an adverse-event finding from MOTS-c administration). This observation is a population-genetic risk signal, NOT an adverse-event finding from MOTS-c administration.
— Zempo / Fuku et al. 2021, Aging (Albany NY) 13(2):1692–1717 (PMID 33468709)
Studies report that the mitochondrial-derived peptide class — MOTS-c, humanin, and SHLP1-6 — declines with age in plasma, and their administration has been associated with extended healthspan markers in rodent models. Direct evidence of life-extension by MOTS-c in mammals remains limited and is reviewed cautiously in the field. Observed in research settings.
— Kim/Yen et al. 2021, GeroScience 43(3):1113–1121 (PMID 32910336); Miller et al. 2022, JCI 132(9):e158449
IMPORTANT EDITORIAL DISTINCTION: CB4211 is a **stabilized synthetic analog**, **structurally distinct** from natural 16-aa MOTS-c. Studies report that in the Phase 1b portion (20 obese subjects with NAFLD on 25 mg subcutaneous CB4211 once daily for 4 weeks), CB4211 produced significant reductions in ALT and AST, a significant decrease in glucose, and a trend toward lower body weight versus placebo; approximately 36% of CB4211-treated subjects showed >30% relative reduction in liver fat. CohBar suspended IND-enabling work in 2022 due to formulation issues; the CB4211 NASH program is effectively dormant after the TuHURA pivot in 2023. These data do **not** transfer directly to the natural peptide.
— CohBar topline release, 10 Aug 2021; AASLD 2021 Poster LB5; ClinicalTrials.gov NCT03998514
Observed in research settings
Studies report that the stabilized analog **CB4211** in the Phase 1a/1b study (NCT03998514) met its primary safety endpoint — well tolerated with no serious adverse events. Important caveat: CB4211 is not identical to natural 16-aa MOTS-c; the safety dataset does not transfer directly to the natural peptide as sold by research-chemical vendors. Long-term human exposure data for synthetic natural-sequence MOTS-c administration are not published. Observed in research settings; for research use only.
Lee C, Zeng J, Drew BG, Sallam T, Martin-Montalvo A, Wan J, Kim S-J, Mehta H, Hevener AL, de Cabo R, Cohen P The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance Cell Metabolism 2015;21(3):443–454. 2015 .
Reynolds JC, Lai RW, Woodhead JST, Joly JH, Mitchell CJ, Cameron-Smith D, Lu R, Cohen P, Graham NA, Benayoun BA, Merry TL, Lee C MOTS-c is an exercise-induced mitochondrial-encoded regulator of age-dependent physical decline and muscle homeostasis Nature Communications 2021;12:470. 2021 .
Zempo H, Kim S-J, Fuku N, Nishida Y, Higaki Y, Wan J, Yen K, Miller B, Vicinanza R, Miyamoto-Mikami E, Kumagai H, Naito H, Xiao J, Mehta HH, Lee C, Hara M, Patel YM, Setiawan VW, Moore TM, Hevener AL, Sutoh Y, Shimizu A, Kojima K, Kinoshita K, Tanaka K, Cohen P A pro-diabetogenic mtDNA polymorphism in the mitochondrial-derived peptide, MOTS-c (m.1382A>C, K14Q variant) Aging (Albany NY) 2021;13(2):1692–1717. 2021 .
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 Metabolism 2018;28(3):516–524.e7. 2018 .
Kim S-J, Miller B, Kumagai H, Silverstein AR, Flores M, Yen K Mitochondrial-derived peptides in aging and age-related diseases GeroScience 2021;43(3):1113–1121. 2021 .
Kim S-J, Mehta HH, Wan J, Kuehnemann C, Chen J, Hu J-F, Hoffman AR, Cohen P The mitochondrial-derived peptide MOTS-c is a regulator of plasma metabolites and enhances insulin sensitivity Physiological Reports 2019;7(13):e14171. 2019 .
Miller B, Kim S-J, Mehta HH, Cao K, Kumagai H, Thumaty N, Leelaprachakul N, Braniff RG, Jiao H, Vaughan J, Diedrich J, Saghatelian A, Arpawong TE, Crimmins EM, Ertekin-Taner N, Tanaka T, Bandinelli S, Ferrucci L, Kennedy BK, Cohen P, Yen K Mitochondria-derived peptides in aging and healthspan The Journal of Clinical Investigation 2022;132(9):e158449. 2022 .
CohBar, Inc. Topline Phase 1a/1b results for CB4211 (a stabilized MOTS-c analog) in NASH and obesity (NCT03998514) — press release, 10 August 2021 GlobeNewswire / corporate communication. 2021 .
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