MOTS-c: Mitochondrial-Derived Peptide Research

For most of the twentieth century the mitochondrial genome was treated as a stripped-down housekeeping document - thirteen protein-coding genes, twenty-two transfer RNAs, two ribosomal RNA genes, and very little else worth annotating. Then in 2015 a laboratory at USC reported finding a short open reading frame hidden inside the 12S ribosomal RNA gene and, more to the point, a 16-amino-acid peptide actually translated from it. The peptide is MOTS-c. Its existence suggests the mitochondrial genome has been producing its own signalling molecules all along, largely unnoticed. Supplied by Kovalabs strictly as a research reagent; everything below describes what published studies have investigated, not any human use.

Key facts

What exactly is MOTS-c, and is the vial real?

MOTS-c belongs to the cellular research pathway category, grouped here by its molecular origin and AMPK-linked signalling pharmacology rather than by any indication. The identity was cross-checked so that the compound name, CAS number and structural record all resolve to the same molecule before any identifiers appeared on a product page.

PubChem holds three records that researchers looking up MOTS-c are likely to encounter. The canonical one - CID 146675088 - carries the stereodefined L,L peptide sequence MRWQEMGYIFYPRKLR (16 residues), the molecular formula C101H152N28O22S2, an average molecular weight of 2174.6 g/mol, and CAS 1627580-64-6. The CAS resolves back to CID 146675088, anchoring name, registry number and structure to a single entity. Two related records also exist: a stereochemistry-unspecified variant (CID 155885767) and a separate connectivity record labelled MOTS-c Peptide (CID 176489569). Neither was used as the canonical identity here. If a database search returns CID 155885767 rather than 146675088, it has delivered a different chemical entity - the stereochemistry is not specified and the record should not be cited as if it were the same molecule. The formula C101H152N28O22S2 is internally consistent with a 16-mer carrying two methionine residues, which accounts for the two sulphur atoms (S2). Batch identity should always be confirmed against the supplied certificate of analysis.

How is MOTS-c thought to work?

Lee et al. (Cell Metabolism, 2015; PMID 25738459) identified the 12S rRNA short open reading frame and characterised the peptide in HEK293 and HeLa cell lines alongside C57BL/6 and ICR mouse models. The investigated endpoints were cellular flux through the folate-methionine one-carbon cycle and its tethered de novo purine biosynthesis pathway, with downstream activation of AMP-activated protein kinase (AMPK). The metabolic-homeostasis readouts were examined in mice under high-fat-diet and age-dependent conditions. That work established the AMPK-linked framing that the subsequent literature builds on; no human outcome arises from an in-vitro and rodent characterisation study.

A second mechanistic layer was added by Kim et al. (Cell Metabolism, 2018; PMID 29983246), who modelled metabolic stress by glucose restriction in HEK293 and HepG2 cell lines and observed that MOTS-c translocates to the nucleus in an AMPK-dependent manner. The endpoints were ARE-gene expression and interaction with the stress-responsive transcription factor NFE2L2/NRF2. The interest here lies in the framing: a peptide whose coding sequence sits in mitochondrial DNA travelling to the nuclear compartment in response to a metabolic cue is a reasonably striking observation about organellar communication, whatever the downstream biology turns out to mean. These are descriptions of what the studies investigated at the pathway level only.

What has the research actually looked at?

Each study below is indexed in PubMed and is described strictly by design and the names of the endpoints measured. None is cited for any effect, benefit or human outcome. These records are listed as research context only.

• Discovery and primary characterisation (in vitro and mouse). Lee et al. identified the 12S rRNA short open reading frame and characterised the peptide in cell lines and mouse models. Investigated endpoint names were cellular folate-cycle and de novo purine biosynthesis flux and AMPK activation, with metabolic-homeostasis readouts in mice under high-fat-diet and age-dependent conditions.
• Mitonuclear signalling (in vitro). Kim et al. examined nuclear translocation under glucose restriction in an AMPK-dependent manner; endpoint names were ARE-gene expression and NFE2L2/NRF2 interaction.
• Vascular-calcification model (rat). Wei et al. used a vitamin-D3 and nicotine-induced vascular-calcification Sprague-Dawley rat model. Endpoint names, read by Western blot, were phosphorylated-AMPK expression and angiotensin-II type-1 (AT-1) and endothelin-B (ET-B) receptor expression, alongside blood pressure, heart rate and echocardiographic measures. The disease-relevant model is cited for mechanistic context only; no effect of the compound is asserted.
• CK2-PTEN-mTORC2-AKT-FOXO1 pathway signalling (myotube and in vitro). Kumagai et al. used differentiated C2C12 myotubes and diet-induced obese mice, with a human plasma correlation analysis. Endpoint names were plasma myostatin level and CK2-PTEN-mTORC2-AKT-FOXO1 phosphorylation in differentiated myotubes following palmitic-acid exposure; study design only, no effect asserted.
• Adipose thermogenic signalling (mouse). Lu et al. used a cold-exposure mouse model. Endpoint names were serum MOTS-c level, brown-adipose-tissue and white-adipose-tissue gene-expression markers, and ERK-pathway phosphorylation; study design only, no effect asserted.
• Myocardial exercise-physiology model (rat). Yuan et al. used an exercise-trained rat model with pressure-volume conductance catheter measurement of cardiac systolic and diastolic function indices and myocardial mechanical efficiency. This is an animal physiology design; no human outcome is asserted.
• Human plasma measurement (observational). Ramanjaneya et al. (Clin Endocrinol, 2019; PMID 31066084) measured circulating endogenous MOTS-c in human plasma by ELISA under a hyperinsulinaemic-euglycaemic clamp combined with intralipid or saline infusion; the measured endpoint was plasma MOTS-c level (percentage of basal). The peptide was measured, not administered, making this an observational measurement design from which no treatment effect arises.
• Narrative review (molecular-pharmacology anchor). Zheng et al. (Front Endocrinol, 2023; PMID 36761202) is cited only to anchor the 16-amino-acid, 12S rRNA molecular-pharmacology grouping; it is not a source of any outcome claim.

How is MOTS-c handled in the laboratory?

MOTS-c is typically supplied as a lyophilised white powder in a sealed vial. Before opening, allow a refrigerated or frozen vial to reach room temperature so that atmospheric moisture does not condense onto the cold powder and cause clumping or a mass-reading error - a small step that pays for itself at the weighing stage. Reconstitution follows the same approach as other 16-mer research peptides: introduce an appropriate laboratory solvent down the inner glass wall rather than directly onto the powder and allow the solid to dissolve without vigorous agitation. The reconstituted solution is used within a defined working window for analysis; see the reconstitution guide for the general laboratory workflow. None of this is a preparation method for any use in humans or animals.

For longer-term storage, lyophilised peptide is kept desiccated, dark and frozen (around -20 C, or colder), with reconstituted solution held at 2-8 C and aliquoted where repeated access is needed to minimise freeze-thaw cycles. Solution stability should be confirmed per laboratory rather than assumed from published estimates.

The quality documentation worth verifying is a per-batch certificate of analysis confirming identity by mass spectrometry against the expected monoisotopic mass (approximately 2173.11, consistent with C101H152N28O22S2) and chromatographic purity by reversed-phase HPLC. Research-grade material is commonly specified at 98% purity or higher. Net peptide content, counter-ion or salt form (a trifluoroacetate salt form appears among the PubChem synonyms) and water content all affect the true mass of peptide per vial and are worth checking before any concentration calculation.

How strong is the evidence, really?

Worth being honest about the tiers. Tier one, the well-established part: MOTS-c is a real, endogenous 16-amino-acid mitochondrial-derived peptide encoded within the 12S rRNA region, with a stereodefined structure, formula C101H152N28O22S2 and a CAS number that resolve to a single PubChem entity - the chemistry is solid. Tier two, the middle ground: the AMPK-linked mechanism, nuclear translocation and the various pathway endpoints rest on in-vitro cell lines and rodent models, and a cell in a dish is not a person. Tier three, the weakest part: the single human study (Ramanjaneya et al., 2019) merely measured endogenous circulating peptide; nobody was administered MOTS-c, so interventional human evidence is effectively absent. It is not a licensed medicine, and it has not been shown to produce defined outcomes in humans. Curiosity is warranted; certainty is not.

Research use only

MOTS-c is supplied by Kovalabs strictly for laboratory research use. It is not a medicine, supplement or cosmetic, and it is not for human or veterinary use, administration or consumption. Nothing in this post constitutes medical, clinical or dosing advice, and no therapeutic or performance outcome is stated or implied. It has not been evaluated by the MHRA or any comparable regulator for safety or efficacy in humans or animals. Every batch is third-party tested with a certificate of analysis. Please read the full research disclaimer before purchase. For a mechanistically distinct compound studied on an overlapping cellular pathway, see NAD+.

Frequently asked questions

What is MOTS-c?

MOTS-c (mitochondrial open reading frame of the 12S rRNA-c) is a 16-amino-acid mitochondrial-derived peptide encoded by a short open reading frame within the mitochondrial 12S rRNA region. Its verified sequence is MRWQEMGYIFYPRKLR. It is supplied for research use only and is not for human or veterinary use.

What are the verified identifiers for MOTS-c?

PubChem CID 146675088, CAS 1627580-64-6, molecular formula C101H152N28O22S2 and average molecular weight 2174.6 g/mol (monoisotopic mass 2173.11). The name, CID and CAS were cross-checked to resolve to the same 16-amino-acid peptide. PubChem also holds related records at CID 155885767 (stereochemistry-unspecified) and CID 176489569 (connectivity record); neither is the canonical identity. Always confirm batch identity against the supplied certificate of analysis.

What signalling pathway has MOTS-c research characterised?

Published in-vitro and animal studies characterise MOTS-c as an AMP-activated protein kinase (AMPK) pathway-associated peptide. Reported mechanistic endpoints include AMPK activation, the folate-methionine one-carbon cycle, and AMPK-dependent nuclear translocation with association to antioxidant-response-element genes and NFE2L2/NRF2. These are pathway descriptions only; no effect is asserted.

Is there any human study of MOTS-c?

One PubMed-confirmed human study (Ramanjaneya et al., 2019; PMID 31066084) measured circulating endogenous MOTS-c in plasma by ELISA using a hyperinsulinaemic-euglycaemic clamp with intralipid or saline infusion. The peptide was measured rather than administered, making this an observational measurement design; the endpoint was plasma MOTS-c level. It is not an interventional efficacy study and no treatment outcome arises.

How is MOTS-c stored and reconstituted in the laboratory?

Lyophilised peptide is stored desiccated, dark and frozen (around -20 C) in sealed packaging, equilibrated to room temperature before opening, and reconstituted with an appropriate laboratory solvent run down the vial wall without vigorous agitation. Reconstituted solution is held at 2-8 C with minimal freeze-thaw cycles. These are laboratory-handling notes only, not administration or dosing guidance. See the reconstitution guide for the full workflow.

How does MOTS-c relate to humanin?

Both MOTS-c and humanin belong to the mitochondrial-derived peptide (MDP) class. Both arise from short open reading frames within the mitochondrial genome: humanin from the 16S rRNA region and MOTS-c from the 12S rRNA region. The grouping is by molecular origin and signalling pathway, not by any indication.

Sources

1. PubChem Compound CID 146675088 (MOTS-c; CAS 1627580-64-6; C101H152N28O22S2; 2174.6 g/mol)
2. Lee C, et al. Cell Metab. 2015;21(3):443-454. PMID 25738459. DOI 10.1016/j.cmet.2015.02.009 (in-vitro and mouse characterisation of the 12S rRNA peptide; folate-cycle, de novo purine biosynthesis and AMPK-activation endpoints; study design only)
3. Kim KH, et al. Cell Metab. 2018;28(3):516-524.e7. PMID 29983246. DOI 10.1016/j.cmet.2018.06.008 (in-vitro study; AMPK-dependent nuclear translocation under glucose restriction; ARE-gene expression and NFE2L2/NRF2 interaction endpoints; study design only)
4. Wei M, et al. Cardiorenal Med. 2019;10(1):42-50. PMID 31694019. DOI 10.1159/000503224 (vitamin-D3/nicotine vascular-calcification rat model; phosphorylated-AMPK, AT-1/ET-B receptor expression and cardiac-measure endpoints; disease-relevant model cited for mechanistic context only, no effect asserted)
5. Kumagai H, et al. Am J Physiol Endocrinol Metab. 2021;320(4):E680-E690. PMID 33554779. DOI 10.1152/ajpendo.00275.2020 (C2C12 myotube and mouse study; plasma myostatin and CK2-PTEN-mTORC2-AKT-FOXO1 phosphorylation endpoints; study design only, no effect asserted)
6. Lu H, et al. Int J Mol Sci. 2019;20(10):2456. PMID 31109005. DOI 10.3390/ijms20102456 (cold-exposure mouse model; serum MOTS-c, brown/white-adipose gene-expression and ERK-phosphorylation endpoints; study design only, no effect asserted)
7. Yuan J, et al. Sci Rep. 2021;11(1):20077. PMID 34635713. DOI 10.1038/s41598-021-99568-3 (exercise-trained rat model; pressure-volume conductance cardiac systolic/diastolic index endpoints; animal physiology study design only, no human outcome asserted)