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MOTS-c
Research Compound Reference | Orion Peptides Learning Library
MOTS-c is a 16-amino-acid peptide encoded by a short open reading frame within mitochondrial DNA. Its name stands for mitochondrial open reading frame of the 12S rRNA-c.
The peptide belongs to a class of molecules known as mitochondrial-derived peptides (MDPs). These peptides are encoded by regions of the mitochondrial genome and have been investigated for their roles in communication between cellular compartments.
MOTS-c has the amino acid sequence MRWQEMGYIFYPRKLR and the molecular formula C₁₀₁H₁₅₂N₂₈O₂₂S₂.
Unlike synthetic analogs containing lipid conjugates or engineered disulfide bridges, the standard MOTS-c reference structure consists of an unmodified linear peptide backbone with free terminal groups.
Experimental research has investigated the relationship between MOTS-c, mitochondrial signaling, AMP-activated protein kinase (AMPK), and nuclear gene regulation.
This technical guide examines the peptide’s molecular origin, sequence chemistry, cellular research findings, physicochemical characteristics, and methods used to establish its analytical identity.
1. MOTS-c Molecular Reference
| Property | Technical information |
|---|---|
| Compound name | MOTS-c |
| Full designation | Mitochondrial open reading frame of the 12S rRNA-c |
| CAS number | 1627580-64-6 |
| PubChem CID | 146675088 |
| Molecular formula | C₁₀₁H₁₅₂N₂₈O₂₂S₂ |
| Average molecular weight | Approximately 2,174.6 g/mol |
| Monoisotopic neutral mass | Approximately 2,173.1077 Da |
| Amino acid count | 16 |
| Peptide sequence | MRWQEMGYIFYPRKLR |
| Three-letter sequence | Met-Arg-Trp-Gln-Glu-Met-Gly-Tyr-Ile-Phe-Tyr-Pro-Arg-Lys-Leu-Arg |
| Molecular structure | Linear peptide |
| N-terminal group | Free amino group |
| C-terminal group | Free carboxylic acid |
| Cysteine residues | None |
| Disulfide bonds | None |
| Sulfur-containing residues | Two methionines |
| Genetic origin | Mitochondrial MT-RNR1 region |
| Research classification | Mitochondrial-derived peptide |
| Major investigated pathways | AMPK-associated signaling and nuclear stress responses |
The values describe the defined free-peptide structure. Counterions and other substances associated with a particular synthetic preparation must be described separately.
2. Why Is MOTS-c Called a Mitochondrial-Derived Peptide?
Mitochondria are cellular organelles containing their own genetic material.
The mitochondrial genome encodes a small set of proteins and RNAs involved in mitochondrial function.
Most mitochondrial proteins are encoded by nuclear DNA, but the mitochondrial genome also contains regions capable of producing smaller peptides.
MOTS-c belongs to this group.
Where Is MOTS-c Encoded?
MOTS-c originates from a short open reading frame associated with the mitochondrial 12S ribosomal RNA gene, MT-RNR1.
An open reading frame, or ORF, is a nucleotide sequence that can potentially be translated into a peptide.
Short open reading frames are commonly abbreviated sORFs.
The MOTS-c sequence was identified through research investigating previously unrecognized coding potential within mitochondrial genetic regions.
How Is a Short Open Reading Frame Different from a Conventional Gene?
Conventional protein-coding genes often contain long nucleotide sequences.
A short open reading frame encodes a much smaller peptide.
The MOTS-c open reading frame corresponds to a 16-residue peptide.
Its discovery provided an example of how genomic regions primarily associated with RNA function may also contain peptide-coding information.
Does MOTS-c Have the Same Structure as a Mitochondrial Protein?
No.
MOTS-c is a short peptide.
It is not a multi-subunit mitochondrial enzyme or a conventional large structural protein.
Its small molecular size and specific amino acid sequence distinguish it from the major proteins involved in mitochondrial respiratory complexes.
3. From a Nucleotide Sequence to a 16-Residue Peptide
The genetic origin of MOTS-c is one of its most interesting scientific characteristics.
Peptide synthesis in biological systems depends on the translation of nucleotide codons into amino acids.
Most of the genome follows the standard genetic code, but mitochondria can use a modified genetic code.
What Is the Mitochondrial Genetic Code?
A genetic code establishes which amino acids correspond to particular nucleotide triplets.
Different biological systems may interpret some codons differently.
Mitochondrial genetic codes contain several differences from the standard nuclear genetic code.
This creates important questions when interpreting short open reading frames embedded within mitochondrial DNA.
Why Does This Matter for MOTS-c?
The MOTS-c sequence is associated with a region of the mitochondrial genome that includes codon-interpretation considerations.
Researchers have discussed the possibility that MOTS-c RNA is translated outside the mitochondrion using the standard genetic code.
However, the precise biological processes responsible for endogenous MOTS-c synthesis and localization remain areas of investigation.
Genetic Origin vs Synthetic Research Material
Naturally encoded MOTS-c and laboratory-synthesized MOTS-c may have the same defined amino acid sequence.
However, their sources are different.
A synthetic reference peptide is produced through chemical synthesis.
Its identity should be established from the resulting material rather than assumed from the nucleotide sequence.
4. Reading the MOTS-c Amino Acid Sequence
MOTS-c contains 16 amino acid residues arranged in a linear chain.
The sequence is:
MRWQEMGYIFYPRKLR
In three-letter notation:
Met-Arg-Trp-Gln-Glu-Met-Gly-Tyr-Ile-Phe-Tyr-Pro-Arg-Lys-Leu-Arg
The complete free-peptide structure may be represented as:
H-Met-Arg-Trp-Gln-Glu-Met-Gly-Tyr-Ile-Phe-Tyr-Pro-Arg-Lys-Leu-Arg-OH
Amino Acid Composition
| Amino acid | Symbol | Number of residues |
|---|---|---|
| Methionine | M | 2 |
| Arginine | R | 3 |
| Tryptophan | W | 1 |
| Glutamine | Q | 1 |
| Glutamic acid | E | 1 |
| Glycine | G | 1 |
| Tyrosine | Y | 2 |
| Isoleucine | I | 1 |
| Phenylalanine | F | 1 |
| Proline | P | 1 |
| Lysine | K | 1 |
| Leucine | L | 1 |
| Total | 16 |
The sequence contains several chemically distinct residue types.
This makes its physicochemical behavior different from peptides composed mainly of one class of amino acids.
5. Three Structural Regions Worth Examining
MOTS-c has no engineered lipid conjugate or disulfide bridge.
Its distinctive chemical properties arise from the arrangement of its natural amino acid residues.
Three regions are particularly relevant.
The Methionine-Containing Region
MOTS-c contains methionine at positions 1 and 6.
Methionine has a sulfur-containing thioether side chain.
This group can undergo oxidation under suitable conditions.
Oxidation may produce methionine sulfoxide or related species.
The two methionine residues therefore represent potential sites for oxidation-related analytical investigation.
The Aromatic Central Region
Residues 8–11 form the sequence:
YIFY
This region contains tyrosine, isoleucine, phenylalanine, and tyrosine.
Three of these residues have aromatic side chains.
Aromatic amino acids contribute to the ultraviolet absorption properties and hydrophobic interactions of peptides.
Published cellular research has also used substitutions in this region to examine MOTS-c localization.
The Basic C-Terminal Region
The final four residues are:
RKLR
This region contains two arginine residues and one lysine residue.
The side chains of arginine and lysine can carry positive charges under many experimental conditions.
Consequently, the C-terminal region contributes strongly to the peptide’s charge-related behavior.
The RKLR sequence has also been examined in experiments involving MOTS-c localization and sequence-function relationships.
6. MOTS-c and Cellular Compartment Signaling
MOTS-c attracted scientific interest because researchers found that a peptide encoded by mitochondrial DNA could participate in communication with other parts of the cell.
One important area of investigation is the relationship between mitochondria and the nucleus.
What Is Mitochondrial-to-Nuclear Communication?
Mitochondria and the nucleus contain separate genetic systems.
Their activities must be coordinated.
Cellular signaling mechanisms allow changes in mitochondrial conditions to influence nuclear gene regulation.
This process is broadly associated with mitochondrial retrograde signaling.
What Did the 2018 Study Report?
Kim and colleagues published research examining the localization of MOTS-c under cellular stress conditions.
The investigators reported that MOTS-c could move into the nucleus in selected experimental cell systems.
The process was associated with AMPK-dependent signaling.
These findings suggested a possible relationship between mitochondrial peptide signaling and nuclear gene regulation.
How Did Researchers Examine Localization?
The study used techniques including immunofluorescence microscopy and subcellular fractionation.
Immunofluorescence allows researchers to investigate the distribution of a target molecule within cells.
Subcellular fractionation separates cellular compartments for further analysis.
Combining these methods can provide complementary evidence about molecular localization.
7. AMPK Signaling and MOTS-c Research
AMPK stands for AMP-activated protein kinase.
It is a protein kinase associated with cellular energy-sensing pathways.
AMPK activity can change in response to differences in cellular energy conditions.
What Is a Protein Kinase?
A protein kinase is an enzyme that transfers phosphate groups to target molecules.
Phosphorylation can influence protein activity, interactions, and cellular signaling.
AMPK participates in complex signaling networks that respond to cellular energy conditions.
How Is MOTS-c Connected to AMPK?
The original 2015 research associated MOTS-c with changes in cellular pathways involving folate metabolism, purine-related metabolites, and AMPK activation.
Later research investigated AMPK-dependent nuclear localization of MOTS-c.
These findings suggest interactions between MOTS-c-associated cellular responses and energy-sensing pathways.
However, they should not be interpreted as proof that MOTS-c directly binds to AMPK.
Direct Binding vs Indirect Signaling
This distinction is important.
A molecule can influence a signaling pathway without directly binding to the central protein in that pathway.
For MOTS-c, several reported findings involve downstream cellular responses.
Its complete primary molecular target has not been conclusively established.
What Can Laboratory Assays Measure?
Researchers can assess phosphorylation states, protein localization, reporter activity, and changes in gene expression.
Each measurement describes a particular part of the experimental response.
A change in one marker does not independently establish the full mechanism of action.
8. Nuclear Localization and Sequence-Function Experiments
The 2018 MOTS-c study also explored whether specific amino acid regions contribute to cellular localization.
Researchers modified selected regions of the peptide and examined their behavior in experimental systems.
The YIFY Region
One experimental approach involved replacing residues 8–11 with alanine.
This produced a sequence variant used to investigate the contribution of the YIFY region.
The RKLR Region
A separate experimental variant replaced the C-terminal RKLR region with alanine residues.
This allowed investigators to examine the relationship between the basic C-terminal sequence and molecular localization.
Why Are Alanine Substitutions Used?
Alanine substitution is a common method in structure-function research.
By replacing selected residues with alanine, researchers can investigate whether the original side chains contribute to a particular experimental outcome.
However, a change in activity following mutation does not necessarily identify a direct binding site.
It may also reflect changes in molecular structure, charge, stability, or interactions with other cellular components.
9. MOTS-c Molecular Mass and Chemical Composition
The reference MOTS-c molecule contains:
C₁₀₁H₁₅₂N₂₈O₂₂S₂
Its average molecular weight is approximately:
2,174.6 g/mol
Its monoisotopic neutral mass is approximately:
2,173.1077 Da
These values describe different mass conventions.
Average Molecular Weight
Average molecular weight uses the natural isotopic abundance of each element.
This value is commonly used in compound reference tables.
Monoisotopic Mass
Monoisotopic mass uses specified isotopes to calculate an exact molecular mass.
It is relevant to high-resolution mass spectrometry.
Why Does Sulfur Matter?
MOTS-c contains two sulfur atoms from its methionine residues.
Sulfur contributes to the molecular formula and isotopic distribution.
Its presence may be relevant when interpreting high-resolution mass spectra.
Does the Peptide Contain Disulfide Bonds?
No.
Although MOTS-c contains sulfur, its sulfur atoms occur in methionine rather than cysteine residues.
The reference sequence contains no cysteine.
Therefore, it does not contain a conventional cysteine-to-cysteine disulfide bridge.
10. Analytical Identification of MOTS-c
A synthetic MOTS-c research material should be evaluated against the expected properties of the defined 16-residue peptide.
Several techniques can contribute to characterization.
Reversed-Phase HPLC
Reversed-phase high-performance liquid chromatography separates sample components according to their interactions with a stationary phase and mobile phase.
MOTS-c contains both polar and hydrophobic residues.
Its chromatographic behavior depends on the analytical conditions.
A suitable method can provide information about the principal peptide peak and certain related impurities.
Mass Spectrometry
Mass spectrometry measures the mass-to-charge ratios of ionized molecular species.
For MOTS-c, a result consistent with the reference molecular mass supports chemical identification.
However, a matching intact mass does not uniquely establish the complete sequence.
Tandem Mass Spectrometry
Tandem mass spectrometry examines fragments generated from a selected molecular ion.
Fragmentation patterns may support peptide sequence identification.
This can be especially valuable when investigating sequence variants or degradation compounds.
Oxidation-Related Analysis
Because MOTS-c contains two methionine residues, oxidation-related species are relevant analytical considerations.
Methionine oxidation to sulfoxide introduces an oxygen atom and produces an increase of approximately 16 Da in molecular mass.
Appropriate analytical methods can help distinguish such species from the unmodified peptide.
Analytical Overview
| Method | Main information provided |
|---|---|
| RP-HPLC | Chromatographic separation and purity |
| ESI-MS | Molecular mass-to-charge information |
| High-resolution MS | Accurate-mass evidence |
| LC-MS/MS | Additional sequence and fragment identification |
| Oxidation analysis | Characterization of selected modified species |
| Peptide content assay | Quantitative content under a specified method |
| Stability-indicating analysis | Changes in molecular composition over time |
These tests describe separate analytical characteristics and should not be treated as interchangeable.
11. Physical Chemistry and Stability Considerations
MOTS-c contains charged, polar, aromatic, and sulfur-bearing amino acid residues.
Its chemical behavior depends on the complete sequence and experimental conditions.
Influence of pH
The peptide contains basic residues such as arginine and lysine, along with acidic functional groups.
Their protonation states depend on solution pH.
Changes in pH can affect charge distribution and molecular interactions.
Hydrophobic and Aromatic Regions
Tryptophan, tyrosine, phenylalanine, isoleucine, leucine, and methionine contribute to the peptide’s interactions with relatively nonpolar environments.
These characteristics may influence chromatography, surface adsorption, and molecular association.
Methionine Oxidation
Methionine residues are potential oxidation sites.
The formation of oxidized species can change molecular mass and other chemical properties.
Oxidation behavior must be evaluated under actual test conditions.
Peptide Backbone Hydrolysis
Under suitable conditions, peptide bonds can undergo hydrolysis.
This may produce shorter peptides with different molecular masses and chromatographic characteristics.
Lyophilized vs Solution-State Material
Lyophilization removes water and may improve the stability of certain peptide preparations.
However, it does not guarantee a specific shelf life.
In solution, chemical changes may occur at rates different from those in dry material.
Validated stability information should correspond to the exact material and conditions studied.
12. What a MOTS-c Certificate of Analysis Should Demonstrate
A Certificate of Analysis provides analytical findings associated with an identified sample or batch.
For MOTS-c, important considerations include molecular identity, purity, and the possibility of oxidation-related variants.
| COA information | Research significance |
|---|---|
| Compound name | Identifies MOTS-c |
| Peptide sequence | MRWQEMGYIFYPRKLR |
| CAS number | Chemical reference identifier |
| Batch number | Links results to a specific material |
| Expected molecular mass | Reference for mass spectrometry |
| Observed mass result | Supports mass-related identity |
| HPLC chromatogram | Shows chromatographic separation |
| HPLC purity | Reports a method-dependent purity value |
| Oxidation-related findings | Identifies relevant chemical modifications, if tested |
| Peptide content | Measures quantitative material content, if tested |
| Counterion content | Describes associated counterions, where determined |
| Water content | Reports moisture, if tested |
| Analytical date | Establishes testing timing |
| Laboratory identification | Identifies the testing organization |
What Does 99% HPLC Purity Mean?
A reported HPLC purity percentage typically represents a chromatographic calculation under specified analytical conditions.
It is not automatically equivalent to the total mass percentage of the intended peptide.
Water, counterions, and undetected substances may affect the overall material composition.
Why Is MS Useful Alongside HPLC?
HPLC provides separation-related information.
Mass spectrometry provides molecular mass-related information.
The two techniques address different analytical questions and can complement one another.
Does a COA Establish Cellular Activity?
Not unless a suitable functional assay has been performed and documented.
Chemical identity and biological activity are different properties.
13. MOTS-c and Other Mitochondrial-Derived Peptides
MOTS-c belongs to a broader group of mitochondrial-derived peptides.
Two related research subjects are Humanin and SHLP peptides.
MOTS-c vs Humanin
Humanin is another mitochondrial-derived peptide identified in research involving small open reading frames.
It differs from MOTS-c in sequence and genomic origin.
The two peptides should not be treated as chemically interchangeable.
MOTS-c vs SHLPs
SHLP stands for small humanin-like peptide.
These peptides have their own sequences and are investigated as separate mitochondrial-derived signaling molecules.
Although they belong to a similar broad research category, they are not identical to MOTS-c.
What About SS-31?
SS-31, also known as Elamipretide, is a synthetic tetrapeptide investigated for its interactions with mitochondrial membranes.
It is not a mitochondrial genome-encoded peptide.
Therefore, SS-31 and MOTS-c represent different molecular categories despite both being associated with mitochondrial research.
| Feature | MOTS-c | Humanin | SS-31 |
|---|---|---|---|
| Peptide origin | Mitochondrial genome-encoded | Mitochondrial genome-associated | Synthetic |
| Peptide length | 16 residues | Commonly 24 residues | 4 residues |
| Primary research distinction | Mitochondrial-to-nuclear signaling | Mitochondrial-derived peptide signaling | Membrane and cardiolipin-related interactions |
| Same molecular sequence? | No | No | No |
14. Frequently Asked Technical Questions About MOTS-c
What is MOTS-c?
MOTS-c is a 16-residue mitochondrial-derived peptide encoded by a short open reading frame associated with mitochondrial 12S rRNA.
What does MOTS-c stand for?
Mitochondrial open reading frame of the 12S rRNA-c.
How many amino acids are in MOTS-c?
Sixteen.
What is the MOTS-c sequence?
MRWQEMGYIFYPRKLR.
What is its molecular formula?
C₁₀₁H₁₅₂N₂₈O₂₂S₂.
What is the molecular weight of MOTS-c?
Approximately 2,174.6 g/mol.
What is the monoisotopic mass?
Approximately 2,173.1077 Da.
What is the CAS number?
1627580-64-6.
What is the PubChem CID?
Is MOTS-c a linear peptide?
Yes. The reference structure contains a linear peptide backbone.
Does MOTS-c contain a disulfide bridge?
No. It contains no cysteine residues.
Why does MOTS-c contain sulfur?
The sequence contains two methionine residues, each containing sulfur.
Where is MOTS-c encoded?
Within a short open reading frame associated with the mitochondrial MT-RNR1 region.
Is MOTS-c the same as Humanin?
No. They are different mitochondrial-derived peptides.
Is MOTS-c the same as SS-31?
No. SS-31 is a synthetic tetrapeptide, while MOTS-c is encoded by mitochondrial DNA.
What is AMPK?
AMPK is an energy-sensing protein kinase involved in cellular signaling.
Does MOTS-c directly bind AMPK?
Direct AMPK binding has not been conclusively established as MOTS-c’s primary molecular mechanism.
What is nuclear translocation?
It is the movement of a molecule into the cell nucleus.
Has MOTS-c nuclear localization been studied?
Yes. A 2018 study investigated AMPK-associated movement of MOTS-c into the nucleus under experimental stress conditions.
Can MOTS-c undergo oxidation?
Yes. Methionine residues are potential sites for oxidation-related chemical changes.
Can HPLC determine MOTS-c purity?
HPLC can provide chromatographic purity information under defined analytical conditions.
Can mass spectrometry verify MOTS-c?
Mass spectrometry can provide molecular mass evidence consistent with the expected peptide structure.
Is 99% HPLC purity the same as 99% peptide content?
No. They represent different analytical measurements.
What is a MOTS-c Certificate of Analysis?
A COA records specified tests and analytical results associated with a particular batch or sample.
Is MOTS-c FDA-approved?
No. MOTS-c is not an FDA-approved drug substance.
15. Scientific References
1. Original MOTS-c Discovery
Lee C. et al. (2015)
The Mitochondrial-Derived Peptide MOTS-c Promotes Metabolic Homeostasis and Reduces Obesity and Insulin Resistance.
Journal: Cell Metabolism, 21(3), 443–454.
Technical relevance: Discovery of MOTS-c, mitochondrial short open reading frames, molecular origin, and cellular pathway experiments.
https://doi.org/10.1016/j.cmet.2015.02.009
2. MOTS-c and Nuclear Localization
Kim K.H. et al. (2018)
The Mitochondrial-Encoded Peptide MOTS-c Translocates to the Nucleus to Regulate Nuclear Gene Expression in Response to Metabolic Stress.
Journal: Cell Metabolism, 28(3), 516–524.e7.
Technical relevance: Subcellular localization, AMPK-associated signaling, sequence-variant experiments, and mitochondrial-to-nuclear communication.
https://doi.org/10.1016/j.cmet.2018.06.008
3. Chemical Structure and Identifiers
PubChem: MOTS-c, CID 146675088
Reference information: Amino acid sequence, CAS number, molecular formula, molecular weight, and chemical structure.
4. Mitochondrial-Derived Peptide Research
Mitochondrial-Derived Peptides: A Review of Their Biological Research
Reference topic: Mitochondrial short open reading frames, mitochondrial peptide signaling, and cellular communication pathways.
Searchable scientific literature:
5. Analytical Research Literature
MOTS-c Peptide Characterization and Mass Spectrometry
Reference topic: Molecular identification, peptide-specific mass spectrometry, and chemical characterization methods.
Conclusion
MOTS-c is a 16-residue mitochondrial-derived peptide with a defined linear amino acid sequence and a molecular weight of approximately 2,174.6 g/mol.
Its most distinctive scientific characteristic is its association with a short open reading frame in mitochondrial DNA.
The molecule contains two methionine residues, several basic amino acids, and an aromatic-rich central sequence.
These structural features influence chemical behavior and provide relevant targets for analytical characterization.
Published laboratory studies have investigated relationships between MOTS-c, AMPK-associated signaling, nuclear localization, and cellular gene regulation.
However, its complete molecular mechanism remains an area of research, and direct biochemical interactions should be distinguished from downstream cellular responses.
For accurate characterization, peptide sequence, theoretical mass, chromatographic purity, measured content, and chemical stability should be considered separate attributes.
Technical research notice: This article provides scientific information about peptide chemistry, mitochondrial genetics, cell-based experimental research, and analytical characterization. It does not include dosing, reconstitution, administration, or personal-use instructions. MOTS-c is not FDA-approved, and chemical testing does not establish the suitability of separately supplied research material for human or veterinary use.
