MOTS-c Molecular Profile: Sequence, Structure, Molecular Weight & Mechanism

MOTS-c (Mitochondrial Open reading frame of the Twelve-S rRNA type-c) is a short bioactive peptide that is unusual for one structural reason: its coding sequence is written inside mitochondrial DNA rather than in the nuclear genome. It was first described by Lee C and colleagues in Cell Metabolism (2015), the paper that defined the peptide, its sequence, and its core mechanism. This page is a molecular profile: it documents the sequence, mass, encoding, and the molecular steps of its mechanism. For the research-evidence overview (insulin-sensitivity and exercise studies) and the side-by-side MOTS-c vs SS-31 comparison, see the MOTS-c Australia research guide →.

MOTS-c belongs to a small family of mitochondrial-derived peptides (MDPs). Structurally it is a linear, unmodified peptide of 16 amino acids with no disulfide bonds and no reported post-translational modification in its canonical form, which keeps the molecule comparatively simple to describe relative to larger, bridged peptides.

At a glance Sequence MRWQEMGYIFYPRKLR · 16 amino acids · average molecular weight ≈ 2174.6 Da · encoded in the mitochondrial 12S rRNA gene · linear peptide, no disulfide bonds.

The canonical MOTS-c sequence is MRWQEMGYIFYPRKLR, read N-terminus to C-terminus. Written in three-letter code: Met-Arg-Trp-Gln-Glu-Met-Gly-Tyr-Ile-Phe-Tyr-Pro-Arg-Lys-Leu-Arg.

Compositionally the peptide carries three arginine and one lysine residue, giving it a net positive charge at physiological pH. This basic, cationic character is consistent with its reported ability to interact with nucleic acids and to translocate into the nucleus (covered below). A proline at position 12 introduces a kink in the backbone, and the two methionine residues (positions 1 and 6) are the residues most susceptible to oxidation, which is relevant to handling and stability.

MOTS-c has an average molecular weight of approximately 2174.6 Da (≈ 2.17 kDa), derived from the sum of the 16 residue masses plus one water molecule for the free peptide. This figure is what should be used for any molarity or reconstitution calculation.

Why the exact mass matters Molar concentration depends on molecular weight. At ≈ 2174.6 Da, 1 mg of MOTS-c ≈ 0.46 µmol; a 10 mg vial therefore contains roughly 4.6 µmol of peptide. Use the measured/stated peptide content of your specific vial (net peptide vs gross/salt mass) for precise lab work.

A molecular formula of approximately C₁₀₁H₁₅₀N₂₈O₂₂S₂ is commonly cited for the free peptide; treat the formula as supplier-dependent and confirm against your certificate of analysis, since salt form (e.g. acetate/TFA) changes the gross mass without changing the peptide identity.

The defining structural fact about MOTS-c is where its gene sits. The coding sequence is embedded within the 12S ribosomal RNA (MT-RNR1) region of the mitochondrial genome, not in nuclear DNA. This was characterised in the original Lee et al. 2015 Cell Metabolism report.

Two consequences follow from this encoding, and both are molecular rather than clinical:

• An alternative open reading frame. MOTS-c is read from a short open reading frame nested inside a ribosomal-RNA gene, which is why it was not catalogued alongside conventional nuclear-encoded peptides for so long.
• Mitochondrial genetic code context. Because the reading frame lies in the mitochondrial genome, its discovery expanded the recognised set of bioactive mitochondrial-derived peptides (the family that also includes humanin and the SHLP series).

This encoding is the structural root of the "retrograde signalling" behaviour discussed next: a molecule made under mitochondrial control that ultimately acts in the nucleus.

MOTS-c does not act as a classical receptor agonist. Its characterised mechanism is intracellular and biochemical, operating through the one-carbon (folate) metabolic pathway. The molecular sequence reported in the founding literature is:

1. Folate-cycle interference. MOTS-c interferes with the one-carbon folate cycle at the de novo purine-synthesis branch, specifically affecting flux through methylenetetrahydrofolate-dependent steps.
2. AICAR accumulation. This interference causes the intermediate AICAR (5-aminoimidazole-4-carboxamide ribonucleotide) to accumulate upstream of the affected step.
3. ZMP forms and mimics AMP. AICAR is phosphorylated to ZMP (AICA-ribonucleotide monophosphate). ZMP is a structural analogue of AMP and binds the γ-subunit of AMP-activated protein kinase (AMPK) at the same allosteric nucleotide-binding site that AMP uses.
4. Allosteric AMPK activation. By occupying the AMP site, ZMP allosterically activates AMPK and protects the activating Thr172 phosphorylation from removal — switching AMPK on without an actual fall in cellular ATP.

The molecular distinction Exercise, metformin and ischaemia activate AMPK by genuinely lowering the ATP:AMP ratio. MOTS-c instead generates an AMP-mimetic (ZMP) through folate-cycle disruption, so AMPK is activated by a metabolite that looks like AMP rather than by true energy depletion. That upstream difference is the core of MOTS-c's molecular identity.

Once AMPK is active, downstream phosphorylation events (ACC, GLUT4 trafficking, PGC-1α, TSC2/mTORC1) follow standard AMPK biology. Those downstream metabolic and exercise-physiology outcomes, and the studies behind them, are covered in the research guide →; this profile stops at the molecular trigger.

Beyond AMPK activation in the cytosol, MOTS-c has a second molecular behaviour that depends directly on its structure: under metabolic stress it moves from the cytosol into the nucleus, where it associates with stress-responsive transcription-factor programmes and influences the expression of antioxidant and metabolic genes.

This translocation is consistent with the peptide's basic, cationic sequence (the arginine/lysine content noted above), which supports interaction with negatively charged nucleic acids. The result is "retrograde" communication — a peptide encoded by the mitochondrial genome ultimately modulating nuclear gene expression. Importantly, MOTS-c has no single well-defined cell-surface receptor; its targets are intracellular (the folate-cycle enzymes/metabolites, AMPK, and nuclear transcriptional machinery) rather than a membrane receptor. For research framing this is a key point: do not describe MOTS-c as a receptor agonist.

Honest statement of the evidence: robust human pharmacokinetic data for exogenous MOTS-c is limited. Endogenous MOTS-c is detectable in human plasma and circulating levels fall with age and rise transiently with exercise (an observation from the exercise/ageing literature), but published, well-characterised half-life, clearance and bioavailability parameters for administered research-grade MOTS-c are not established. Any specific numeric half-life should be treated as unverified.

What can be stated on structural grounds:

• Small, linear peptide. As an unbridged 16-mer with no stabilising disulfide bonds, MOTS-c is expected to be susceptible to peptidase activity in the way short linear peptides generally are; this is a structural inference, not a measured PK value.
• Oxidation-sensitive residues. The two methionine residues and the tryptophan are the most oxidation-prone positions, which is the main chemical-stability consideration for handling and storage.
• Lyophilised stability. Supplied as a lyophilised powder, MOTS-c is stable frozen for extended periods; once reconstituted it should be refrigerated and protected from repeated freeze–thaw and light. Follow your vial's certificate of analysis and the general peptide reconstitution & storage guide →.

Limited PK data Where this profile cannot cite a verified value (e.g. a precise serum half-life for administered MOTS-c), it deliberately says so rather than inventing a number.

Reconstitution is governed by the molecular weight and the vial content. This section gives the math for a 10 mg MOTS-c vial; for the general step-by-step procedure (drawing bacteriostatic water, swirling, storage), defer to the peptide reconstitution & storage guide →.

The relationship is simply: concentration = vial mass ÷ solvent volume. For a 10 mg vial:

Converting mass to moles (where the molecular weight matters): at ≈ 2174.6 Da, 10 mg of MOTS-c ≈ 4.6 µmol. Reconstituted in 1 mL that is a ≈ 4.6 mM solution; in 2 mL, ≈ 2.3 mM. Use these molar figures when a protocol specifies concentration in molarity rather than mg/mL. Always base calculations on the net peptide content stated on your certificate of analysis, not the gross vial mass, because counter-ion salt adds mass without adding peptide.

Calculate any target concentration for any vial size with the OzPeps reconstitution calculator →.

What is the amino-acid sequence of MOTS-c?

MOTS-c is a 16-amino-acid peptide with the sequence MRWQEMGYIFYPRKLR (Met-Arg-Trp-Gln-Glu-Met-Gly-Tyr-Ile-Phe-Tyr-Pro-Arg-Lys-Leu-Arg). It is linear with no disulfide bonds.

What is the molecular weight of MOTS-c?

Approximately 2174.6 Da (about 2.17 kDa) for the free peptide. At that mass, 1 mg is roughly 0.46 µmol and a 10 mg vial about 4.6 µmol.

Where is MOTS-c encoded?

Within the 12S ribosomal RNA gene (MT-RNR1) of mitochondrial DNA, not the nuclear genome — which makes it a mitochondrial-derived peptide (MDP).

How does MOTS-c work at the molecular level?

It interferes with the one-carbon folate cycle, causing AICAR to accumulate. AICAR is converted to ZMP, an AMP analogue that allosterically activates AMPK without an actual drop in cellular ATP. MOTS-c can also translocate to the nucleus to influence gene expression.

What is the half-life of MOTS-c?

Well-characterised human pharmacokinetic data for administered MOTS-c, including a verified half-life, is limited. Endogenous plasma MOTS-c declines with age, but a specific, reliable half-life value for exogenous research-grade peptide is not established — so this profile does not quote one.

Does MOTS-c bind a cell-surface receptor?

No single well-defined membrane receptor has been established. Its molecular targets are intracellular: the folate-cycle pathway, AMPK, and nuclear transcriptional machinery. It is best described as an intracellular signalling peptide rather than a receptor agonist.

This molecular profile is a scientific reference for laboratory researchers. MOTS-c is supplied strictly for in-vitro research use only. It is research-grade material, NOT FOR HUMAN CONSUMPTION, not for animal use, and not TGA-approved. Nothing here is medical advice, a dosing recommendation, or a therapeutic claim; concentration figures describe handling of research material, not a human dose. Order research-grade MOTS-c 10mg → or read the full MOTS-c research guide →.