How many mitochondrial-derived peptides are known?

Eight are well described: humanin, MOTS-c and SHLP1 through SHLP6. Whether others exist in unannotated reading frames is an open question.

Why were they not found earlier?

Their reading frames overlap the rRNA genes, which were already annotated. Nobody was looking for protein-coding sequence inside a ribosomal RNA gene.

Are they made in the mitochondrion or the cytosol?

This is still debated and may differ between peptides. Both mitochondrial and cytosolic translation have been proposed, depending on the transcript involved.

MOTS-c (Mitochondrial Peptide)

What Is a Mitochondrial-Derived Peptide?

JMWritten & reviewed by Jack Muncaster · Founder, UK PeptidesLast reviewed 2026-08-233 cited sources

Mitochondrial-derived peptides are short peptides encoded by open reading frames within the mitochondrial genome rather than nuclear DNA. The known members include humanin, MOTS-c and the six small humanin-like peptides. Their existence means mitochondria transmit signals to the rest of the cell, not just produce energy.

Key facts

Known members: Humanin, MOTS-c, SHLP1–6
Encoded in: Mitochondrial DNA (mtDNA)
Humanin location: 16S rRNA gene
MOTS-c location: 12S rRNA gene
Humanin identified: 2001
MOTS-c identified: 2015
Mitochondrial genome size: 16,569 base pairs, 37 genes

Why nobody expected them

The human mitochondrial genome is small — 16,569 base pairs encoding 37 genes — and was considered thoroughly characterised by the 1980s. Its content was taken to be 13 respiratory-chain proteins, 22 transfer RNAs and 2 ribosomal RNAs, and nothing else. Mitochondrial-derived peptides were missed because their open reading frames sit inside the rRNA genes, overlapping sequence already annotated as doing something else.

Humanin came first

Humanin was identified in 2001 from the surviving neurons of an Alzheimer's disease brain, encoded within the 16S rRNA gene. It was the first demonstration that the mitochondrial genome encoded anything beyond the classical 37 genes, and it established the category that MOTS-c later joined.

Research material referenced

MOTS-C 10mg — third-party HPLC tested

View — £24.99

MOTS-c and the SHLPs

MOTS-c was identified in 2015 within the 12S rRNA gene. The six small humanin-like peptides, SHLP1 through SHLP6, were described around the same period, all encoded within the 16S rRNA gene near humanin. Each has a distinct reported profile, and the group as a whole remains far less studied than the two named peptides.

Why the origin actually matters

It reframes what a mitochondrion is. If the organelle encodes and releases peptides that act on the nucleus and on distant tissues, then it is a signalling hub reporting on its own state, not simply a supplier of ATP. MOTS-c translocating to the nucleus to regulate nuclear gene expression under metabolic stress is the clearest demonstration of that, and it establishes communication running from the mitochondrial genome back to the nuclear one.

A note on interpreting this literature

Mitochondrial-derived peptides sit at an intersection of ageing biology, metabolism and mitochondrial genetics, which attracts more speculation than most fields. The published work is overwhelmingly preclinical. Human data is largely observational — measuring circulating concentrations and correlating them with age or condition — and correlation in that setting does not establish what administration would do.

Extended research context

The MOTS-c (Mitochondrial Peptide) deep dive

Deep dive: why a peptide encoded in mitochondrial DNA is unusual

The human mitochondrial genome is 16,569 base pairs encoding 37 genes, and was considered fully characterised by the 1980s: thirteen respiratory-chain proteins, twenty-two transfer RNAs, two ribosomal RNAs. MOTS-c is encoded by a short open reading frame nested inside the 12S rRNA gene — sequence already annotated as doing something else, which is exactly why it went unnoticed. Humanin, found in 2001 inside the 16S rRNA gene, established that the genome held more than its annotation suggested; MOTS-c was found in 2015 by looking deliberately. The implication is that the mitochondrion encodes and releases signalling molecules of its own, rather than only executing instructions sent from the nucleus.

Deep dive: AMPK activation without touching AMPK

AMPK is normally activated when AMP and ADP bind its gamma subunit, making it a direct sensor of the AMP-to-ATP ratio. MOTS-c does not raise that ratio and does not bind the kinase. It inhibits the folate cycle, the one-carbon pathway feeding de novo purine biosynthesis, and the intermediate AICAR accumulates as a result. AICAR is an AMP mimetic — phosphorylated to ZMP, it binds the same regulatory site AMP occupies. So the peptide reaches a cytosolic energy sensor through one-carbon metabolism and a diffusible small molecule, which is a materially different architecture from a receptor-ligand interaction, and different again from metformin's inhibition of complex I.

Deep dive: reading a preclinical literature honestly

Roughly 250 indexed papers exist, and the overwhelming majority are cell and rodent studies. Where humans appear, the work is generally observational: measuring circulating concentrations and correlating them with age, fitness or metabolic state. The 2021 Nature Communications paper is the clearest example of the structure — the human arm measured MOTS-c before and after exercise, finding roughly a 12-fold rise in skeletal muscle against 1.6-fold in circulation, while the interventional work was done in mice. Two inferences the secondary literature routinely makes and the primary literature does not support: that a correlation between low concentrations and poor metabolic health establishes direction, and that a molecule which rises during exercise would reproduce exercise if administered.

Research applications

▸Study of mitochondrial-derived peptides and retrograde signalling
▸AMPK pathway research through non-canonical activation
▸One-carbon and folate-cycle metabolism models
▸Exercise physiology and mitochondrial bioenergetics research
▸Ageing biology and mitochondrial genome expression studies

Handling checklist

✓Store lyophilised material cold, dry and protected from light
✓Expect methionine oxidation as the primary degradation route (+16 Da per residue)
✓No reducing agent needed — the sequence contains no cysteine
✓Introduce diluent gently against the vial wall; swirl rather than shake
✓Aliquot to avoid repeated freeze-thaw cycles
✓Check mass spectrometry for +16 and +32 satellites before relying on a batch

Common research-handling mistakes

Learnt from thousands of researcher orders across our UK labs.

✗ Reading exercise induction as proof that administration mimics exercise

Fix: The papers report that exercise raises MOTS-c. The reverse inference is not supported and is not claimed.

✗ Treating human observational data as interventional evidence

Fix: Human work measures endogenous concentrations; administration studies were conducted in mice.

✗ Assuming MOTS-c has a cell-surface receptor like humanin

Fix: No receptor is established. Its characterised activity is intracellular.

✗ Storing reconstituted material as though it were as stable as the powder

Fix: Solution-phase material is subject to hydrolysis and oxidation; the lyophilised form is far more stable.

✗ Overlooking WADA status in athlete-adjacent research

Fix: MOTS-c is on the prohibited list; this is relevant to any research context involving competitors.

Continue researching

Peer-reviewed guides, comparators and matched reference materials.

Frequently asked questions

How many mitochondrial-derived peptides are known?: Eight are well described: humanin, MOTS-c and SHLP1 through SHLP6. Whether others exist in unannotated reading frames is an open question.
Why were they not found earlier?: Their reading frames overlap the rRNA genes, which were already annotated. Nobody was looking for protein-coding sequence inside a ribosomal RNA gene.
Are they made in the mitochondrion or the cytosol?: This is still debated and may differ between peptides. Both mitochondrial and cytosolic translation have been proposed, depending on the transcript involved.

Primary sources & clinical trials

Peer-reviewed research and registered trials from PubMed, ClinicalTrials.gov, PubChem, FDA and NIH. All links open in a new tab and point to the primary source, so every claim can be verified at origin.

Written and reviewed by

Jack Muncaster · Founder, UK Peptides

Jack founded UK Peptides in Manchester after repeatedly receiving research compounds with missing or recycled paperwork. He is responsible for supplier selection, batch release decisions and the content published in this research library. Every article here is sourced to primary literature and every product page to a signed third-party certificate.

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