Mitochondrial-Derived Peptides Mechanism Map

An organelle that codes for its own signalling molecules — how MOTS-c, humanin and the SHLPs are produced, secreted and act on distant tissues.

Educational research-literacy content only. Not medical advice, not dosing guidance, not sourcing advice, and not a protocol for human or animal use. See our responsible information policy.

Not every peptide is nuclear-encoded

Most peptides your body produces are coded in the nucleus and translated by ribosomes in the cytosol. A small but distinctive class is coded inside the mitochondrial genome — a circular 16.5 kb DNA molecule that mitochondria carry independently of the nuclear chromosomes, translated by mitochondrial ribosomes. The peptides these genes produce are the mitochondrial-derived peptides (MDPs): humanin, the SHLPs (Small Humanin-Like Peptides 1–6), and MOTS-c.

The three families

Humanin

24 amino acids. Encoded within MT-RNR2, the mitochondrial 16S rRNA gene — the peptide's coding sequence overlaps the rRNA sequence in a different reading frame.

Receptors: two independent binding sites. FPRL1 (formyl peptide receptor-like 1, also FPR2) and FPR3 mediate anti-apoptotic effects; a heterotrimeric CNTFR/WSX-1/gp130 complex mediates a JAK/STAT3 signal in neurons.

Dominant role: cytoprotection under ischaemic / oxidative stress. Neurons and cardiomyocytes are the tissues where humanin's anti-apoptotic effect is best established.

SHLPs 1–6

Six additional short peptides encoded in the same MT-RNR2region as humanin, discovered by predicted ORF analysis of the 16S rRNA gene. Individual SHLPs share partial receptor engagement with humanin but have distinct tissue-specific effects. Human evidence is thinner than for humanin or MOTS-c.

MOTS-c

16 amino acids. Encoded within MT-RNR1, the mitochondrial 12S rRNA gene (a different region from humanin/SHLPs).

Receptors: a direct binding target has not been definitively identified. The dominant systemic effect is AMPK activation, but whether that's via a cell-surface receptor or via intracellular action after cellular uptake is still under investigation.

Dominant role: metabolic. Increases glucose uptake in skeletal muscle, improves hepatic insulin sensitivity, promotes mitochondrial biogenesis via PGC-1α. Positioned in the literature as an exercise-mimetic hormone.

What links them functionally

The three families arose independently in the literature but share important properties:

Endocrine mechanism. All three circulate in plasma and act on distant tissues — they're hormones, not intracellular regulators.
Age-related decline. Circulating MDP concentrations fall with age in every population studied. This is one of the reasons MDPs are treated as candidate mediators of the metabolic phenotype of ageing.
Exercise responsiveness. Acute and chronic exercise elevate plasma MDP levels — MOTS-c most strongly (Woodhead 2021).
Signalling from organelle to organism. They're evidence that mitochondria communicate with the nucleus and with other tissues, not just process ATP.

Not to be confused with mitochondria-targeted synthetics

The SS-31 / elamipretide class is a different category entirely. SS-31 is a synthetic, nuclear-encoded (in the sense that it doesn't come from mtDNA — it's not endogenous), small tetrapeptide designed to accumulate at the inner mitochondrial membrane and stabilise cardiolipin. It's a drug you add. MDPs are signalling molecules your body already makes.

Both categories concern mitochondrial function, but they operate at different levels. See our SS-31 vs MOTS-c comparison for a side-by-side breakdown of the two approaches.

Regulatory context

None of the endogenous MDPs is a licensed medicine anywhere. Research peptides sold under these names are unlicensed. SS-31/elamipretide was FDA-approved in 2024 (Forzinity) for Barth syndrome — a rare mitochondrial disease — but not by MHRA, and not for the anti-ageing / metabolic uses commonly discussed online. See our POM advertising hub for the framework.

Published: 2026-06-20Last updated: 2026-06-20Last reviewed: 2026-06-20

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