Mitochondrial Peptides: MOTS-c, NAD+ and SS-31 Compared

Mitochondrial peptides are a loose group of research compounds studied for their effects on the energy-producing organelles inside cells. The three most searched in the UK are MOTS-c, a peptide encoded in mitochondrial DNA that signals through AMPK; SS-31 (elamipretide), a synthetic tetrapeptide that binds cardiolipin in the inner mitochondrial membrane; and NAD+, a coenzyme rather than a peptide, which is central to mitochondrial redox reactions and declines with age.

They are often grouped together, but they work in very different ways and sit at very different points on the evidence ladder. This article compares the three, summarises the published research honestly, and explains their legal status for UK laboratories.

Why mitochondria are a research target

Mitochondria generate most of a cell's ATP through oxidative phosphorylation. As tissues age, mitochondrial function tends to decline: membranes lose integrity, reactive oxygen species increase, and the NAD+ pool shrinks. These changes are implicated in sarcopenia, metabolic disease, heart failure and neurodegeneration, which is why compounds that act on mitochondria attract so much attention.

The mitochondrial peptide field took a leap forward when researchers discovered that the mitochondrial genome, long assumed to encode only 13 proteins, also contains short open reading frames producing signalling peptides. Humanin was the first; MOTS-c followed in 2015.

MOTS-c: the exercise-mimetic mitochondrial peptide

MOTS-c (mitochondrial open reading frame of the 12S rRNA type-c) is a 16-amino-acid peptide identified by Changhan Lee, Pinchas Cohen and colleagues at the University of Southern California and published in Cell Metabolism in 2015. It is encoded within the 12S rRNA gene of mitochondrial DNA and acts as a signalling molecule that travels to the nucleus under metabolic stress.

In the original mouse work, MOTS-c activated AMPK via the folate-AICAR pathway, improved insulin sensitivity and prevented diet-induced obesity. Later studies reported that it accumulates in the nucleus after exercise and regulates genes under the control of NRF2 and other stress-response factors. A 2021 paper in Nature Communications showed that circulating MOTS-c rose in humans after exercise and that treated aged mice improved their physical performance. Because of this, MOTS-c is frequently described in the literature as an exercise mimetic.

Human evidence remains thin. A MOTS-c analogue, CB4211, completed an early phase 1 study for non-alcoholic fatty liver disease and obesity, but MOTS-c itself has no completed late-stage human trials and no marketing authorisation anywhere in the world. The biology is consistent and reproducible in preclinical models; clinical effect in people is unproven.

SS-31 (elamipretide): the only one with phase 3 data

SS-31 was developed by Hazel Szeto and Peter Schiller in the early 2000s and later licensed to Stealth BioTherapeutics under the name elamipretide. It is an aromatic-cationic tetrapeptide (D-Arg-Dmt-Lys-Phe-NH2) that concentrates in the inner mitochondrial membrane and binds cardiolipin, the phospholipid that anchors the electron transport chain. By stabilising cardiolipin, SS-31 has been shown in preclinical models to improve ATP output and reduce reactive oxygen species.

Elamipretide is the only mitochondrial peptide with late-stage human trial data. The TAZPOWER trial in Barth syndrome, a rare mitochondrial cardiomyopathy, missed its primary endpoint in the randomised phase but showed sustained improvements in the open-label extension. In September 2025 the US FDA granted accelerated approval to elamipretide, marketed as Forzinity, for Barth syndrome, based on improvements in knee extensor muscle strength. Trials in heart failure (PROGRESS-HF), dry age-related macular degeneration (ReCLAIM-2) and primary mitochondrial myopathy have produced mixed results.

It is important to be clear that elamipretide has no MHRA marketing authorisation in the UK, and that research-grade SS-31 supplied to laboratories is not the licensed medicine Forzinity, even where the sequence is identical.

NAD+: the coenzyme in the mix

NAD+ (nicotinamide adenine dinucleotide) is not a peptide at all. It is a coenzyme found in every cell, shuttling electrons in glycolysis, the TCA cycle and oxidative phosphorylation, and serving as a substrate for sirtuins and PARP enzymes involved in DNA repair. Tissue NAD+ levels are widely reported to fall with age, and restoring them is a major theme in longevity research.

Most human trials have used oral precursors, nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN), rather than NAD+ itself. These trials reliably raise blood NAD+ but have shown modest and inconsistent functional outcomes in healthy adults. Direct NAD+ administration has been studied in small trials for its pharmacokinetics; the published literature on functional benefit is limited. NAD+ in research pen form is used by laboratories investigating redox biology, sirtuin activation and cellular ageing models.

MOTS-c vs SS-31 vs NAD+: side-by-side comparison

The table below sets out the key differences between the three compounds. The evidence column reflects the highest level of published human data for the compound itself, not for analogues or precursors.

Where SLU-PP-332 fits

Researchers comparing mitochondrial compounds increasingly include SLU-PP-332, a small-molecule ERR (oestrogen-related receptor) agonist developed at Saint Louis University. It is not a peptide, but it is studied for similar reasons: in mouse work it increased mitochondrial biogenesis and oxidative muscle fibre content and was described as an exercise mimetic. It has no human trial data at all and, like MOTS-c, is strictly a preclinical research compound.

Are mitochondrial peptides legal in the UK?

MOTS-c, SS-31 and NAD+ are all legal to buy, sell and possess in the UK as research chemicals. None is controlled under the Misuse of Drugs Act 1971. However, none has a UK marketing authorisation, so supplying any of them for human medicinal use, or advertising them with medicinal claims, is unlawful under the Human Medicines Regulations 2012.

For laboratories that means sourcing is straightforward, but the material must be handled and described as a research reagent. Reputable UK suppliers state this explicitly and publish independent purity testing so researchers can verify what they are working with.

Sourcing mitochondrial peptides for UK research

Quality matters more with this group than most. SS-31 contains an unusual amino acid (2,6-dimethyltyrosine) that is difficult to synthesise, so identity confirmation by mass spectrometry is essential. NAD+ is chemically unstable and should be supplied in a format that protects it from heat and moisture. MOTS-c is a 16-residue peptide where truncated sequences can pass a casual purity check but fail a proper one.

• Look for a batch-specific certificate of analysis from an independent laboratory. Calibre pens are tested by Janoshik Analytical with COAs published on the COA page.
• Check the HPLC purity figure (Calibre targets above 99%) and that the mass spec result matches the expected molecular weight.
• Pre-filled, precision-made pens avoid reconstitution errors and are useful where the study design needs consistent concentration between runs.
• Store as directed; NAD+ in particular should be kept cold and used promptly once in solution.

Summary

MOTS-c, SS-31 and NAD+ are frequently grouped as mitochondrial peptides, but only two are peptides and only one, SS-31, has late-stage human data. MOTS-c has consistent preclinical biology as an AMPK-activating exercise mimetic; SS-31 has an FDA accelerated approval for a rare disease but no UK licence; NAD+ is a well-understood coenzyme whose direct administration remains under-studied. All three are legal research chemicals in the UK when sold and used as such.