MOTS-c, SS-31 and Humanin: The Mitochondrial Peptides Explained

Mitochondria do more than make ATP. Two of the peptides in this guide, MOTS-c and humanin, are encoded in mitochondrial DNA itself. The third, SS-31, is a synthetic peptide designed to reach the inner mitochondrial membrane, and in September 2025 it became the first mitochondria-targeted therapy to receive US FDA approval.

Here is where each one comes from, what the research actually shows, how they differ, and what to check when sourcing them in Canada.

Peptides from mitochondrial DNA

Human mitochondria carry their own small, circular genome, separate from the DNA in the cell nucleus. Inside its ribosomal RNA genes, researchers found short open reading frames that encode small peptides. These mitochondrial-derived peptides, or MDPs, are a young field: humanin was the first identified, in 2001, and MOTS-c followed in 2015.

SS-31 belongs in the same conversation for a different reason. The body doesn’t make it at all, but it was designed to concentrate in mitochondria, so researchers often study it alongside the natural MDPs.

MOTS-c

MOTS-c was described in 2015 by a University of Southern California team. In mice it acted mainly on skeletal muscle: it inhibited the folate cycle, which raised levels of a metabolite called AICAR and activated AMPK, the cell’s energy sensor. Treated mice on a high-fat diet were protected against diet-induced obesity and insulin resistance.

Follow-up work found that MOTS-c moves into the cell nucleus under metabolic stress, where it can influence nuclear gene expression. A 2021 study then connected it to exercise. In people, a bout of exercise raised MOTS-c levels in skeletal muscle and in the blood. In mice, MOTS-c treatment improved physical capacity in young, middle-aged and old animals.

That human finding is observational. It shows the body makes more of its own MOTS-c during exercise, not what happens when MOTS-c is given. No human intervention trials have been published.

Humanin

Humanin was discovered in 2001 by a team in Japan (Hashimoto, Nishimoto and colleagues) that screened a cDNA library for genes able to protect neurons from death caused by familial Alzheimer’s disease mutations and amyloid-β. The gene they found encoded a 24-residue peptide that blocked that cell death in culture and was secreted by the cells that made it.

Later work traced humanin to the 16S rRNA region of mitochondrial DNA. It appears to act both inside cells, where it binds proteins involved in programmed cell death such as IGFBP-3, and outside them, through cell-surface receptor complexes. Research has since spread into cardiovascular, metabolic and ageing models, nearly all of it in cells and animals.

SS-31 (elamipretide)

SS-31 belongs to the Szeto-Schiller peptides, named after Hazel Szeto of Weill Cornell Medical College and Peter W. Schiller of the Institut de recherches cliniques de Montréal, who collaborated on them during research into opioid peptides. Its four residues alternate positive charges with aromatic rings (D-arginine, dimethyltyrosine, lysine and phenylalanine), a pattern that lets it cross cell membranes and concentrate in mitochondria.

Inside mitochondria, SS-31 binds cardiolipin, a phospholipid found only in the inner mitochondrial membrane. In a 2014 study it interacted only with membranes containing cardiolipin, blocked the peroxidase activity that cytochrome c develops when bound to cardiolipin, and improved the efficiency of ATP synthesis in isolated mitochondria.

Under the drug name elamipretide, it went through a long clinical programme. On September 19, 2025, the FDA granted accelerated approval to elamipretide (brand name Forzinity) to improve muscle strength in people with Barth syndrome, a rare inherited mitochondrial disease, based on knee-extensor strength in the TAZPOWER trial. The approval requires a confirmatory trial. Research-grade SS-31 is a laboratory reagent and is not the approved drug product.

Side-by-side comparison

Where NAD+ fits

NAD+ isn’t a peptide. It’s a coenzyme that shuttles electrons through the reactions mitochondria use to make ATP, and it’s widely studied in ageing research. Labs working on mitochondrial function often keep it alongside the peptides above, which is why it appears in the shelf below.

MOTS-cThe 16-residue peptide from the 12S rRNA gene.View product and COA SS-31The cardiolipin-binding Szeto-Schiller tetrapeptide.View product and COA HumaninThe first mitochondrial-derived peptide identified.View product and COA NAD+The coenzyme at the centre of mitochondrial energy metabolism.View product and COA

Sourcing mitochondrial peptides in Canada

Pure Peptides Canada is a Canadian-owned supplier of laboratory research peptides, established in 2023. These three peptides each bring their own quality questions, so check:

• Identity by mass. Mass spectrometry should match 2,174.6 g/mol for MOTS-c, 2,687.3 g/mol for humanin and 639.8 g/mol for SS-31. SS-31 contains two non-natural residues, so identity testing matters even more.
• Oxidation-prone residues. MOTS-c contains two methionines, and humanin a methionine and a cysteine, which oxidize easily. Keep vials sealed, cold and dark.
• A batch-specific COA. The lot number should match your vial. See our COA guide.
• Purity and identity both. Here’s what HPLC and mass spectrometry each tell you.

Regulatory status in 2026

In April 2026, Health Canada’s advisory on unauthorized injectable peptides listed MOTS-c, SS-31 and NAD+ among products it had seized, and stated that “For Research Use Only” labelling does not make such products legal or exempt from regulatory requirements. In the United States, an FDA advisory committee voted 7 to 5 on July 23, 2026 to recommend adding MOTS-c to the list of substances pharmacies may compound, overriding FDA staff, who had recommended against it. That vote is advisory: MOTS-c has not been added to the list and is not an approved drug. Humanin was not part of the review, and SS-31’s only approval remains the elamipretide product for Barth syndrome.

Frequently asked questions

Prepared by Pure Peptides Canada. Sources checked October 2026. For laboratory research use only; not for human or veterinary use. This article summarizes published research for education and is not medical advice. Nothing here is intended to diagnose, treat, cure or prevent any disease.