MOTS-c vs SS-31
MOTS-c is a 16-residue peptide encoded in mitochondrial DNA and studied as a metabolic signal; SS-31 (elamipretide) is a synthetic tetrapeptide that targets cardiolipin. SS-31 is FDA-approved for Barth syndrome; MOTS-c is preclinical.
Both MOTS-c and SS-31 are described as mitochondrial peptides, but in different senses. MOTS-c is a mitochondrial-derived peptide: it is encoded by a short open reading frame within the mitochondrial 12S rRNA gene and was reported in 2015 as a regulator of metabolism. SS-31, also known as elamipretide, is a synthetic Szeto-Schiller tetrapeptide designed to concentrate in the inner mitochondrial membrane.
Their stages of development also differ sharply. MOTS-c research is mainly preclinical, in cell culture and rodent models of metabolism and aging. Elamipretide went through clinical development and received FDA accelerated approval in September 2025 as Forzinity for Barth syndrome.
Side-by-side
| Attribute | MOTS-c | SS-31 (elamipretide) |
|---|---|---|
| Origin | Encoded in the mitochondrial genome (12S rRNA region); endogenous | Synthetic; designed Szeto-Schiller peptide |
| Length | 16 residues | 4 residues |
| Structure | Linear, standard L-amino acids | D-Arg-Dmt-Lys-Phe-NH<sub>2</sub>; contains a D-amino acid and 2',6'-dimethyltyrosine |
| Primary target | Proposed AMPK activation and folate-methionine cycle effects; can move to the nucleus under stress | Binds cardiolipin in the inner mitochondrial membrane |
| Research areas | Rodent models of insulin resistance, obesity, exercise capacity and aging | Mitochondrial myopathies, Barth syndrome, heart failure and ischemia models |
| Evidence level | Preclinical | Approved |
| FDA status | Not FDA-approved; PCAC voted 7-5 (2 abstentions) in July 2026 to recommend 503A bulk listing, no final FDA action | Accelerated approval September 19, 2025 as Forzinity for Barth syndrome (patients ≥30 kg) |
| WADA | Check the current WADA Prohibited List | Check the current WADA Prohibited List |
| Analytical pitfalls | Two Met residues and one Trp are oxidation-prone (+16 Da species); hydrophobic stretches can aggregate | Confirm D-Arg and Dmt identity; diastereomer impurities; acetate vs other salt forms |
Mitochondrial-derived vs mitochondria-targeted
MOTS-c is made by the cell from mitochondrial genetic information and is thought to act as a signal from mitochondria to the rest of the cell and possibly to other tissues. SS-31 is not made in the body. It is a small synthetic molecule whose alternating aromatic and basic residues let it cross membranes and accumulate at the inner mitochondrial membrane. One is a candidate endogenous hormone; the other is an engineered drug acting on membrane structure.
Mechanisms
Proposed actions of MOTS-c include inhibiting the folate cycle, which raises AICAR levels and activates AMPK, and moving into the nucleus under metabolic stress to influence gene expression. These come mainly from cell and rodent studies. SS-31 binds cardiolipin, a phospholipid found mainly in the inner mitochondrial membrane, and is thought to stabilize cristae structure and electron transport chain function. Barth syndrome, its approved indication, is a disorder of cardiolipin remodeling.
Evidence and regulatory contrast
Elamipretide has an FDA accelerated approval based on clinical data in Barth syndrome, with continued approval potentially depending on confirmatory evidence. MOTS-c has no approved use. In July 2026 the FDA's compounding advisory committee voted 7-5, with two abstentions, to recommend it for the 503A bulk list; this is advisory and not a final FDA action. Human data on MOTS-c consist mainly of observational measurements of circulating levels rather than interventional trials.
Frequently asked questions
What is the difference between MOTS-c and SS-31?
MOTS-c is a 16-residue peptide encoded in mitochondrial DNA and studied as a metabolic signal, mainly in cells and rodents. SS-31, or elamipretide, is a synthetic four-residue peptide that binds cardiolipin in the inner mitochondrial membrane. SS-31 is FDA-approved for Barth syndrome, while MOTS-c remains preclinical.
Is SS-31 FDA approved?
Yes. Elamipretide (SS-31) received FDA accelerated approval on September 19, 2025, marketed as Forzinity by Stealth BioTherapeutics, for Barth syndrome in patients weighing at least 30 kg. Accelerated approval can depend on confirmatory studies.
Is MOTS-c naturally produced?
Yes. MOTS-c is encoded by a short open reading frame in the mitochondrial 12S rRNA gene and has been detected in human plasma and tissues. Research material is chemically synthesized to match this sequence. Its physiological role in humans is still under investigation.
Full entries
- MOTS-c
MOTS-c is a 16-amino-acid peptide encoded within the mitochondrial 12S rRNA gene, described in 2015 as a regulator of metabolic homeostasis. Research is mainly in cell and rodent models, with limited human data.
- SS-31 (elamipretide)
SS-31, known as elamipretide, is a synthetic mitochondria-targeted tetrapeptide that binds the inner-membrane lipid cardiolipin. It received FDA accelerated approval in September 2025 as Forzinity for Barth syndrome.
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