MOTS-c vs SS-31: two mitochondria-focused peptides compared

In short: MOTS-c is a 16-amino-acid peptide encoded in mitochondrial DNA. SS-31 (elamipretide) is a synthetic four-residue peptide designed to bind cardiolipin in the inner mitochondrial membrane. MOTS-c evidence is mainly cell and animal work; SS-31 has many registered human trials and US accelerated approval. Neither has an ARTG entry.

Both peptides are linked to mitochondria, the compartments inside cells that produce most of the cell’s chemical energy, but they differ in almost every other respect. This comparison covers origin, structure, the mechanisms researchers have studied, the type of evidence and regulatory status. Our guide to how to read a peptide study explains the evidence labels used here. Each compound also has its own full review: MOTS-c in published research and SS-31 (elamipretide) research record.

How do MOTS-c and SS-31 compare at a glance?

The table below sets the verified identifiers and status of each compound side by side.

Property	MOTS-c	SS-31 (elamipretide)
Origin	Encoded in mitochondrial DNA (12S rRNA gene, MT-RNR1) 1 10	Synthetic, designed in the laboratory 4
Sequence	MRWQEMGYIFYPRKLR 10	D-Arg-Dmt-Lys-Phe-NH2 12
Length	16 amino acids	4 residues
Non-standard features	None in the reference sequence	D-arginine, 2′,6′-dimethyltyrosine (Dmt), C-terminal amide
Molecular formula	C101H152N28O22S2 11	C32H49N9O5 12
Molecular weight	2174.6 g/mol 11	639.8 g/mol 12
CAS number	1627580-64-6 11	736992-21-5 12
PubChem CID	146675088	11764719
Main mechanisms studied	Folate and purine metabolism, AMPK, movement into the nucleus 1 2	Binding to cardiolipin and mitochondrial membranes 5 6
Evidence base	Cell and animal studies; human observational studies; no published placebo-controlled trial results	Cell and animal studies; registered phase 1 to phase 4 trials
US status	No Drugs@FDA record found 20	Accelerated approval (Forzinity), 19 September 2025 13
WADA 2026	Named in S4.4.1 (activators of AMPK) 14	Not named 14
ARTG (Australia)	No entry found 16	No entry found 16

How do their origins differ?

MOTS-c is produced by cells from a gene in the mitochondrial genome, while SS-31 is a compound designed by chemists.

In a 2015 cell and mouse study, Lee et al. reported a short open reading frame (a stretch of genetic code that can be read into a peptide) inside the mitochondrial 12S ribosomal RNA gene that encodes the 16-amino-acid MOTS-c. They reported that it is translated in the cytoplasm using the standard genetic code 1. This places MOTS-c among the mitochondrial-derived peptides, a group that a 2022 review counted at eight members, including humanin 3.

SS-31 comes from the Szeto-Schiller peptides. In a 2004 study, Zhao et al. described cell-permeable peptides built on alternating aromatic and basic amino acids, and reported that they concentrated about 1,000-fold in the inner mitochondrial membrane 4. The compound was later developed as elamipretide by Stealth BioTherapeutics 13.

How do their structures compare?

MOTS-c is a longer peptide made only of standard amino acids, while SS-31 is very short and includes building blocks not found in proteins.

Illustration: a long and a short peptide chain side by side, not the exact structures of MOTS-c or SS-31.

• Size. MOTS-c has 16 residues and a molecular weight of 2174.6 g/mol 11. SS-31 has 4 residues and a molecular weight of 639.8 g/mol 12.
• Building blocks. MOTS-c uses standard L-amino acids, including two methionines 10. SS-31 starts with D-arginine (the mirror-image form of protein arginine), includes the modified tyrosine Dmt and ends in an amide 12.
• Charge pattern. SS-31 alternates positively charged and ring-containing (aromatic) residues, which is why it is described as aromatic-cationic 7. In the 2004 study, analogues without Dmt did not reduce mitochondrial reactive oxygen species 4.
• Known variants. Zempo et al. described a human mitochondrial DNA variant that changes position 14 of MOTS-c from lysine to glutamine (K14Q) 9. SS-31 has no genetic variants, because no gene encodes it.

What mechanisms have researchers studied for each?

Research on MOTS-c has focused on metabolism and gene regulation, while research on SS-31 has focused on how it binds mitochondrial membranes.

MOTS-c. In human cell lines, Lee et al. reported that MOTS-c altered folate-methionine metabolism, blocked the linked pathway that builds purines, and caused a build-up of AICAR that was linked to activation of AMPK, an enzyme that senses low cellular energy 1. In a 2018 cell study, Kim et al. reported that MOTS-c moved into the nucleus under metabolic stress and regulated genes with antioxidant response elements 2.

SS-31. In a 2013 study, Birk et al. used a fluorescent analogue to report that SS-31 binds cardiolipin, an anionic phospholipid of the inner mitochondrial membrane, with high affinity. In rats, pretreatment with SS-31 protected the inner membrane folds (cristae) during kidney ischaemia 5. In a 2020 biophysical study, Mitchell et al. reported that SS-31 partitions into the membrane surface region and changes its surface electrical charge 6.

Both sets of mechanisms come from cells, isolated mitochondria, model membranes and animals. None has been confirmed in people.

How does the evidence base differ?

The biggest difference is human data: no placebo-controlled trial of MOTS-c in people has published results, while SS-31 has been tested in a series of registered trials.

MOTS-c. Findings about effects come from cell and rodent studies. Human studies have measured MOTS-c in blood or looked at genotypes, and published blood levels differ widely between measurement methods 8. ClinicalTrials.gov lists a phase 2a, randomised, double-blind, placebo-controlled trial of MOTS-c in adults with prediabetes, with an insulin sensitivity index and adverse events as primary endpoints, recruiting in 2026 17. The discovery paper disclosed author links to CohBar, Inc., the company that licensed the related intellectual property 1 3.

SS-31. When searched on 28 September 2026, ClinicalTrials.gov listed 30 records naming elamipretide or its earlier code names as an intervention, 28 sponsored by Stealth BioTherapeutics 15. Published trials include MMPOWER-3, a phase 3, randomised, double-blind, placebo-controlled trial in 218 adults with primary mitochondrial myopathy, with the 6-minute walk test and a fatigue score as primary endpoints 19. A 2020 mechanism paper discloses that Szeto, who invented the SS peptides, founded Stealth BioTherapeutics and has financial interests in it 6. The US approval rests on an intermediate clinical endpoint, and the FDA requires a confirmatory randomised trial 13.

Trials are described here by design and endpoints only. Our explainer on why most peptide research is preclinical covers why animal findings cannot be applied to people.

How does their regulatory and anti-doping status compare?

Neither compound has an entry in the Australian Register of Therapeutic Goods, but they differ overseas and on the WADA list.

• Australia. ARTG searches on 28 September 2026 returned no entry for MOTS-c, elamipretide or Forzinity 16. The TGA’s advisory of 13 April 2026 defines unapproved peptide products as goods not included in the ARTG 18.
• United States. The FDA granted accelerated approval to Forzinity (elamipretide) on 19 September 2025 for a labelled indication in Barth syndrome, a rare inherited disorder 13. A search of FDA drug approval data found no record for MOTS-c 20.
• WADA. The 2026 Prohibited List names MOTS-c in section S4.4.1, activators of AMPK, prohibited at all times. SS-31 and elamipretide are not named in the 2026 list 14. See our anti-doping status table and the current WADA Prohibited List.

How are they characterised in the lab?

Both are checked for identity and purity in the same general way, but each has its own analytical points to watch.

Illustration: a mass spectrometer, the instrument used to confirm peptide identity by mass.

• Expected mass. PubChem lists monoisotopic masses of 2173.108 Da for MOTS-c and 639.386 Da for SS-31 11 12. Mass spectrometry identity testing compares a sample against these values.
• MOTS-c. Its two methionines can oxidise; Knoop et al. included two oxidation products in their validated mass spectrometry method 8.
• SS-31. Mass alone cannot distinguish D-arginine from L-arginine, because mirror-image forms have the same mass, so confirming the D configuration needs a separation method such as chiral chromatography.
• Purity and content. Both are assessed by HPLC, and both are usually supplied as salts, which affects net peptide content. See how to read a peptide COA and HPLC purity explained.

Frequently asked questions

Is SS-31 a mitochondrial-derived peptide like MOTS-c?

No. Mitochondrial-derived peptides such as MOTS-c and humanin are encoded in mitochondrial DNA 1 3. SS-31 is a synthetic tetrapeptide from the Szeto-Schiller series, designed to concentrate in the inner mitochondrial membrane 4. The two share a research focus on mitochondria but have different origins and structures. Our SS-31 research review covers its design.

Which is larger, MOTS-c or SS-31?

MOTS-c is larger. It has 16 amino acids and a molecular weight of 2174.6 g/mol, according to PubChem CID 146675088 11. SS-31 has four residues and a molecular weight of 639.8 g/mol, according to PubChem CID 11764719 12. SS-31 also contains non-standard building blocks: D-arginine, 2′,6′-dimethyltyrosine and an amidated C-terminus.

Have MOTS-c and SS-31 been tested in human trials?

SS-31 has. ClinicalTrials.gov listed 30 elamipretide records when searched on 28 September 2026, and the FDA granted accelerated approval in 2025 15 13. No placebo-controlled trial of MOTS-c in people has published results; a phase 2a placebo-controlled trial was recruiting in 2026 17. Human data on MOTS-c so far are observational studies of blood levels and genotypes. See our MOTS-c research review.

Are MOTS-c and SS-31 on the WADA Prohibited List?

MOTS-c is. The 2026 WADA Prohibited List names it in section S4.4.1, activators of AMPK, under hormone and metabolic modulators, prohibited at all times 14. SS-31 and elamipretide are not named in the 2026 list, but the list also works through general categories, so check the current WADA Prohibited List and our anti-doping status table.

Are MOTS-c or SS-31 in the Australian Register of Therapeutic Goods?

No. ARTG searches on 28 September 2026 returned no entry for MOTS-c, elamipretide or Forzinity 16. The TGA’s April 2026 advisory defines unapproved peptide products as goods that are not included in the ARTG 18. The US approval of elamipretide does not create an Australian registration. This article describes regulatory status only.

References

1. Lee C, Zeng J, Drew BG, et al. The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance. Cell Metabolism. 2015;21(3):443-454. doi:10.1016/j.cmet.2015.02.009. PMID: 25738459. PMCID: PMC4350682. [cell and mouse study]
2. Kim KH, Son JM, Benayoun BA, et al. The mitochondrial-encoded peptide MOTS-c translocates to the nucleus to regulate nuclear gene expression in response to metabolic stress. Cell Metabolism. 2018;28(3):516-524.e7. doi:10.1016/j.cmet.2018.06.008. PMID: 29983246. PMCID: PMC6185997. [cell study]
3. Miller B, Kim SJ, Kumagai H, et al. Mitochondria-derived peptides in aging and healthspan. Journal of Clinical Investigation. 2022;132(9):e158449. doi:10.1172/JCI158449. PMID: 35499074. PMCID: PMC9057581. [narrative review]
4. Zhao K, Zhao GM, Wu D, et al. Cell-permeable peptide antioxidants targeted to inner mitochondrial membrane inhibit mitochondrial swelling, oxidative cell death, and reperfusion injury. Journal of Biological Chemistry. 2004;279(33):34682-34690. doi:10.1074/jbc.M402999200. PMID: 15178689. [cell, isolated mitochondria and ex vivo heart study]
5. Birk AV, Liu S, Soong Y, et al. The mitochondrial-targeted compound SS-31 re-energizes ischemic mitochondria by interacting with cardiolipin. Journal of the American Society of Nephrology. 2013;24(8):1250-1261. doi:10.1681/ASN.2012121216. PMID: 23813215. PMCID: PMC3736700. [biochemical and rat study]
6. Mitchell W, Ng EA, Tamucci JD, et al. The mitochondria-targeted peptide SS-31 binds lipid bilayers and modulates surface electrostatics as a key component of its mechanism of action. Journal of Biological Chemistry. 2020;295(21):7452-7469. doi:10.1074/jbc.RA119.012094. PMID: 32273339. PMCID: PMC7247319. [biophysical and isolated mitochondria study]
7. Karaa A, Haas R, Goldstein A, et al. Randomized dose-escalation trial of elamipretide in adults with primary mitochondrial myopathy. Neurology. 2018;90(14):e1212-e1221. doi:10.1212/WNL.0000000000005255. PMID: 29500292. PMCID: PMC5890606. [phase 1/2 randomised controlled trial]
8. Knoop A, Thomas A, Thevis M. Development of a mass spectrometry based detection method for the mitochondrion-derived peptide MOTS-c in plasma samples for doping control purposes. Rapid Communications in Mass Spectrometry. 2019;33(4):371-380. doi:10.1002/rcm.8337. PMID: 30394592. [analytical method validation]
9. Zempo H, Kim SJ, Fuku N, et al. A pro-diabetogenic mtDNA polymorphism in the mitochondrial-derived peptide, MOTS-c. Aging (Albany NY). 2021;13(2):1692-1717. doi:10.18632/aging.202529. PMID: 33468709. PMCID: PMC7880332. [human genetic association study with mouse and cell work]
10. UniProt. A0A0C5B5G6 (MOTSC_HUMAN): Mitochondrial-derived peptide MOTS-c. https://www.uniprot.org/uniprotkb/A0A0C5B5G6/entry. Accessed 28 September 2026.
11. PubChem. Mots-c, compound summary, CID 146675088. https://pubchem.ncbi.nlm.nih.gov/compound/146675088. Accessed 28 September 2026.
12. PubChem. Elamipretide, compound summary, CID 11764719. https://pubchem.ncbi.nlm.nih.gov/compound/11764719. Accessed 28 September 2026.
13. US Food and Drug Administration. NDA 215244 accelerated approval letter, Forzinity (elamipretide), 19 September 2025. https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2025/215244Orig1s000ltr.pdf. Accessed 28 September 2026.
14. World Anti-Doping Agency. Prohibited List 2026 (in force 1 January 2026). https://www.wada-ama.org/en/prohibited-list. Accessed 28 September 2026.
15. ClinicalTrials.gov. Search of interventions for elamipretide, MTP-131, SS-31 or Bendavia (30 records). https://clinicaltrials.gov/search?intr=elamipretide. Accessed 28 September 2026.
16. Therapeutic Goods Administration. Australian Register of Therapeutic Goods (ARTG) search. https://www.tga.gov.au/resources/artg. Accessed 28 September 2026.
17. ClinicalTrials.gov. NCT07505745: MOTS-c in adults with prediabetes and overweight/obesity (phase 2a). https://clinicaltrials.gov/study/NCT07505745. Accessed 28 September 2026.
18. Therapeutic Goods Administration. Understanding your responsibilities when importing, compounding and supplying unapproved peptide products (safety advisory, 13 April 2026). https://www.tga.gov.au/safety/safety-monitoring-and-information/safety-alerts/understanding-your-responsibilities-when-importing-compounding-and-supplying-unapproved-peptide-products. Accessed 28 September 2026.
19. Karaa A, Bertini E, Carelli V, et al. Efficacy and safety of elamipretide in individuals with primary mitochondrial myopathy: the MMPOWER-3 randomized clinical trial. Neurology. 2023;101(3):e238-e252. doi:10.1212/WNL.0000000000207402. PMID: 37268435. PMCID: PMC10382259. [phase 3 randomised controlled trial]
20. US Food and Drug Administration. Drugs@FDA (openFDA drugsfda dataset), searched for elamipretide and MOTS-c. https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=215244. Accessed 28 September 2026.