Data edition of
Residue An evidence-graded reference for peptide science

A peptide class of 2 compounds

Mitochondria-targeted peptides

What separates MOTS-c from elamipretide (SS-31)?

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The two members of this class reach mitochondria from opposite directions. MOTS-c is a 16-residue peptide encoded within the mitochondrial 12S rRNA gene, described in 2015 as a regulator of insulin sensitivity in mice1PubMedThe mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance. Lee C et al. Cell Metab. 2015.. Elamipretide (SS-31) is a synthetic tetrapeptide that binds cardiolipin in the inner mitochondrial membrane; it received FDA accelerated approval in September 2025 for Barth syndrome2PubMedElamipretide: First Approval. Shirley M Drugs. 2026.,3FDADrugs@FDA: FORZINITY (NDA215244). STEALTH BIOTHERAPS; original approval 2025-09-19; Prescription..

The evidence gap is wide: elamipretide has randomized trials (with mixed results outside Barth syndrome4PubMedEfficacy and Safety of Elamipretide in Individuals With Primary Mitochondrial Myopathy: The MMPOWER-3 Randomized Clinical Trial. Karaa A et al. Neurology. 2023.), while MOTS-c's human data are observational measurements of circulating levels5PubMedPlasma MOTS-c levels are associated with insulin sensitivity in lean but not in obese individuals. Cataldo LR et al. J Investig Med. 2018.. FDA lists MOTS-c among withdrawn compounding nominations with recorded safety concerns6FDACertain Bulk Drug Substances for Use in Compounding that May Present Significant Safety Risks. U.S. FDA, content current as of 04/22/2026..

Table 1. Mitochondria-targeted peptides on Residue, by best evidence grade. Bars show PubMed records on a log scale; counts are from the data edition.
GradeCompoundClassLiteratureRegistered studies
A ElamipretideFDA accelerated approval — Forzinity (2025) Mitochondrial 470 29 · 3 active
D MOTS-cNot FDA-approved · FDA compounding nomination withdrawn Mitochondrial 264 5 · 4 active

Monographs in this class

  • A
    Elamipretide

    SS-31, a four-residue peptide that binds cardiolipin in the inner mitochondrial membrane — approved in 2025 for Barth syndrome after a mixed trial record elsewhere.

  • D
    MOTS-c

    A 16-residue peptide encoded inside mitochondrial DNA, discovered in 2015. In mice it improves insulin sensitivity and physical capacity; in people, it has so far only been measured, not tested.

Comparisons

References

Every source below was retrieved from its official API or page and cached on the data-edition date. Numbers match the margin notes.

  1. 1 PubMed Lee C, Zeng J, Drew BG, et al. The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance. Cell Metab 2015. PMID 25738459; doi:10.1016/j.cmet.2015.02.009.
  2. 2 PubMed Shirley M. Elamipretide: First Approval. Drugs 2026. PMID 41335372; doi:10.1007/s40265-025-02269-8.
  3. 3 FDA Drugs@FDA: FORZINITY (NDA215244). STEALTH BIOTHERAPS; original approval 2025-09-19; Prescription.
  4. 4 PubMed 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. PMID 37268435; doi:10.1212/WNL.0000000000207402.
  5. 5 PubMed Cataldo LR, Fernández-Verdejo R, Santos JL, et al. Plasma MOTS-c levels are associated with insulin sensitivity in lean but not in obese individuals. J Investig Med 2018. PMID 29593067; doi:10.1136/jim-2017-000681.
  6. 6 FDA Certain Bulk Drug Substances for Use in Compounding that May Present Significant Safety Risks. U.S. FDA, content current as of 04/22/2026.