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Elamipretide (SS-31) vs MOTS-c

A Elamipretide Mitochondrial cardiolipin binder FDA accelerated approval — Forzinity (2025) D MOTS-c Mitochondrial-derived peptide; folate-cycle inhibition and AMPK activation in muscle Not FDA-approved · FDA compounding nomination withdrawn

Residue Editorial Team · updated

In brief

Both are linked to mitochondria but are otherwise unalike. Elamipretide (SS-31) is a synthetic cardiolipin-binding tetrapeptide with FDA accelerated approval as Forzinity for Barth syndrome1FDAFORZINITY prescribing information: Indications and Usage. FDA-approved labeling via openFDA/DailyMed, version effective 2025-12-10.. MOTS-c is a 16-residue peptide encoded in mitochondrial DNA; given to mice, it prevented diet-induced obesity and insulin resistance2PubMedThe mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance. Lee C et al. Cell Metab. 2015., but no human treatment results are published and it is not FDA-approved3FDACertain Bulk Drug Substances for Use in Compounding that May Present Significant Safety Risks. U.S. FDA, content current as of 04/22/2026..

How do Elamipretide and MOTS-c compare at a glance?

Table 1. Elamipretide and MOTS-c on the dimensions that matter most; every entry is cited.
DimensionElamipretideMOTS-c
OriginSynthetic tetrapeptide4PubChemPubChem compound record: Elamipretide. C32H49N9O5 · MW 639.8 g/mol.Encoded in the mitochondrial 12S rRNA gene2
MechanismMitochondrial cardiolipin binder1Folate-cycle inhibition → AMPK activation2
Human trialsTAZPOWER, MMPOWER-3, heart failure5PubMedA phase 2/3 randomized clinical trial followed by an open-label extension to evaluate the effectiveness of elamipretide in Barth syndrome, a genetic disorder of mitochondrial cardiolipin metabolism. Reid Thompson W et al. Genet Med. 2021.,6PubMedEfficacy and Safety of Elamipretide in Individuals With Primary Mitochondrial Myopathy: The MMPOWER-3 Randomized Clinical Trial. Karaa A et al. Neurology. 2023.,7PubMedNovel Mitochondria-Targeting Peptide in Heart Failure Treatment: A Randomized, Placebo-Controlled Trial of Elamipretide. Daubert MA et al. Circ Heart Fail. 2017.Phase 2 in prediabetes recruiting8TrialMOTS-c for Improving Insulin Sensitivity in Adults With Prediabetes and Overweight/Obesity. Hudson Biotech · PHASE2 · recruiting.
Key result6MWT +95.9 m in Barth open-label phase5Better physical capacity in old mice9PubMedMOTS-c is an exercise-induced mitochondrial-encoded regulator of age-dependent physical decline and muscle homeostasis. Reynolds JC et al. Nat Commun. 2021.
Negative resultMMPOWER-3 missed endpoints6—
FDAAccelerated approval: Forzinity10FDADrugs@FDA: FORZINITY (NDA215244). STEALTH BIOTHERAPS; original approval 2025-09-19; Prescription.Withdrawn nomination; no human exposure data3
Evidence gradeAD

Written by Residue Editorial Team

Reviewed by Residue Editorial Team · source-by-source check,

First published

Last updated

Registry data · How we grade · Markdown + sources

Figure 1. Size of the research record, from PubMed and ClinicalTrials.gov at the data edition. Bars are scaled to the larger value in each row; volume is not quality.
PubMed records 470 264
Trial publications 21 5
Registered studies 29 5
Phase 3 studies 4 0

Elamipretide MOTS-c

How are the two molecules different?

Elamipretide is a synthetic four-residue peptide containing a modified tyrosine4, described in its label as a mitochondrial cardiolipin binder1. MOTS-c is encoded by a short open reading frame in the mitochondrial 12S rRNA gene; in muscle cells it inhibits the folate cycle and activates AMPK2.

What have elamipretide trials shown?

In Barth syndrome, TAZPOWER's randomized crossover part missed both primary endpoints, but at 36 weeks of open-label treatment the 6-minute walk improved by 95.9 m5, sustained at 96.1 m over 168 weeks in 8 patients11PubMedLong-term efficacy and safety of elamipretide in patients with Barth syndrome: 168-week open-label extension results of TAZPOWER. Thompson WR et al. Genet Med. 2024.. FDA's accelerated approval rests on knee-extensor strength1. In primary mitochondrial myopathy, MMPOWER-3 (218 adults) found no benefit over placebo6. A single infusion in heart failure was well tolerated and reduced left-ventricular volumes at the highest dose7.

What is the evidence for MOTS-c?

MOTS-c treatment prevented age- and diet-related insulin resistance and diet-induced obesity in mice2 and improved physical performance in young, middle-aged and old mice9. In humans, exercise raised endogenous MOTS-c9, and plasma levels were similar in lean and obese adults12PubMedPlasma MOTS-c levels are associated with insulin sensitivity in lean but not in obese individuals. Cataldo LR et al. J Investig Med. 2018.. No human treatment results are published; a phase 2 trial in prediabetes is recruiting8.

Are they FDA-approved?

Forzinity (elamipretide) received FDA accelerated approval in September 202510,13PubMedElamipretide: First Approval. Shirley M Drugs. 2026.. FDA lists MOTs-C among withdrawn compounding nominations and has identified no human exposure data3.

Two identical glass beakers, one holding pale amber liquid and one clear, standing either side of a brass balance

Why do they get these evidence grades?

A Elamipretide
FDA accelerated approval (Forzinity, 2025) for Barth syndrome, contingent on confirmatory evidence. A phase 3 trial in primary mitochondrial myopathy failed its endpoints. Grade A: Approved / regulatory-grade.
D MOTS-c
Effects of giving MOTS-c are shown only in cells and mice. Human studies measure naturally occurring levels; a phase 2 trial is recruiting. Grade D: Preclinical only.

Questions readers ask

Is SS-31 the same as MOTS-c?

No. SS-31 (elamipretide) is a synthetic tetrapeptide that binds cardiolipin1; MOTS-c is a naturally encoded 16-amino-acid mitochondrial peptide2.

Which has human evidence?

Elamipretide, from randomized trials in Barth syndrome, primary mitochondrial myopathy and heart failure5,6,7. MOTS-c human studies measure natural levels12; a treatment trial is recruiting8.

Is elamipretide approved for anti-aging or energy?

No. Its only approved indication is to improve muscle strength in Barth syndrome patients weighing at least 30 kg, under accelerated approval1.

Can you take elamipretide and MOTS-c together?

No published trial among the sources we cite tested them together. Elamipretide (Forzinity) is labeled only for Barth syndrome under accelerated approval1; MOTS-c has no approved indication3.

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 FDA FORZINITY prescribing information: Indications and Usage. FDA-approved labeling via openFDA/DailyMed, version effective 2025-12-10.
  2. 2 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.
  3. 3 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.
  4. 4 PubChem PubChem compound record: Elamipretide. C32H49N9O5 · MW 639.8 g/mol.
  5. 5 PubMed Reid Thompson W, Hornby B, Manuel R, et al. A phase 2/3 randomized clinical trial followed by an open-label extension to evaluate the effectiveness of elamipretide in Barth syndrome, a genetic disorder of mitochondrial cardiolipin metabolism. Genet Med 2021. PMID 33077895; doi:10.1038/s41436-020-01006-8.
  6. 6 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.
  7. 7 PubMed Daubert MA, Yow E, Dunn G, et al. Novel Mitochondria-Targeting Peptide in Heart Failure Treatment: A Randomized, Placebo-Controlled Trial of Elamipretide. Circ Heart Fail 2017. PMID 29217757; doi:10.1161/CIRCHEARTFAILURE.117.004389.
  8. 8 ClinicalTrials.gov MOTS-c for Improving Insulin Sensitivity in Adults With Prediabetes and Overweight/Obesity. Hudson Biotech · PHASE2 · recruiting.
  9. 9 PubMed Reynolds JC, Lai RW, Woodhead JST, et al. MOTS-c is an exercise-induced mitochondrial-encoded regulator of age-dependent physical decline and muscle homeostasis. Nat Commun 2021. PMID 33473109; doi:10.1038/s41467-020-20790-0.
  10. 10 FDA Drugs@FDA: FORZINITY (NDA215244). STEALTH BIOTHERAPS; original approval 2025-09-19; Prescription.
  11. 11 PubMed Thompson WR, Manuel R, Abbruscato A, et al. Long-term efficacy and safety of elamipretide in patients with Barth syndrome: 168-week open-label extension results of TAZPOWER. Genet Med 2024. PMID 38602181; doi:10.1016/j.gim.2024.101138.
  12. 12 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.
  13. 13 PubMed Shirley M. Elamipretide: First Approval. Drugs 2026. PMID 41335372; doi:10.1007/s40265-025-02269-8.