Skip to content
The Peptide Effect
Comparison

SS-31 vs MOTS-c

SS-31 (elamipretide) and MOTS-c are both mitochondria-targeting peptides, but they work through fundamentally different mechanisms. SS-31 is a synthetic tetrapeptide that binds cardiolipin in the inner mitochondrial membrane to stabilize electron transport chain complexes and reduce reactive oxygen species (ROS) production. MOTS-c is an endogenous mitochondrial-derived peptide (MDP) encoded by mitochondrial DNA that activates AMPK signaling to regulate cellular metabolism, glucose homeostasis, and exercise adaptation. SS-31 is further along in clinical development with Phase 3 trials for mitochondrial myopathy and heart failure, while MOTS-c remains primarily in preclinical research with emerging human data on metabolic function.

Side-by-side comparison diagram of SS-31 and MOTS-c mechanisms of action
Conceptual comparison — not to scale

Head-to-Head Comparison

CriteriaSS-31MOTS-c
Primary mechanismBinds cardiolipin in inner mitochondrial membrane, stabilizes electron transport chain complexes, reduces ROSActivates AMPK signaling pathway, regulates cellular metabolism and glucose uptake
OriginSynthetic tetrapeptide (D-Arg-Dmt-Lys-Phe-NH₂)Endogenous mitochondrial-derived peptide (encoded by 12S rRNA gene)
Primary targetInner mitochondrial membrane — direct biophysical interaction with cardiolipinCytoplasmic and nuclear — AMPK activation, AICAR accumulation, gene regulation
Best forMitochondrial diseases (Barth syndrome, LHON), heart failure, ischemia-reperfusion injury, age-related mitochondrial declineMetabolic dysfunction, insulin resistance, exercise performance, obesity, age-related metabolic decline
Route of administrationSubcutaneous injection or IV infusion (clinical trials)Subcutaneous injection (research); endogenously produced during exercise
Clinical trial statusPhase 3 completed (Barth syndrome — TAZPOWER); Phase 2/3 for heart failure (multiple trials)Preclinical with early human observational studies; no formal clinical trials completed
Effect on ROSDirectly reduces mitochondrial ROS production by stabilizing electron transportIndirectly reduces oxidative stress via AMPK-mediated antioxidant gene expression
Effect on metabolismImproves mitochondrial ATP production efficiency; minimal direct metabolic signalingDirectly enhances glucose uptake, fatty acid oxidation, and metabolic flexibility via AMPK
Exercise connectionMay improve exercise tolerance in mitochondrial disease patientsEndogenous levels increase with exercise; may mimic exercise-induced metabolic benefits
Age-related declineRestores cardiolipin structure that degrades with aging, reversing age-related mitochondrial dysfunctionCirculating levels decline with age; supplementation may restore youthful metabolic signaling
Safety profileWell-tolerated in clinical trials; injection site reactions most common adverse eventLimited human safety data; animal studies show good tolerability
Research depthExtensive — hundreds of preclinical papers, multiple Phase 2/3 clinical trialsModerate — growing rapidly since discovery in 2015, mostly preclinical

When to Choose Each

Choose SS-31

Mitochondrial diseases (Barth syndrome, primary mitochondrial myopathy), heart failure with mitochondrial dysfunction, ischemia-reperfusion protection, age-related mitochondrial decline

Choose MOTS-c

Metabolic syndrome and insulin resistance, exercise mimetic effects, age-related metabolic decline, obesity and glucose homeostasis, longevity-focused protocols

Verdict

SS-31 (elamipretide) is the stronger choice for individuals dealing with primary mitochondrial dysfunction, mitochondrial diseases, or cardiac conditions where direct stabilization of the electron transport chain is needed — it has the clinical trial data to back it. MOTS-c is more suited for metabolic optimization, insulin sensitivity, and mimicking the metabolic benefits of exercise, particularly in the context of aging and metabolic syndrome. For general longevity and anti-aging purposes, MOTS-c offers a broader metabolic signaling effect, while SS-31 provides targeted mitochondrial membrane repair.

References

  1. Mitochondria-targeted peptide SS-31 prevents mitochondrial depolarization, reduces islet cell apoptosis, and improves posttransplant function (2011) — PubMed
  2. MOTS-c is an exercise-induced mitochondrial-encoded regulator of age-dependent physical decline and muscle homeostasis (2021) — PubMed
  3. The mitochondrial-derived peptide MOTS-c: a player in exceptional longevity? (2020) — PubMed
  4. Elamipretide (SS-31) for Barth syndrome (TAZPOWER): a Phase 2/3 trial results (2022) — PubMed
  5. Szeto-Schiller peptides target mitochondria and reduce oxidative stress in aging (2014) — PubMed

Frequently Asked Questions

Can SS-31 and MOTS-c be used together?
While there are no published studies on combining SS-31 and MOTS-c, their mechanisms are complementary — SS-31 targets the structural integrity of the inner mitochondrial membrane while MOTS-c activates downstream metabolic signaling via AMPK. In theory, combining them could address both mitochondrial efficiency and metabolic regulation simultaneously. However, this remains speculative and should only be considered under medical supervision.
Is SS-31 (elamipretide) available by prescription?
SS-31, developed under the name elamipretide by Stealth BioTherapeutics, is not yet FDA-approved despite completing Phase 3 trials for Barth syndrome. The FDA issued a Complete Response Letter in 2022 requesting additional data. It remains available through clinical trials and some compounding pharmacies. It is not available as a standard prescription medication.
Does MOTS-c actually mimic exercise?
MOTS-c activates AMPK — the same master metabolic switch triggered by exercise — and enhances glucose uptake and fatty acid oxidation in skeletal muscle. Studies in mice show MOTS-c improves exercise capacity and prevents diet-induced obesity. While it shares key signaling pathways with exercise, it does not replicate all exercise benefits (cardiovascular conditioning, muscle fiber recruitment, neuroplasticity). It is better described as a metabolic regulator that overlaps with exercise signaling rather than a complete exercise replacement.
Why do MOTS-c levels decline with age?
MOTS-c is encoded by mitochondrial DNA and produced by mitochondria themselves. As mitochondrial function deteriorates with age — due to accumulated mtDNA mutations, reduced mitochondrial biogenesis, and declining membrane integrity — MOTS-c production decreases. Studies show significantly lower circulating MOTS-c levels in elderly individuals compared to younger adults, which correlates with age-related metabolic dysfunction and insulin resistance.
How much do SS-31 and MOTS-c cost compared to each other?
Both peptides are primarily available through research chemical suppliers and specialized compounding pharmacies, with pricing that varies significantly by source and purity. SS-31 (elamipretide) tends to be more expensive due to its complex synthesis and inclusion of a non-standard amino acid (2,6-dimethyltyrosine), with research-grade pricing typically in the range of $100 to $300 per month. MOTS-c is generally more affordable at approximately $80 to $200 per month from research suppliers. Neither is available as a standard prescription medication. Consulting a healthcare provider about access options and quality verification is advisable.

Explore next

More comparisons