Peptide comparison
MOTS-c vs SS-31
MOTS-c and SS-31 are both research peptides. This side-by-side compares their mechanism, typical research dosing, half-life, routes and safety so you can see how they differ. For research use only.
| MOTS-c | SS-31 | |
|---|---|---|
| Category | Metabolic | Longevity |
| Overview | Mitochondrial-derived peptide studied preclinically for AMPK activation, insulin sensitivity and exercise capacity; no approved human therapy. | An aromatic-cationic mitochondria-targeted tetrapeptide that selectively concentrates at the inner mitochondrial membrane by binding cardiolipin; it has reached Phase II... |
| How it works | MOTS-c is proposed to act primarily by activating AMP-activated protein kinase (AMPK), a master regulator of cellular energy balance. Mechanistic work suggests it interferes with the folate-methionine cycle and de novo purine biosynthesis, causing accumulation of the intermediate AICAR, which in turn activates AMPK. Downstream effects in skeletal muscle (its apparent main target) include increased GLUT4-mediated glucose uptake and improved insulin sensitivity. Under metabolic stress, MOTS-c can also translocate from mitochondria to the nucleus and modulate stress-responsive nuclear gene expression in an AMPK-dependent manner. These mechanisms are established mostly in cell and animal models; human mechanistic confirmation is limited. | SS-31 concentrates at the IMM through electrostatic interaction with cardiolipin's anionic phosphate head groups, with hydrophobic stabilization from the dimethyltyrosine and phenylalanine residues. The peptide does not require mitochondrial membrane potential (ΔΨm) for uptake — a key mechanistic advantage over cationic lipophilic compounds like MitoQ. Biophysical studies show SS-31 reduces the electrostatic surface potential of cardiolipin-containing membranes by approximately 30 mV, blunting calcium-induced membrane stress. The primary downstream effect is prevention of cardiolipin peroxidation: without SS-31, cytochrome c acquires cardiolipin peroxidase activity under oxidative stress, oxidizing cardiolipin and triggering cytochrome c release (apoptosis initiation) and ETC supercomplex disassembly. SS-31 blocks this by sequestering cardiolipin in a protected conformation. Reported functional consequences in preclinical models include improved state 3 (ADP-stimulated) respiration, restored cristae architecture, reduced mtROS generation, improved ATP synthesis rates, and prevention of mPTP opening. In ischemia-reperfusion models, SS-31 administered before reperfusion reduces infarct size in rodents and pigs. These mechanisms are well supported in vitro and in preclinical models; human replication remains limited. |
| Half-life | Estimated short (~1-2 hours); exercise-induced circulating MOTS-c returns to baseline within ~4 hours. The pharmacokinetic half-life of injected MOTS-c in humans has not been formally established. | Approximately 1–2 hours terminal half-life after intravenous or subcutaneous administration; rapid systemic clearance. Exact human pharmacokinetic parameters are not fully published in peer-reviewed literature, but clearance is rapid. The clinical trial dosing intervals (once daily SC in PROGRESS-HF) suggest that biological effects may outlast plasma concentrations, consistent with the membrane-binding mechanism producing durable structural changes at the IMM that persist after peptide clearance. |
| Dosing reference | No established clinical dosing in humans. MOTS-c is not an approved therapy; dosing is being explored in early-phase trials (e.g., subcutaneous administration over ~12 weeks in prediabetes/overweight adults) and standardized human therapeutic doses have not been published. | No approved clinical dosing exists. Phase II trial doses used: PROGRESS-HF — 4 mg/day or 40 mg/day subcutaneous injection once daily for 28 days (primary endpoint: change in left ventricular end-systolic volume — not significantly different from placebo for either dose). EMBRACE-STEMI — IV infusion at 0.05 mg/kg/hour for 1 hour administered before primary PCI (primary endpoint: CK-MB area under the curve as infarct size surrogate — no significant reduction vs. placebo). These doses are from discontinued clinical development programs, not current approved protocols. |
| Routes | subcutaneous | subcutaneous, intravenous |
| Safety & side effects | Human safety has not been established; long-term data in people is lacking. Rodent studies up to several weeks generally showed no overt toxicity. Reported side effects from guides and self-experimenters (anecdotal) include injection-site redness/irritation, flushing or skin warmth, fatigue, headache, insomnia, and palpitations/increased heart rate. Because it influences glucose metabolism, caution is warranted in people on diabetes medication (theoretical additive blood-sugar effects). Product purity and sterility are real concerns with research-grade peptides. Research-use-only; not for human consumption. Consult a qualified clinician before considering any use. | SS-31/elamipretide has been consistently well tolerated across Phase I and Phase II clinical trials, with no serious drug-related adverse events attributed to it. The most common adverse event across trials was injection site reactions (pain, erythema, induration at the subcutaneous injection site), which were mild and transient. No significant organ toxicity, QTc prolongation, or laboratory abnormalities were identified in trial populations. However, Phase II trials were of short duration (28 days in PROGRESS-HF) in specific cardiovascular patient populations; long-term safety has not been systematically studied. SS-31 is not FDA-approved and is not available as a pharmaceutical. Research-grade SS-31 sold online is unregulated and carries product purity, sterility, and dosage accuracy risks. The compound is not on the WADA Prohibited List as of current published prohibited lists. It is research use only and not for human consumption in any therapeutic or performance context. |
For research use only. Not for human consumption. Always verify against current literature.