Both molecules work around the mitochondrion, but from different sides. MOTS-c is a 16-amino-acid peptide encoded in mitochondrial DNA itself and described as an exercise mimetic acting through the energy sensor AMPK. SS-31, also known as elamipretide, is a tetrapeptide that accumulates in the inner membrane and binds cardiolipin, restoring electron transport.
Key parameters side by side
Parameter
MOTS-c
SS-31
Evidence status
Experimental
Approved
Sequence length
16
4
Molecular weight
2174.50 Da
640.80 Da
Same for both: Category — Longevity
Frequently asked questions
By origin and point of action. MOTS-c is encoded in the mitochondrial 12S rRNA gene and shifts metabolism through AMPK, insulin sensitivity and fat oxidation. SS-31 was engineered externally, concentrates in the inner membrane and stabilises the respiratory chain complexes.
SS-31 went further: as elamipretide it obtained a narrow, conditional FDA approval after an initial rejection. MOTS-c has no completed interventional human trial of its own, yet WADA already lists it as prohibited.
Longevity
MOTS-c
Experimental
MOTS-c (Mitochondrial Open Reading Frame of the Twelve S rRNA type-c) is a 16-amino acid mitochondrial-derived peptide encoded in the 12S rRNA gene of mitochondrial DNA. Discovered in 2015 by Dr. Pinchas Cohen's laboratory at USC, MOTS-c was the first mitochondrial-encoded peptide shown to have profound metabolic effects — functioning as an exercise mimetic that enhances insulin sensitivity, promotes fat oxidation, and improves metabolic homeostasis.
MOTS-c's discovery expanded the concept of mitochondrial-derived peptides (MDPs) as a new class of signaling molecules. Remarkably, MOTS-c translocates to the nucleus during metabolic stress, directly regulating gene expression — the first example of a mitochondrial-encoded peptide acting as a nuclear transcription regulator. It declines with age, suggesting a role in age-related metabolic dysfunction.
SS-31 (elamipretide, Bendavia, MTP-131) is a mitochondria-targeted tetrapeptide developed at Weill Cornell Medical College that selectively concentrates in the inner mitochondrial membrane, binding to cardiolipin — a unique phospholipid essential for electron transport chain complex organization and function. By stabilizing cardiolipin-protein interactions, SS-31 restores efficient mitochondrial electron transport, reduces ROS production, and improves ATP synthesis.
SS-31 has undergone extensive clinical trials for heart failure (EMBRACE trial), mitochondrial myopathy (MMPOWER trials), and Barth syndrome. Its ability to directly target mitochondrial dysfunction addresses a fundamental mechanism underlying aging, neurodegeneration, cardiomyopathy, and metabolic disease.
MOTS-c (Mitochondrial Open Reading Frame of the Twelve S rRNA type-c) is a 16-amino acid mitochondrial-derived peptide encoded in the 12S rRNA gene of mitochondrial DNA. Discovered in 2015 by Dr. Pinchas Cohen's laboratory at USC, MOTS-c was the first mitochondrial-encoded peptide shown to have profound metabolic effects — functioning as an exercise mimetic that enhances insulin sensitivity, promotes fat oxidation, and improves metabolic homeostasis.
MOTS-c's discovery expanded the concept of mitochondrial-derived peptides (MDPs) as a new class of signaling molecules. Remarkably, MOTS-c translocates to the nucleus during metabolic stress, directly regulating gene expression — the first example of a mitochondrial-encoded peptide acting as a nuclear transcription regulator. It declines with age, suggesting a role in age-related metabolic dysfunction.
SS-31 (elamipretide, Bendavia, MTP-131) is a mitochondria-targeted tetrapeptide developed at Weill Cornell Medical College that selectively concentrates in the inner mitochondrial membrane, binding to cardiolipin — a unique phospholipid essential for electron transport chain complex organization and function. By stabilizing cardiolipin-protein interactions, SS-31 restores efficient mitochondrial electron transport, reduces ROS production, and improves ATP synthesis.
SS-31 has undergone extensive clinical trials for heart failure (EMBRACE trial), mitochondrial myopathy (MMPOWER trials), and Barth syndrome. Its ability to directly target mitochondrial dysfunction addresses a fundamental mechanism underlying aging, neurodegeneration, cardiomyopathy, and metabolic disease.