MOTS-c
Metabolic
ABOUT
MOTS-c is a mitochondrial-derived peptide. Foundational work reported metabolic effects in cellular and mouse models; human studies cited here measure endogenous levels rather than establishing treatment benefit.
EVIDENCE OVERVIEW
Reasoned from mechanism, not measured in people
WHAT THIS MEANS
Theoretical. Review the research and limitations before relying on this record.
IDENTITY
HALF-LIFE
HOW IT IS THOUGHT TO WORK
MOTS-c is a 16-amino-acid peptide encoded within the mitochondrial 12S rRNA gene - a mitochondrial-derived peptide acting as a retrograde signal from mitochondrion to nucleus. It inhibits the folate cycle and the de novo purine biosynthesis tethered to it, which raises AICAR and activates AMPK. Under metabolic stress it translocates to the nucleus and regulates nuclear gene expression through antioxidant response elements and NRF2.
PHARMACOKINETICS
No pharmacokinetic data exists in any species. All intervention studies used mouse models with no reported exposure profile.
REVIEW
PUBLISHED PAIR RECORDS
with Humanin
Converging on mitochondrial functionMOTS-c and Humanin both act on mitochondrial biology, so their proposed effects converge rather than complement. MOTS-c and humanin are both mitochondrial-derived peptides encoded in mitochondrial DNA and described as retrograde signals to the nucleus; their reported metabolic and cytoprotective effects overlap substantially, and human data for both is observational - circulating levels associated with age and disease - with no interventional trial for either. No study has characterised this combination. Peppy reports curated pharmacology, not a safety verdict. A prescriber or pharmacist should review any intended combination.
Reviewed 21 Aug 2026with SS-31
Converging on mitochondrial functionMOTS-c and Elamipretide (SS-31) both act on mitochondrial biology, so their proposed effects converge rather than complement. Elamipretide is the only one of this group tested in a large controlled human trial, and MMPOWER-3 did not meet either primary endpoint; the mitochondrial-derived peptide in this pair has no interventional human data at all. Their mechanisms differ within the same organelle - cardiolipin binding on the inner membrane versus retrograde signalling to the nucleus - so overlap is at the level of target tissue rather than target molecule. No study has characterised this combination. Peppy reports curated pharmacology, not a safety verdict. A prescriber or pharmacist should review any intended combination.
Reviewed 21 Aug 2026HUMAN EVIDENCE
Human data is observational only. Plasma MOTS-c decreases with age, and reduced serum and tumour MOTS-c in ovarian cancer patients is associated with poorer prognosis. Those are associations, not effects of administration. No interventional human trial has been reported. Every efficacy finding - insulin sensitisation, exercise capacity, gestational diabetes models - is from mice.
REPORTED EFFECTS
No human safety data exists. MOTS-c was added to FDA's Category 2 interim compounding list in September 2023 as a substance that may present significant safety risks. No regulator has approved this substance for the use described here, so there is no label-verified dose, purity standard, or safety monitoring requirement behind it.
RESEARCH LIMITATIONS
Preclinical and biomarker observations are not evidence that administered MOTS-c is effective or safe in people. No dose, protocol, or interaction conclusion is provided.
CURATED SOURCES · 4