MOTS-c
Mitochondrial-derived peptide (16 aa)
Exercise in a peptide.
Half-life
~ minutes to hours
Mol. weight
2192.5 g/mol
Sequence
MRWQEMGYIFYPRKLR
Discussions
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Overview
A 16-amino-acid peptide encoded within the mitochondrial genome (not the nuclear genome) — one of a newly recognized class of mitochondrial-derived peptides. MOTS-c is researched as an 'exercise mimetic' that improves insulin sensitivity, supports metabolic homeostasis, and combats diet-induced obesity and insulin resistance in preclinical models by activating AMPK and regulating nuclear gene expression from its mitochondrial origin.
Mechanism of action
MOTS-c is encoded in the mitochondrial DNA and translocates to the nucleus under metabolic stress, where it regulates nuclear gene expression to promote metabolic adaptation. It activates AMPK — the master cellular energy sensor that endurance exercise also activates — and improves insulin-stimulated glucose uptake in skeletal muscle, the tissue that disposes of the majority of post-meal glucose. In preclinical diet-induced-obesity models, MOTS-c improved insulin sensitivity, reduced body weight and fatty liver, and lowered plasma markers across sphingolipid, monoacylglycerol, and dicarboxylate pathways that are elevated in obesity and type 2 diabetes. Plasma MOTS-c levels correlate negatively with fasting insulin and HbA1c in human cohorts.
Researched benefits
- Improves insulin sensitivity and glucose homeostasis (preclinical + cohort data)
- Activates AMPK — the same energy-sensing pathway as endurance exercise
- Reduces diet-induced obesity and fatty liver in animal models
- Plasma MOTS-c inversely correlates with fasting insulin and HbA1c in humans
Considerations
- Human interventional data still limited
- Preclinical efficacy does not guarantee human translation
- Sourcing and stability vary
Key Academic Literature & Studies
Search more in PubMedPeer-reviewed citations and clinical trials evaluating MOTS-c in scientific literature.
The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces diet-induced obesity
Cell Metabolism · 2015 · PMID: 25738459 · DOI: 10.1016/j.cmet.2015.02.009
MOTS-c is an exercise-induced mitochondrial-encoded regulator of walking capacity and muscle metabolism
Nature Communications · 2021 · PMID: 33473133 · DOI: 10.1038/s41467-020-20790-0
Mitokines as bioenergetic stress signals in cardiovascular disease: mitochondrial communication, endocrine adaptation, and translational implications
Journal of Bioenergetics and Biomembranes · 2024 · PMID: 42734848 · DOI: 10.1007/s10863-026-10136-8
Mitochondrial-derived peptides in aging and metabolic diseases: focus on MOTS-c and humanin
Frontiers in Endocrinology · 2023 · PMID: 37426895 · DOI: 10.3389/fendo.2023.1203498
Articles & logs
AMPK and the Exercise Mimetic
How MOTS-c activates the same energy-sensing pathway as endurance training.
By Dr. M. Reyes
Cell Metabolism 2015 Landmark: Decoding Mitochondrial Retrograde Signaling
The Lee et al. discovery showing mitochondrial DNA encodes endocrine-acting peptides.
By Dr. M. Reyes
Physical Performance & Age-Associated Decline: The Nature Communications Data
How MOTS-c regulates walking capacity, skeletal muscle metabolism, and exercise adaptation.
By Editorial Team