Research Profile — Longevity and Anti-aging Research
MOTS-c: Complete Mitochondrial Peptide Research Profile
Mitochondrial-derived peptideMDP MOTS-c
MOTS-c is a 16-amino-acid mitochondrial-derived peptide (MDP) that represents a paradigm shift in understanding mitochondrial biology. Discovered by Lee et al. in 2015 and published in Cell Metabolism, MOTS-c is encoded within the 12S rRNA gene of the mitochondrial genome. This was a groundbreaking finding because mitochondrial DNA was previously thought to encode only 13 proteins involved in the electron transport chain. MOTS-c demonstrated that the mitochondrial genome contains previously unrecognized open reading frames encoding bioactive signaling peptides. MOTS-c is notable for its ability to translocate to the cell nucleus under stress conditions and directly regulate nuclear gene expression — representing a novel form of mitochondria-to-nucleus communication (retrograde signaling). It has become a focus of longevity, metabolic, and exercise physiology research.
Technical Specifications
CAS Number
1627580-64-6
Molecular Formula
C101H152N28O22S2
Molecular Weight
2174.62 g/mol
Amino Acids
16
Sequence
MRWQEMGYIFYPRKLR
Purity
≥99% (HPLC)
Appearance
White lyophilized powder
Salt Form
Acetate
Solubility
Soluble in water, DMSO
Storage
-20°C lyophilized, 2-8°C reconstituted
Origin & Discovery
MOTS-c was discovered in 2015 by Changhan Lee's laboratory at the University of Southern California. It is encoded within the mitochondrial genome (12S rRNA gene) rather than the nuclear genome, making it one of the first identified mitochondrial-derived peptides (MDPs) with hormonal signaling functions. This discovery challenged the long-held view that the mitochondrial genome only encodes 13 proteins involved in oxidative phosphorylation.
Mechanism of Action
MOTS-c operates through a unique mechanism involving AMPK activation and direct nuclear translocation.
AMPK Activation: MOTS-c activates AMP-activated protein kinase (AMPK), the master metabolic sensor and regulator. AMPK activation promotes glucose uptake, fatty acid oxidation, and mitochondrial biogenesis while suppressing energy-consuming anabolic processes. This mechanism mimics the metabolic effects of exercise and caloric restriction — both well-established interventions in longevity research.
MTHFD2 Inhibition: MOTS-c inhibits the folate cycle enzyme Methylenetetrahydrofolate Dehydrogenase 2 (MTHFD2), leading to accumulation of the purine biosynthesis intermediate AICAR (5-aminoimidazole-4-carboxamide ribonucleotide). AICAR is an endogenous AMPK activator, providing the mechanistic link between MOTS-c and AMPK pathway activation.
Nuclear Translocation: Under metabolic stress conditions (glucose restriction, oxidative stress), MOTS-c translocates from the cytoplasm to the nucleus, where it interacts with nuclear DNA and regulates gene expression. This retrograde signaling from mitochondria to nucleus allows MOTS-c to coordinate cellular stress responses at the transcriptional level.
Exercise Mimetic: MOTS-c's AMPK activation, glucose metabolism enhancement, and stress-responsive nuclear translocation collectively produce a metabolic profile that resembles the cellular effects of physical exercise, leading researchers to characterize it as an "exercise mimetic" peptide.
Metabolic Regulation & Exercise Biology
The discovery paper by Lee et al. (2015) in Cell Metabolism demonstrated that MOTS-c treatment in mice prevented age-dependent and high-fat diet-induced insulin resistance. MOTS-c-treated mice showed improved glucose tolerance, reduced fat accumulation, and enhanced insulin sensitivity. The metabolic effects were traced to AMPK activation through MTHFD2 inhibition and AICAR accumulation. Kim et al. (2018) further published in Cell Metabolism that endogenous MOTS-c levels increase during exercise in both mice and humans, and that MOTS-c translocates to the nucleus in response to metabolic stress. This finding established MOTS-c as both an exercise-responsive peptide and a potential mediator of exercise's metabolic benefits.
Citations
Lee C, et al. (2015) "MOTS-c: mitochondrial-derived peptide regulates metabolism." Cell Metab, 21(3), 443-454.
Kim KH, et al. (2018) "MOTS-c nuclear translocation during exercise." Cell Metab, 28(3), 516-524.
Aging & Longevity Research
Reynolds et al. (2021) published in Nature Communications that MOTS-c treatment improved physical performance in aged mice (23.5 months, equivalent to ~70 human years). Treated mice showed improved treadmill endurance, grip strength, and gait parameters compared to age-matched controls. Importantly, MOTS-c levels decline with age in humans, suggesting that supplementation restores signaling that is lost during aging. The study also demonstrated that MOTS-c activated an adaptive stress response in skeletal muscle, with gene expression changes associated with enhanced mitochondrial function and reduced inflammatory markers.
Citations
Reynolds JC, et al. (2021) "MOTS-c improves physical function in aged mice." Nat Commun, 12(1), 3181.
Frequently Asked Questions
What is MOTS-c?▼
MOTS-c (Mitochondrial Open Reading Frame of the 12S rRNA Type-c) is a 16-amino-acid peptide encoded in the mitochondrial genome. Discovered in 2015, it activates AMPK and can translocate to the nucleus to regulate gene expression. It is studied for metabolic regulation and longevity.
How does MOTS-c relate to exercise?▼
MOTS-c levels increase during exercise in both mice and humans. It activates AMPK (the same pathway activated by exercise) and produces metabolic effects similar to physical activity. Kim et al. (2018) showed that MOTS-c nuclear translocation occurs during exercise stress, suggesting it may mediate some exercise benefits.
What is the CAS number of MOTS-c?▼
The CAS registry number for MOTS-c is 1627580-64-6.