MOTS-c
Also known as: Mitochondrial Open Reading Frame of the 12S rRNA-c
A 16-amino-acid, mitochondrial-DNA-encoded peptide studied as an exercise mimetic for its effects on AMPK activation and metabolic homeostasis.
Molecular Data
- Class
- 16-amino-acid mitochondrial-derived peptide (MDP) / Metabolic regulator
- Molecular Weight
- 2,174.59 Da
- Molecular Formula
- C₁₀₁H₁₅₂N₂₈O₂₂S₂
- Half-Life
- Short (estimated from rodent pharmacokinetic data; precise human half-life not established)
- Sequence / Structure
- Met-Arg-Trp-Gln-Glu-Met-Gly-Tyr-Ile-Phe-Tyr-Pro-Arg-Lys-Leu-Arg
Mechanism of Action
MOTS-c is unusual among signaling peptides in that it is encoded within the mitochondrial genome itself — specifically the 12S rRNA region of mitochondrial DNA — rather than the nuclear genome. Once translated, it translocates to the cytoplasm and nucleus to influence metabolic gene programs.
- AMPK activation: MOTS-c inhibits the folate-methionine cycle and its linked de novo purine biosynthesis pathway, causing AICAR to accumulate and activate AMP-activated protein kinase (AMPK) — the same energy-sensing pathway engaged by exercise and caloric restriction.
- Glucose uptake: Downstream of AMPK activation, MOTS-c promotes GLUT4 translocation to the cell membrane, increasing glucose uptake in skeletal muscle independent of insulin signaling.
- Mitochondrial–nuclear communication: Under metabolic stress, MOTS-c translocates to the nucleus and regulates antioxidant response element (ARE)-containing genes, positioning it as a messenger between mitochondrial status and nuclear gene expression.
- Exercise mimetic activity: Because MOTS-c reproduces several molecular signatures of aerobic exercise training (AMPK activation, improved insulin sensitivity, enhanced mitochondrial respiratory capacity), it is studied as a tool for isolating exercise-associated metabolic pathways from physical activity itself.
Research History
MOTS-c was first described in 2015 by Changhan Lee and colleagues at the University of Southern California's Leonard Davis School of Gerontology, in a study published in Cell Metabolism. The discovery was notable because MOTS-c is one of only a small number of peptides now known to be encoded by mitochondrial rather than nuclear DNA.
The foundational study demonstrated that MOTS-c administration improved insulin sensitivity on euglycemic clamp testing in mice, and that sustained lower-dose administration over 8 weeks attenuated diet-induced obesity and restored glucose tolerance in a high-fat-diet model. These findings established MOTS-c's core research profile as a regulator of glucose and lipid metabolism acting through AMPK.
Subsequent research has extended into exercise physiology (MOTS-c levels rise in response to physical activity in both rodent and human studies), aging biology (age-related decline in circulating MOTS-c has been reported), and pancreatic islet cell senescence. As of the most recent published research, MOTS-c remains an investigational compound studied in preclinical and early translational settings; it has not been evaluated in large-scale human clinical trials or approved for any therapeutic use.
Notable Studies
The Mitochondrial-Derived Peptide MOTS-c Promotes Metabolic Homeostasis and Reduces Obesity and Insulin Resistance
2015Lee C, Zeng J, Drew BG, et al. · Cell Metabolism
Foundational paper describing MOTS-c's discovery and demonstrating improved insulin sensitivity (euglycemic clamp) and attenuated diet-induced obesity with sustained lower-dose administration in mice.
MOTS-c is an exercise-induced mitochondrial-encoded regulator of age-dependent physical decline and muscle homeostasis
2021Reynolds JC, Lai RW, Woodhead JST, et al. · Nature Communications
Demonstrated that MOTS-c levels rise with exercise and decline with age, and that administration in older mice improved physical performance and muscle function.
MOTS-c: A promising mitochondrial-derived peptide for therapeutic exploitation
2023Kim KH, Son JM, Benayoun BA, Lee C. · Frontiers in Endocrinology
Review summarizing MOTS-c's proposed mechanisms and research applications across metabolic disease, aging, and exercise physiology.
Research Protocols
The following protocols describe doses used in published research studies. They are not prescriptions or recommendations for human use.
Diet-induced obesity mouse model
- Dose
- 0.5 mg/kg/day
- Route
- Subcutaneous or intraperitoneal
- Frequency
- Once daily
- Duration
- 8 weeks
Dose from Lee et al. 2015; attenuated weight gain and restored glucose tolerance in high-fat-diet mice. Animal research dose, not established for human use.
Acute insulin-sensitivity study (euglycemic clamp)
- Dose
- 5 mg/kg/day
- Route
- Intraperitoneal
- Frequency
- Once daily
- Duration
- 7 days
Higher, short-duration dose used to demonstrate acute effects on insulin sensitivity in the original 2015 study.
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