Abstract
MOTS-c is a 16-amino-acid peptide encoded within the mitochondrial 12S rRNA gene, representing a class of mitochondrial-derived peptides (MDPs) that facilitate communication between mitochondria and nuclear processes. Under conditions of metabolic stress, MOTS-c translocates to the nucleus where it modulates gene expression to enhance adaptive responses, primarily through activation of AMP-activated protein kinase (AMPK).
Introduction
The interplay between mitochondrial function and nuclear gene regulation forms a cornerstone of cellular adaptation to environmental and physiological stressors. MOTS-c emerges as a prototypical MDP, encoded not by nuclear DNA but by the mitochondrial genome itself. Discovered through bioinformatic screening, MOTS-c exemplifies how non-canonical translation from rRNA regions can yield functional peptides with broad regulatory influence.
Molecular Background
MOTS-c originates from the mitochondrial genome, a compact 16.6 kb circular DNA molecule. The 12S rRNA locus conceals a 51-nucleotide small open reading frame translating to the sequence MRWQEMGYIFYPRKLR. This 16-residue peptide undergoes post-translational amidation at the C-terminus.
Phylogenetic analysis across mammalian species reveals stringent conservation, suggesting evolutionary pressures favoring functional versatility. Tissue distribution correlates with metabolic demand—higher in oxidative slow-twitch muscle fibers versus glycolytic fast-twitch fibers.
Mechanisms of Action
AMPK Activation
Central to MOTS-c activity is AMP-activated protein kinase activation. MOTS-c indirectly engages AMPK by inhibiting the folate cycle at the MTHFD2 step, curtailing de novo purine synthesis. This elevates AICAR (5-aminoimidazole-4-carboxamide ribonucleotide), an AMP mimetic that allosterically activates AMPKα.
Activated AMPK then phosphorylates acetyl-CoA carboxylase (ACC), promoting fatty acid oxidation and GLUT4 translocation for enhanced glucose uptake.
mTOR Modulation
MOTS-c tempers mTOR in nutrient-replete states while enhancing mTORC2 for survival signaling. This duality echoes caloric restriction mimetics.
FOXO3 Interactions
Through AMPK-mediated phosphorylation, FOXO3 is sequestered in the cytoplasm, reducing atrogin-1 and MuRF1 transactivation in muscle tissue.
NRF2 Engagement
NRF2 activation occurs via antioxidant response element (ARE) binding after MOTS-c nuclear translocation, promoting SOD2 and GPx expression.
Metabolic and Physiological Roles
MOTS-c orchestrates metabolic partitioning toward oxidation. Key effects include:
- Enhanced insulin responsiveness (~30% increased glucose infusion rates in clamp studies)
- Reduced lipogenesis via PPARγ attenuation
- Improved endurance (~2-fold distance gains in rodent treadmill assays)
- Circadian rhythm restoration
- Anti-inflammatory effects via NF-κB/STAT1 suppression
Preclinical Research
In Vitro Studies
- HEK293 overexpression alters 194 metabolites with purine pathway suppression
- C2C12 myotubes show ~2-fold viability preservation under palmitate stress
- BMSC cultures demonstrate increased osteoblast differentiation
Animal Models
- Diet-induced obesity (C57BL/6J): 5 mg/kg IP × 8 weeks prevents 20% weight gain, reduces hepatic steatosis
- Aging cohorts (2-22 mo): Uniform endurance improvements with HSF1-dependent effects
- Late-life dosing (23.5 mo): Improved grip strength (+15%), stride length (+12%), walking velocity (+18%)
- Vascular calcification: 50% reduction in aortic calcium deposits
- Sepsis models: 40% improved survival, 50% reduction in TNF-α/IL-6
Human Research
Human data remain primarily observational:
- Plasma MOTS-c shows 21% reduction in elderly (70-81 years) versus young (18-30 years)
- Exercise induces ~12-fold increase in skeletal muscle MOTS-c mRNA
- Plasma levels rise ~50% transiently with exercise
- Age-related decline correlates inversely with lean mass
- Low circulating levels associate with endothelial dysfunction
Safety Profile
Preclinical dosing (0.5-15 mg/kg, IP/SC, acute/chronic) shows no overt toxicity with normal organ indices and histology. No human interventional trials exist as of December 2025.
Summary Table
| Aspect | Key Findings | Model |
|---|---|---|
| AMPK Activation | AICAR accumulation, ACC/CPT-1 modulation | C2C12/DIO mice |
| Exercise Capacity | ~2× treadmill distance | Aged mice (2-22 mo) |
| Insulin Sensitivity | +30% glucose infusion rate | HFD mice |
| Human Levels | -21% in elderly; exercise +12× mRNA | Males 18-81 y |
Conclusion
MOTS-c embodies the paradigm of mitochondrial endocrinology—a compact envoy from mtDNA that reprograms nuclear responses to safeguard metabolic balance. Its AMPK-centric mechanism, combined with effects on HSF1 and TGF-β pathways, yields broad protective effects against metabolic dysregulation and age-related decline.
While human interventional data are needed, the convergence of mechanistic understanding and preclinical efficacy positions MOTS-c as an important subject for continued research into mitochondrial-derived peptides and their roles in metabolic regulation.