MOTS-c
Mitochondrial-derived peptide · Research-grade reference material
Identity
- Molecular formula
- Not consistently reported across sources — confirm against internal reference standard before publishing
- Molecular weight
- 2174.6 g/mol
- CAS number
- 1627580-64-6
Research Background
MOTS-c is a 16-amino-acid peptide encoded not by nuclear DNA but by a short open reading frame within the mitochondrial 12S rRNA gene (MT-RNR1), one of a rare class of “mitochondrial-derived peptides,” molecular messages produced directly from the mitochondrial genome rather than the cell’s nucleus.
First identified in 2015 by Changhan David Lee and colleagues at the University of Southern California (Lee et al.). MOTS-c’s primary, best-established research area is metabolic regulation. A separate, much newer and still-developing line of research examines its relationship to cancer biology, addressed below with the caution that early-stage findings warrant.
Lab-tested research material
Mechanism
MOTS-c activates AMPK, the same cellular energy-sensing pathway triggered by exercise and fasting, by inhibiting the folate cycle and de novo purine biosynthesis, which increases AICAR (a natural AMPK activator) and drives AMPK activation. Under metabolic stress, MOTS-c also translocates into the cell nucleus in an AMPK-dependent manner, where it binds the transcription factor NRF2 to activate antioxidant stress-response genes (Kim et al.). In mouse models, MOTS-c treatment improved insulin sensitivity and prevented diet-induced obesity (Lee et al.).
A newer, separate research area examines MOTS-c’s relationship to tumor biology. A 2024 study found MOTS-c levels significantly reduced in both blood and tumor tissue from ovarian cancer patients, and that restoring MOTS-c in cell culture and animal models slowed tumor cell growth via a specific protein-degradation mechanism (Yin et al.). A separate study on adrenal tumors found a more complicated, tissue- and disease-state-dependent pattern rather than a single consistent rule. This is exclusively cell culture and animal model research. No human clinical trial has tested MOTS-c for cancer, and none of this constitutes or implies a treatment claim for any human disease.
First described by Lee et al. (2015), MOTS-c helped establish that the mitochondrial genome encodes signaling peptides — reframing mitochondria from passive energy suppliers to active participants in cellular communication. Research since has focused on metabolic regulation, exercise adaptation, and stress response. Findings below derive from cell-culture and animal systems. They are not established effects in humans.
AMPK activation (central mechanism). Reported to act indirectly by inhibiting the folate cycle and de novo purine synthesis, raising AICAR and activating AMPK — distinct from direct AMPK activators.
Glucose handling. Enhanced glucose flux and GLUT4-associated uptake in skeletal muscle models; reduced glucose levels in treated mice.
Fatty-acid oxidation & mitochondrial biogenesis. ACC phosphorylation and PGC-1α-associated adaptations reported in animal models.
Nuclear translocation. Under metabolic stress, MOTS-c has been reported to move to the nucleus and influence nuclear gene expression.
Exercise interaction. Reported synergy with exercise intervention on PGC-1α expression and insulin resistance via AMPK signaling in mice.
Proposed pathways investigated in preclinical (in-vitro / animal) models. Schematic only; not a claim of established human effect.
State of the Evidence
MOTS-c’s metabolic research base is animal and cell-culture work, consistent and mechanistically well-characterized, but without large-scale human trial data. Its cancer-biology research is considerably earlier stage: a single 2024 mechanistic study in ovarian cancer models, with a separate adrenal tumor study showing a more complicated, non-uniform pattern across tumor types. Treat the cancer-related findings as an active, unresolved research question, not a settled or generalizable result.
1. Animal — “The Mitochondrial-Derived Peptide MOTS-c Promotes Metabolic Homeostasis and Reduces Obesity and Insulin Resistance,” Cell Metabolism, 2015. PMID 25738459
2. In Vitro / Animal — “The Mitochondrial-Encoded Peptide MOTS-c Translocates to the Nucleus to Regulate Nuclear Gene Expression in Response to Metabolic Stress,” Cell Metabolism, 2018. PMID 29983246
3. Animal / In Vitro — “Mitochondrial-Derived Peptide MOTS-c Suppresses Ovarian Cancer Progression…,” Advanced Science, 2024. Preclinical only; no human trial exists. DOI 10.1002/advs.202405620
What the Literature Supports — and What It Doesn’t
MOTS-c has a coherent and actively replicated preclinical mechanism. The human literature is largely observational — associating endogenous plasma MOTS-c levels with metabolic states — rather than interventional. That distinction matters.
Evidence at a glance
Human work to date largely reports endogenous plasma MOTS-c associations with metabolic states (a 2024 systematic review and meta-analysis in Diabetol Metab Syndr examined MDP–metabolic correlations).
Lower circulating MOTS-c has been reported in type 2 diabetes, gestational diabetes, and obesity cohorts — an association, not a demonstrated causal or therapeutic effect.
Interventional data on exogenous administration is animal-model based; no approved human indication.
The “exercise mimetic” description originates in preclinical transcriptional findings and should not be read as an established human outcome.
Appropriate characterization: a mitochondrial-derived peptide with a distinctive, well-described preclinical AMPK mechanism and consistent observational human associations, awaiting interventional human study.
Regulatory & status notes
Selected references
- 1. Lee C, et al. The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance. Cell Metab. 2015.
- 2. Zhou Q, Yin S, Lei X, et al. The correlation between mitochondrial derived peptide (MDP) and metabolic states: a systematic review and meta-analysis. Diabetol Metab Syndr. 2024;16:200.
- 3. Zheng Y, Wei Z, Wang T. MOTS-c: A promising mitochondrial-derived peptide for therapeutic exploitation. Front Endocrinol. 2023;14:1120533.
- 4. Yang B, et al. MOTS-c interacts synergistically with exercise intervention to regulate PGC-1α expression… via AMPK. BBA Mol Basis Dis. 2021;1867:166126.
- 5. Pham T, et al. Mitochondria-derived peptide MOTS-c restores mitochondrial respiration in type 2 diabetic heart. Front Physiol. 2025;16:1602271.
Safety Information
Research-use compound with limited human data. Evidence strength varies — see the Evidence section above.
No established clinical contraindications. This is an investigational compound with limited human data and has not been evaluated by the FDA for safety in this context. Consult a qualified clinician. Nothing on this page implies or claims any therapeutic, preventive, or treatment benefit for any human disease, including cancer. For research and educational purposes only, not for human or veterinary use.
Related Compounds
For research and educational purposes only. Not for human or veterinary use.