MOTS-c is a 16-residue peptide whose coding sequence sits inside the mitochondrial genome, in the gene for 12S ribosomal RNA. Its name is an acronym for “mitochondrial open reading frame of the 12S rRNA type-c”. Reported in 2015 by Pinchas Cohen’s group at the University of Southern California, it joined humanin as one of the first mitochondrial-derived peptides with a defined signaling role.
The peptide matters to researchers because it challenges a long-held assumption: that the 37 genes of human mitochondrial DNA only build respiratory machinery and the RNA needed to translate it. MOTS-c suggests that mitochondria can also send coded messages to the rest of the cell. The sections below look at how it was found, the folate–AMPK and nuclear-signaling mechanisms described so far, the main model systems, and where the evidence is still thin.
At a glance
- Class: Mitochondrial-derived peptide (MDP), 16 amino acids
- Origin: Identified by Lee, Cohen and colleagues at USC; first described in 2015
- Structure: Met-Arg-Trp-Gln-Glu-Met-Gly-Tyr-Ile-Phe-Tyr-Pro-Arg-Lys-Leu-Arg; C101H152N28O22S2; MW 2174.6 g/mol; CAS 1627580-64-6
- Main research areas: AMPK and folate–methionine metabolism, skeletal muscle insulin signaling, nuclear stress-response genes, mitochondrial-nuclear communication
- Regulatory status: Not approved by the FDA for any use; research reagent only
Structure and origin
The discovery came from a deliberate search. After humanin was found within the 16S rRNA gene, the Cohen laboratory scanned the mitochondrial genome for other short open reading frames that could encode bioactive peptides. One such frame, within the 12S rRNA gene (MT-RNR1), predicted a 16-amino-acid product. Antibodies raised against it detected the peptide in multiple rodent tissues and in plasma, and the synthetic version was active in cultured cells (Lee et al., 2015).
An unusual detail concerns translation. The mitochondrial genetic code differs from the standard nuclear code at a few codons, and the authors proposed that the MOTS-c transcript is exported and translated by cytoplasmic ribosomes using the standard code. That would make it a mitochondrially encoded peptide made outside the organelle. The sequence is hydrophobic in its middle section and strongly basic at the C-terminus, where three arginines and a lysine cluster within the last five residues, a feature later linked to its ability to enter the nucleus (Lee, Kim and Cohen, 2016).
Mechanism: what the research shows
The first mechanistic model centered on one-carbon metabolism. In HEK293 cells, MOTS-c reduced flux through the folate cycle and the linked de novo purine synthesis pathway. This led to accumulation of the purine intermediate AICAR (5-aminoimidazole-4-carboxamide ribonucleotide), an endogenous activator of AMP-activated protein kinase (AMPK). AMPK activation, increased glucose uptake and changes in lipid handling followed. In mice, skeletal muscle appeared to be the main target tissue (Lee et al., 2015).
A second model added the nucleus. Kim and colleagues found that under metabolic stress, including glucose restriction, serum deprivation and oxidative stress, MOTS-c moved from the cytoplasm into the nucleus in an AMPK-dependent manner. There it bound chromatin and worked with stress-responsive transcription factors such as NRF2 to regulate genes carrying antioxidant response elements (Kim et al., 2018). Together the two papers describe a loop in which a mitochondrial peptide senses energy status and then adjusts nuclear gene expression.
Key areas of study
AMPK and one-carbon metabolism
Metabolomic tracing, AMPK phosphorylation assays and folate-cycle measurements in cultured cells remain the core of mechanistic MOTS-c work. These experiments separate the peptide’s effect on purine intermediates from direct kinase activation and connect it to methionine and folate metabolism (Lee et al., 2015).
Skeletal muscle and insulin signaling in rodents
In mice fed a high-fat diet, MOTS-c treatment was associated with better glucose tolerance and insulin sensitivity in skeletal muscle than in untreated controls, and with less diet-induced weight gain. Similar readouts were reported in older mice with age-related insulin resistance (Lee et al., 2015). These rodent findings made muscle glucose handling the most common in vivo endpoint in later MOTS-c studies.
Nuclear translocation and stress-response genes
Imaging of tagged and endogenous peptide, chromatin binding assays and gene-expression profiling have been used to follow MOTS-c into the nucleus during stress. This line of work treats the peptide as a model for retrograde signaling from mitochondria to the nuclear genome (Kim et al., 2018).
Circulating levels, aging and broader physiology
Reviews of the field summarize studies measuring MOTS-c in plasma and tissues across age, exercise and disease states, and rodent work extending into bone, vascular and inflammatory models (Wan et al., 2023). Most of these are association or single-model studies, and they point to questions for further research rather than settled roles.
What the evidence does not show
Much of the foundational work comes from one laboratory network, and independent reproduction of the folate-cycle mechanism is limited. Measuring endogenous MOTS-c is technically difficult: reported plasma levels vary between studies, and antibody-based assays for very short peptides can lack specificity. The proposed cytoplasmic translation of a mitochondrial transcript is plausible but not fully characterized, and no dedicated cell-surface receptor has been identified. In vivo findings come from rodents, often with short treatment periods. None of this establishes any effect outside the models studied.
Regulatory status
MOTS-c is not approved by the FDA for any use and is not approved for human use. Rogue Compounds sells it as a research reagent only.
Handling and storage in the lab
Lyophilized MOTS-c should be kept sealed and refrigerated at 2–8°C (36–46°F), protected from light. Leave the vial closed until it is needed so the powder is not exposed to moisture.
Sourcing and documentation
Rogue Compounds has MOTS-c made in small batches. Every vial carries a batch number and a QR code that opens the independent U.S. testing lab’s own report for that batch. The same batch COA is posted on the product page and in the COA Library.
View MOTS-C on Rogue Compounds
References
- Lee C, et al. The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance. Cell Metab. 2015;21(3):443-454. PMID 25738459
- Kim KH, et al. The mitochondrial-encoded peptide MOTS-c translocates to the nucleus to regulate nuclear gene expression in response to metabolic stress. Cell Metab. 2018;28(3):516-524. PMID 29983246
- Lee C, Kim KH, Cohen P. MOTS-c: a novel mitochondrial-derived peptide regulating muscle and fat metabolism. Free Radic Biol Med. 2016;100:182-187. PMID 27216708
- Wan W, et al. Mitochondria-derived peptide MOTS-c: effects and mechanisms related to stress, metabolism and aging. J Transl Med. 2023;21:36. PMID 36670507
Research use only. Rogue Compounds products are sold strictly for laboratory research. They are not for human or veterinary use, and nothing in this article is medical advice. The studies cited here describe published research, not this product or any use of it.