Key findings
- The identifying report located a short open reading frame within the mitochondrial 12S ribosomal RNA gene encoding a 16-amino-acid peptide, and reported that its cellular actions inhibit the folate cycle and the de novo purine biosynthesis tethered to it, leading to AMPK activation. [1]
- Under metabolic stress the peptide translocated from mitochondria to the nucleus in an AMPK-dependent manner and regulated nuclear genes including those carrying antioxidant response elements, interacting with the transcription factor NFE2L2, also called NRF2. [2]
- In differentiated C2C12 myotubes the peptide prevented palmitic-acid-induced atrophy, and the authors traced the effect through CK2, PTEN, mTORC2, AKT and FOXO1 to lower myostatin expression. [3]
- A mutant peptide carrying a single Y8F substitution in the YIFY region failed to reproduce the wild-type effects on myotube formation and on STAT3 transcriptional activity, identifying that region as necessary in these assays. [4]
Identity and structure
- Origin
- Encoded by a short open reading frame within the mitochondrial 12S ribosomal RNA gene, in the mitochondrial rather than the nuclear genome [1][2]
- Length
- 16 amino acids [1]
- Sequence feature
- A putative Src homology 2 binding motif was identified in silico in the YIFY region; substituting the tyrosine at position 8 with phenylalanine abolished the reported effects in muscle cell models [4]
- Form as supplied
- Sterile lyophilized powder
Mechanism as studied
The identifying report proposes a metabolic route rather than a receptor. The peptide's cellular actions inhibited the folate cycle and the de novo purine biosynthesis tethered to it, which led to AMPK activation, and the authors name skeletal muscle as the apparent primary target tissue. [1]
Later work adds a second, transcriptional route: under glucose restriction the peptide moved to the nucleus in an AMPK-dependent manner and regulated a broad set of nuclear genes, including antioxidant response element genes, through interaction with stress-responsive transcription factors such as NFE2L2. The authors present this as a mitochondrially encoded factor acting on the nuclear genome. [2]
Two muscle reports converge on signaling downstream of the peptide. One traces a CK2, PTEN, mTORC2, AKT and FOXO1 chain to reduced myostatin expression in myotubes and in obese mice; the other reports that the peptide blocks interleukin-6-induced STAT3 transcriptional activity through the YIFY region, and that this accompanies increased myotube formation. [3][4]
Research findings
Preclinical in vivo
- System
- Mice, including aged animals and animals fed a high-fat diet; the material is synthetic peptide rather than the endogenously encoded sequence
- Measured
- Insulin sensitivity, metabolic homeostasis measures, and diet-induced obesity
- Reported
- Age-dependent and high-fat-diet-induced insulin resistance were prevented, as was diet-induced obesity. [1]
In vitro
- System
- Cells under glucose restriction and other metabolic stress, with subcellular localization and transcription factor interaction assays
- Measured
- Nuclear translocation of the peptide, AMPK dependence, nuclear gene expression and interaction with antioxidant-response-element-regulating transcription factors
- Reported
- The peptide translocated to the nucleus in an AMPK-dependent manner, regulated a broad range of genes including antioxidant response element genes, and interacted with NFE2L2. [2]
In vitro
- System
- Differentiated C2C12 myotubes challenged with palmitic acid
- Measured
- Atrophy markers, myostatin expression, AKT phosphorylation, FOXO1 activity, mTORC2, PTEN and CK2 activity
- Reported
- Palmitic-acid-induced atrophy was prevented; AKT phosphorylation rose and FOXO1 activity fell, with increased mTORC2 and CK2 activity and inhibited PTEN. [3]
Preclinical in vivo
- System
- Diet-induced obese mice
- Measured
- Plasma myostatin levels
- Reported
- Plasma myostatin decreased in the peptide-exposed animals. [3]
In vitro
- System
- Human LHCN-M2 and murine C2C12 muscle progenitor cells, with a Y8F mutant peptide as the comparator; peptides applied at the onset of differentiation or after myotubes had formed
- Measured
- Myotube formation, nuclear myogenin staining under interleukin-6 challenge, and STAT3 transcriptional activity
- Reported
- The wild-type peptide increased myotube formation, protected against the interleukin-6-induced reduction in nuclear myogenin staining and blocked interleukin-6-induced STAT3 transcriptional activity; the Y8F mutant did none of these. [4]
Handling for in-vitro work
- Sequence controls in the cited work
- One cited report uses a single-residue Y8F variant as its negative control, so the exact sequence of a supplied peptide determines whether it matches the active or the inactive construct [4]
- Assay timing
- In the muscle differentiation work the peptide was applied either at the onset of differentiation or after myotubes had formed, so the timing of addition is part of the method record [4]
- Storage
- Lyophilized at −20 °C, dark and dry; reconstituted aliquots kept cold and used promptly
Open questions
- The cited work does not report an amino acid sequence for the peptide in its abstracts, so a supplied material cannot be matched to these papers by sequence alone.
- Identification of an endogenously encoded sequence and experiments with synthetic peptide are separate evidence questions, and neither establishes the composition of an individual supplied lot.
- The cited work proposes both a folate-cycle route and a nuclear transcriptional route, and does not establish how the two relate in a single cell type.
Lot records
Check the record for the exact material you order. A published paper and a batch certificate answer different questions.
- RV-24-0032-2 ↗MOTS-c · 99.10% HPLC2026-09-22
- RV-24-0032-1 ↗MOTS-c · 99.10% HPLC2026-09-16
References
- Lee C, Zeng J, Drew BG, et al. The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance. Cell metabolism. 2015.
- Kim KH, Son JM, Benayoun BA, et al. The Mitochondrial-Encoded Peptide MOTS-c Translocates to the Nucleus to Regulate Nuclear Gene Expression in Response to Metabolic Stress. Cell metabolism. 2018.
- Kumagai H, Coelho AR, Wan J, et al. MOTS-c reduces myostatin and muscle atrophy signaling. American journal of physiology. Endocrinology and metabolism. 2021.
- García-Benlloch S, Revert-Ros F, Blesa JR, et al. MOTS-c promotes muscle differentiation in vitro. Peptides. 2022.
Publication records fetched from PubMed on 2026-09-20. Profile text reviewed 2026-09-20.