MOTS-c (Mitochondrial-Derived Peptide)
A 16-amino-acid peptide encoded within the mitochondrial genome, studied for its role in AMPK signalling, folate-cycle regulation, and communication between the mitochondrial and nuclear genomes.
Overview
MOTS-c (Mitochondrial Open Reading Frame of the 12S rRNA type-c) is a 16-amino-acid peptide encoded by a short open reading frame located within the mitochondrial 12S ribosomal RNA gene (MT-RNR1). It was first characterised by Lee et al. in a 2015 paper published in Cell Metabolism, which described it as a peptide encoded by the mitochondrial genome rather than the nuclear genome.
MOTS-c belongs to a small class of molecules referred to in the literature as mitochondrial-derived peptides (MDPs), a group that also includes humanin. Research interest in this class centres on the observation that the mitochondrial genome appears to encode peptides which act outside the mitochondrion, a concept described in published work as mitochondrial-to-nuclear signalling.
Molecular Profile
Mechanism of Action
The published literature describes several mechanisms associated with MOTS-c in cell and animal research models:
- Folate cycle and purine biosynthesis: Lee et al. (2015) reported that MOTS-c targets the folate cycle and de novo purine biosynthesis pathway, and observed a greater than 20-fold increase in endogenous AICAR levels in the models studied.
- AMPK activation: The same work reported activation of AMP-activated protein kinase (AMPK) signalling in HEK293 cells and in skeletal muscle in mice, with skeletal muscle identified as the primary target tissue in that study (Lee et al., 2015).
- Nuclear translocation: Kim et al. (2018) observed that MOTS-c translocates to the nucleus under metabolic stress and regulates nuclear gene expression in an AMPK-dependent manner, including genes carrying antioxidant response elements (AREs).
- Transcription factor interaction: The same study reported interaction with ARE-regulating stress-responsive transcription factors, including nuclear factor erythroid 2-related factor 2 (NFE2L2/NRF2), which the authors framed as evidence of coordinated mitochondrial and nuclear genome communication (Kim et al., 2018).
- Exercise-associated expression: Reynolds et al. (2021) reported that exercise induced an approximately 12-fold increase in skeletal-muscle MOTS-c and an approximately 1.6-fold increase in circulating levels in the human cohort measured.
MOTS-c and NAD+ in the Literature
MOTS-c and NAD+ are frequently discussed alongside one another in mitochondrial metabolism research, but they are structurally and functionally distinct. MOTS-c is a mitochondrially encoded peptide, whereas NAD+ (nicotinamide adenine dinucleotide) is a coenzyme involved in redox reactions and as a substrate for enzymes including the sirtuins and PARPs. They are not analogues of one another and the published research on each has developed along separate lines.
A side-by-side treatment of the two, including how the respective literatures differ in scope and maturity, is covered in the companion reference: MOTS-c vs NAD+.
Key Published Research
The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance
Lee C, Zeng J, Drew BG, et al. Cell Metabolism. 2015; 21(3):443-454. PMID: 25738459
The originating characterisation of MOTS-c. Reported inhibition of the folate cycle and de novo purine biosynthesis leading to AMPK activation, using HEK293 and HeLa cells, rat L6 myotubes, and C57BL/6 and CD-1 mouse models.
The mitochondrial-encoded peptide MOTS-c translocates to the nucleus to regulate nuclear gene expression in response to metabolic stress
Kim KH, Son JM, Benayoun BA, Lee C. Cell Metabolism. 2018; 28(3):516-524.e7. PMID: 29983246
Reported nuclear translocation of MOTS-c under metabolic stress and AMPK-dependent regulation of antioxidant response element genes, including interaction with NFE2L2/NRF2.
MOTS-c is an exercise-induced mitochondrial-encoded regulator of age-dependent physical decline and muscle homeostasis
Reynolds JC, Lai RW, Woodhead JST, et al. Nature Communications. 2021; 12:470
Examined MOTS-c expression following exercise in human skeletal muscle and circulation, and assessed physical capacity in young, middle-aged, and old mouse cohorts.
The mitochondrial-derived peptide MOTS-c: a player in exceptional longevity?
Fuku N, Pareja-Galeano H, Zempo H, et al. Aging Cell. 2015; 14(6):921-923. PMID: 26289118
Population-genetics discussion proposing the m.1382A>C polymorphism in the MOTS-c-encoding region of mtDNA as a candidate mechanism of interest in Northeast Asian longevity research.
Storage and Handling
Lyophilised (unreconstituted):Store at -20°C for long-term stability. Stable at 2-8°C for shorter periods. Protect from light.
Reconstituted:Store at 2-8°C. Use within 30 days. Avoid repeated freeze-thaw cycles.
Recommended solvent: Bacteriostatic water or sterile water for laboratory use.
Frequently Asked Questions
What does the name MOTS-c stand for?
Mitochondrial Open Reading Frame of the 12S rRNA type-c. The name describes its origin: a short open reading frame located within the MT-RNR1 (12S ribosomal RNA) region of mitochondrial DNA.
How does MOTS-c differ from a conventional peptide?
Most peptides studied in laboratory research are encoded by nuclear DNA. MOTS-c is encoded by the mitochondrial genome, which is why the literature classes it as a mitochondrial-derived peptide (MDP) alongside humanin.
Is MOTS-c the same thing as NAD+?
No. MOTS-c is a 16-amino-acid peptide. NAD+ is a coenzyme, not a peptide, and has an entirely separate research literature. The two are often mentioned together because both appear in mitochondrial metabolism research, not because they are related compounds.
What research areas reference MOTS-c?
Published work referencing MOTS-c spans metabolic research, skeletal muscle and exercise physiology, mitochondrial biology, and ageing research. The primary mechanisms of interest in the literature are AMPK signalling and mitochondrial-to-nuclear gene regulation.
Disclaimer: This information is compiled from published peer-reviewed literature and is provided for educational and research reference purposes only. It does not constitute medical advice. MOTS-c sold by Enhanced Research Compounds is intended exclusively for in-vitro research and laboratory use. It is not a therapeutic good, is not listed on the ARTG, and is not approved for human or animal consumption.