MOTS-C

Origin and Structure of MOTS-C

MOTS-C (Mitochondrial Open Reading Frame of the 12S rRNA Type-C) is a 16-amino acid mitochondrial-derived peptide (MDP). Unlike most biologically active peptides, MOTS-C is not encoded by nuclear DNA but by the MT-RNR1 gene (12S rRNA) located in the mitochondrial genome. The peptide was first identified and described in 2015 by Changhan David Lee's research group at the University of Southern California.

The sequence MRWQEMGYIFYPRKLR with a mass of ~2174.6 Da contains two methionine residues (positions 1 and 6), making the molecule susceptible to oxidation. MOTS-C belongs to a new class of signaling molecules — mitochondrial-derived peptides (MDPs), alongside humanin and the SHLP1-6 family. The discovery that the mitochondrial genome encodes short peptides with regulatory functions opened a new research direction into retrograde communication between mitochondria and the cell nucleus.

Mechanism of Action

The central element of the molecular mechanism of MOTS-C, described in cellular and mouse models, is activation of AMPK (AMP-activated protein kinase), a key cellular energy sensor. MOTS-C does not activate AMPK directly but acts on a metabolic pathway upstream in the cascade, targeting the AICAR transformylase enzyme (ATIC) in the folate-methionine cycle.

Inhibition of ATIC by MOTS-C leads to accumulation of endogenous AICAR (5-aminoimidazole-4-carboxamide ribonucleotide), an intermediate metabolite in de novo purine synthesis. AICAR is a well-known AMPK activator, which explains the indirect mechanism of kinase activation by the peptide. Consequently, MOTS-C inhibits de novo purine biosynthesis, affecting cellular metabolism and energy homeostasis in the studied mouse models.

In 2018, Lee's group demonstrated in cell cultures that under metabolic stress conditions, MOTS-C translocates to the cell nucleus, where it regulates expression of nuclear genes related to stress response. This observation suggests that a mitochondrial-derived peptide can serve as a signaling molecule in retrograde mitochondria-to-nucleus communication.

Research Overview

Discovery of MOTS-C

MOTS-C was described by Lee C, Zeng J, Drew BG, et al. in a landmark 2015 publication in Cell Metabolism (21(3):443-454). The authors identified the peptide as a product of an open reading frame in the 12S rRNA gene of mitochondrial DNA and demonstrated its ability to regulate metabolic homeostasis in cellular models ^[1].

AMPK activation and the folate cycle

In the same publication, Lee et al. described the molecular mechanism: MOTS-C targets the ATIC enzyme in the folate-methionine cycle, leading to AICAR accumulation and AMPK activation. Kim SJ, Xiao J, Wan J, Cohen P, and Yen K in a Journal of Physiology review (2017, 595(21):6613-6621) discussed the role of MOTS-C and other MDPs as a new class of signaling molecules ^[1,2].

Nuclear translocation

Kim KH, Son JM, Benayoun BA, and Lee C (2018) demonstrated in Cell Metabolism (28(3):516-524) that under metabolic stress, MOTS-C translocates to the cell nucleus, where it regulates expression of genes related to antioxidant response. This was the first report of a mitochondrial-derived peptide serving a direct regulatory function in the nucleus ^[3].

MOTS-C in animal models

In the original work by Lee et al. (2015), studies on C57BL/6J mice demonstrated significant changes in metabolic parameters, including improved insulin sensitivity measured by glucose tolerance test and changes in folate cycle metabolite profiles. Increased oxygen consumption and metabolic activity in muscle tissue were shown, correlating with enhanced AMPK phosphorylation ^[1].

Structural Features

MOTS-C is a 16-amino acid peptide with a mass of ~2175 Da, characterized by:

• Mitochondrial origin — encoded by mtDNA (MT-RNR1 gene), not nuclear DNA, which is unique among peptides
• Two methionine residues (Met¹, Met⁶) — susceptible to oxidation, requiring appropriate storage conditions
• Sequence MRWQEMGYIFYPRKLR — rich in aromatic (Trp, Tyr×2, Phe) and basic (Arg×2, Lys) amino acids
• No disulfide bridges — the peptide contains no cysteine, simplifying storage

Intended Use

This product is a chemical raw material intended exclusively for in vitro research, scientific, and analytical applications. It is not intended for human or veterinary use, including for diagnostic, therapeutic, prophylactic, or nutritional purposes.

Handling

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Regulatory Classification

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