5 Things You Should Know About MOTS-c
Origins and applications of the peptide world's exercise mimetic
What is the peptide otherwise known as the Mitochondrial Open Reading Frame of the 12S rRNA type-c, or MOTS-c for short? Here are five facts about its synthesis, applications, and impact.
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1. It’s derived from mitochondrial DNA
A 2023 study in the Journal of Translational Medicine described MOTS-c as “a peptide encoded by the short open reading frame of the mitochondrial 12S gene.”
To understand what this scientific jargon is and why it’s describing something significant, you’ll need to know how most peptides are synthesized. Every cell contains DNA “blueprints” for the synthesis of proteins within its nucleus. Cells transcribe nuclear DNA into messenger RNA (mRNA), which then binds to ribosomes — aka cellular protein factories — capable of reading the mRNA’s genetic code and synthesizing individual amino acids together into a chain.
MOTS-c is different because it’s transcribed by mitochondrial DNA (mtDNA) as opposed to nuclear DNA. Mitochondria are the powerhouses of the cell, responsible for breaking down nutrients from the food we’ve eaten and turning it into adenosine triphosphate (ATP), otherwise known as our body’s chemical energy. This is why MOTS-c’s production is so closely linked to the sort of metabolic demand we experience during exercise — its site of synthesis is also where the body’s chemical energy is created.
2. It was discovered in 2015
MOTS-c was discovered in the Pinchas Cohen laboratory at the USC Davis School of Gerontology in 2015. The research team reported a 16-amino-acid peptide encoded by a “short open reading frame” (sORF) within the mtDNA.
The researchers observed MOTS-c’s effects in “regulating insulin sensitivity and metabolic homeostasis” in mice:
“MOTS-c treatment in mice prevented age-dependent and high-fat-diet-induced insulin resistance, as well as diet-induced obesity. These results suggest that mitochondria may actively regulate metabolic homeostasis at the cellular and organismal level via peptides encoded within their genome.”
3. It mimics the effects of physical exercise by promoting insulin sensitivity
MOTS-c promotes glucose uptake into cells and enhances fatty acid oxidation, or the process of turning food intake into ATP.
The way MOTS-c does this is through activation of the AMPK pathway, or the AMP-activated protein kinase pathway. AMPK is a compound that functions in our bodies like an energy sensor, setting right metabolic systems that have been thrown out of balance. When cellular energy drops, AMPK activates metabolic pathways that promote the synthesis of ATP — more fat-burning and cellular energy — and slow down high-energy-consuming processes like cell growth and protein synthesis.
4. MOTS-c helps build bone mass
A May 2023 study in Frontiers of Physiology found the MOTS-c promotes the formation and growth of osteoblasts, cells specializing in new bone growth and the ongoing reformation of existing bone tissue.
The researchers also found that MOTS-c inhibits the production of osteoclasts, which break down old or damaged bone tissue.
5. MOTS-c is banned in sports
In 2024, the World Anti-Doping Agency added MOTS-c to its list of prohibited performance-enhancing substances. This is because its up-regulating effects on the metabolic system could give athletes a massive competitive advantage when it comes to strength and endurance.
MOTS-c is banned under sections 4.4 (Metabolic Modulators) and (4.4.1 Activators of AMPK).
Further reading:
“Mitochondrial-encoded peptide MOTS-c prevents pancreatic islet cell senescence to delay diabetes.” Nature
“Injections of MOTS-c can make you live longer. If you are a mouse.” The Montreal Gazette