MOTS-c discovery study 2015 by Lee et al. explained

The MOTS-c discovery study by Changhan Lee and colleagues was published in March 2015 in Cell Metabolism. Its title is The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance. The research was carried out at the University of Southern California, the University of California Los Angeles and the National Institute on Aging. This is the paper in which MOTS-c was first described, so everything that has been written about the peptide since then goes back to it. This article explains what the researchers were looking for, how they found the peptide, what they observed in cells and mice and what the study leaves open.

What the MOTS-c discovery study asked

Mitochondria are best known as the structures that produce energy inside cells. They also carry their own small genome, the mitochondrial DNA. For a long time this genome was thought to code only for 13 proteins involved in energy production. That view changed when researchers found a short open reading frame in mitochondrial DNA that codes for a small signalling peptide called humanin.

The authors of this study asked whether humanin was a special case or whether there might be other short open reading frames in mitochondrial DNA that code for signalling peptides. They searched the gene for the mitochondrial 12S ribosomal RNA and found a candidate sequence. The second question was then what this peptide does in the body.

How the MOTS-c discovery study was done

The study combines several approaches. The researchers first identified the short open reading frame within the 12S rRNA gene and showed that it codes for a 16 amino acid peptide. They named it MOTS-c, which stands for mitochondrial open reading frame of the 12S rRNA-c.

They then studied the peptide in cell culture to work out which biochemical pathways it affects. Finally, they treated mice with synthetic MOTS-c and tested two situations in which insulin resistance normally develops: ageing and a high fat diet. Mice on a high fat diet usually become obese and insulin resistant, which makes this a standard model for metabolic disease. The abstract does not give group sizes or the dosing schedule, so we do not state them here. This is an animal and cell study. No humans were treated.

What the MOTS-c discovery study found

The abstract reports the following main results:

• A new peptide: MOTS-c is a 16 amino acid peptide encoded within the mitochondrial 12S rRNA gene. It regulates insulin sensitivity and metabolic homeostasis.

• Target tissue: The primary target organ of MOTS-c appears to be skeletal muscle.

• Mechanism in cells: MOTS-c inhibits the folate cycle and the de novo purine biosynthesis that is linked to it. This leads to activation of AMPK, an enzyme that acts as a central energy sensor in cells and switches on pathways that take up and burn glucose.

• Effects in mice: Treatment with MOTS-c prevented age-dependent insulin resistance and insulin resistance caused by a high fat diet. It also prevented diet-induced obesity.

The authors concluded that mitochondria may actively regulate metabolism at the level of the whole organism through peptides encoded in their own genome. This was a new idea at the time and is the reason the paper attracted so much attention. The underlying biology is explained further in our mitochondrial peptides collection.

Limitations of the MOTS-c discovery study

The study is well regarded, but it has clear limits:

• Animal model: All treatment results come from mice. Mouse metabolism differs from human metabolism in important ways, and many findings in mouse obesity models have not translated to people.

• Prevention, not reversal: The abstract says that MOTS-c prevented insulin resistance and obesity. This is not the same as reversing a condition that already exists.

• Single research network: The study came from one group of collaborating laboratories. At the time of publication there was no independent replication.

• Mechanism partly open: The link between the folate cycle, purine synthesis and AMPK was shown in cells. How much of the effect in mice runs through this pathway was not fully established.

• No safety data: The study was not designed to assess safety, and the abstract reports no safety outcomes.

• No human data: Nothing in the paper describes effects of synthetic MOTS-c in humans.

What this means for MOTS-c research

This paper opened a new field. Before 2015, mitochondrial DNA was not thought to produce signalling peptides beyond humanin. The discovery of MOTS-c suggested that the mitochondrial genome is a source of regulatory molecules, and later work has looked for further peptides of this type. For metabolic research, the mouse data provide a starting point for studies on skeletal muscle, AMPK signalling and insulin sensitivity.

The study does not show effects in humans and does not support any use outside controlled laboratory research. For laboratories working in this area, our MOTS-c 20 mg is supplied as lyophilised powder for research use, and our guide on how to reconstitute peptides covers the practical handling steps. Related compounds are listed in our anti-aging and longevity peptides collection.

Sources

• Lee C, Zeng J, Drew BG, Sallam T, Martin-Montalvo A, Wan J, Kim SJ, Mehta H, Hevener AL, de Cabo R, Cohen P (2015). The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance. Cell Metabolism, 21(3), 443-454. doi:10.1016/j.cmet.2015.02.009

This article summarises published research for information only. It is not medical advice. All products on this site are sold for laboratory research use only and are not intended for human or veterinary use.