Discovery and Background

The story of MOTS-c is recent. It begins with a question about whether mitochondrial DNA holds more genes than the textbooks listed.

Looking Again at Mitochondrial DNA

Human mitochondrial DNA is small, about 16,500 base pairs, and its 37 classic genes were mapped decades ago. In the early 2000s, the discovery of humanin, a peptide coded within a mitochondrial RNA gene, suggested that more short coding regions could be hiding in plain sight.

The 2015 Paper

A team at the University of Southern California led by Changhan Lee and Pinchas Cohen searched the 12S rRNA gene and found the code for MOTS-c. Their March 2015 report in Cell Metabolism described how the peptide activates AMPK, targets muscle and prevents diet-induced obesity and insulin resistance in mice. It drew wide attention because it suggested that mitochondria send hormone-like signals to the rest of the body.

Nucleus and Genes

In 2018 Lee's group showed in the same journal that MOTS-c moves into the nucleus when cells are under metabolic stress, where it helps control a broad range of genes.

Exercise and Ageing

A 2021 study in Nature Communications reported that MOTS-c improved physical performance in young, middle-aged and old mice. Treatment started late in life improved physical capacity. The same paper showed that exercise raised MOTS-c levels in human muscle and blood.

Commercial Interest

The discoverers disclosed that they were consultants and shareholders of CohBar, a US biotechnology company. CohBar ran a Phase 1a/1b trial of a compound called CB4211, which the company described as an analogue of MOTS-c. The trial enrolled 88 healthy volunteers and people with fatty liver disease and was completed in 2021. No results appear on the public trial registry.

Anti-Doping Attention

Because MOTS-c activates AMPK, sports scientists quickly saw doping potential. The Cologne anti-doping laboratory published a detection method in 2019, and the World Anti-Doping Agency later listed MOTS-c by name.