MOTS‑c: a mitochondrial peptide in exercise and metabolism

Mitochondria are usually described as the cell's power stations. They also carry their own small genome, separate from the DNA in the nucleus. In 2015, researchers reported that this mitochondrial genome encodes a short peptide, MOTS-c, that appears to influence metabolism far beyond the mitochondrion. The discovery has made MOTS-c a prominent subject in metabolic and ageing research. This article reviews what is known, and distinguishes carefully between findings in cells, in mice and in people.

A peptide hidden in the mitochondrial genome

Mitochondrial DNA was long thought to encode only a small, fixed set of components for energy production and for building mitochondrial proteins. The earlier discovery of humanin, a signalling peptide encoded within mitochondrial DNA, suggested there might be other such short open reading frames. MOTS-c (mitochondrial open reading frame of the 12S rRNA type-c) is one of them: a 16-amino-acid peptide encoded within the gene for the mitochondrial 12S ribosomal RNA^[1].

That location is unusual. The 12S rRNA gene is best known for its role in mitochondrial protein synthesis, so a peptide-coding sequence overlapping it was unexpected. MOTS-c is therefore described as a mitochondrial-derived peptide, part of a broader proposal that mitochondria communicate with the rest of the cell, and possibly the body, through peptides encoded in their own genome.

Proposed mechanisms

In the original study, the main target of MOTS-c appeared to be skeletal muscle. In cells, it inhibited the folate cycle and the linked pathway of de novo purine synthesis, and this led to activation of AMPK, an energy-sensing enzyme that promotes glucose uptake and fat oxidation^[1].

A 2018 study added a second layer. Under metabolic stress such as glucose restriction, MOTS-c moved from the cytoplasm into the nucleus in an AMPK-dependent manner. There it regulated a broad set of genes, including those controlled by antioxidant response elements, and interacted with stress-responsive transcription factors including NRF2^[2]. The authors interpreted this as evidence that the mitochondrial and nuclear genomes regulate each other.

These mechanisms were established in cultured cells and are internally consistent. They are the basis for the hypothesis that MOTS-c links mitochondrial status to whole-body metabolism.

Evidence from mice

Most of the functional evidence comes from mouse studies in which MOTS-c was injected.

• Insulin resistance and obesity. MOTS-c treatment prevented both age-related and high-fat-diet-induced insulin resistance, as well as diet-induced obesity^[1].
• Metabolic profile. In diet-induced obese mice, MOTS-c reduced several plasma metabolic pathways, including sphingolipid metabolism, that are raised in obesity and type 2 diabetes. It also increased fat oxidation, consistent with reduced fat accumulation^[3].
• Physical capacity and ageing. MOTS-c improved physical performance in young, middle-aged and old mice. Intermittent treatment started late in life, at about 23.5 months, increased physical capacity and healthspan^[4].
• Gestational diabetes. In a mouse model combining a high-fat diet with a toxin that damages insulin-producing cells, daily MOTS-c during pregnancy reduced high blood glucose, improved insulin sensitivity and reduced adverse outcomes in the offspring^[5].

The findings are consistent across several models. Most come from a connected group of laboratories, with the gestational diabetes study an independent exception. All remain findings in mice given the peptide by injection.

Exercise research

MOTS-c's reputation as an exercise-related peptide rests on two kinds of observation. In mice, it improved physical performance. In humans, the same 2021 study reported that exercise increased MOTS-c in skeletal muscle and in the circulation^[4].

A separate controlled study tested this more directly. Thirty people were randomised to a session of endurance exercise, resistance exercise or no exercise, with blood samples and muscle biopsies taken before and after. Humanin, a related mitochondrial peptide, rose significantly after endurance exercise. MOTS-c showed only a trend towards an increase. Plasma levels of these peptides were not related to fitness, as measured by maximal oxygen uptake, leg strength or muscle mitochondrial DNA content^[6].

Human genetics and observational studies

Some of the most interesting human data come from genetics. A variant in mitochondrial DNA, m.1382A>C, changes one amino acid in MOTS-c (K14Q). It is specific to Northeast Asian populations. In 2015, researchers suggested it might contribute to the exceptional longevity of Japanese people, while stressing that more research was needed^[7].

A larger 2021 analysis combined three cohorts totalling 27,527 people. Men carrying the variant had a higher prevalence of type 2 diabetes, and the association was concentrated among the least physically active. Women showed no association. In matching mouse experiments, the normal peptide improved glucose tolerance in male mice fed a high-fat diet, but the K14Q form did not^[8]. Genetic association studies of this kind can suggest that a peptide's activity matters in people, but they do not test treatment.

Cross-sectional data point in a similar direction. In a study of 225 people, serum MOTS-c was lower in those with type 2 diabetes than in controls^[9]. A single measurement at one point in time cannot show whether low MOTS-c contributes to diabetes or results from it.

Evidence at each level

Translating from mice to people

Several gaps separate the mouse findings from any conclusion about human health:

• No controlled human treatment trials. Among the sources reviewed, we found no randomised trial of administered MOTS-c in people.
• Different biology. Laboratory mice on high-fat diets model some features of human metabolic disease, but not all. Their lifespans, activity patterns and responses to injected peptides differ from ours.
• Uncertain exposure. The concentrations reached in mouse studies may not correspond to anything achievable or safe in people.
• Conflicts of interest. Several of the foundational studies disclose that senior authors are consultants for, and shareholders of, the company CohBar^[2][4]. This does not invalidate the work, but it makes independent replication especially valuable.

Recent reviews summarise the growing literature on MOTS-c in diabetes, stress responses and ageing-related disease, and describe its therapeutic potential as a subject for further study^[10][11][12].

Summary

MOTS-c is a genuine and intriguing discovery: a peptide encoded in mitochondrial DNA that acts on cellular metabolism and can enter the nucleus under stress. Mouse studies consistently show improvements in insulin sensitivity, body weight and physical capacity with MOTS-c treatment. Human evidence so far consists of genetic associations, cross-sectional measurements and exercise studies with mixed results. None of these tests whether giving MOTS-c benefits people. Until controlled human trials exist, the animal findings should be read as reasons for further research, not as evidence of human benefit.