MOTS-c is a small peptide encoded by the DNA inside mitochondria rather than by the cell nucleus. It is studied as a signal cells use when their energy supply comes under stress.
MOTS-C · Mitochondrial-encoded signalling peptide
Mitochondria are usually described as the parts of the cell that turn fuel into usable energy. They also carry their own small genome. MOTS-c is one of a handful of peptides made from that genome, and researchers want to know whether it acts as a message to the rest of the cell when energy is scarce. The evidence is from cells, mice, and measurements of the naturally occurring peptide in people.
MOTS-c stands for mitochondrial open reading frame of the 12S rRNA-c. It is a 16-amino-acid peptide encoded within the mitochondrial 12S ribosomal RNA gene, described by Lee et al. in 2015. Together with humanin it belongs to a small class called mitochondrial-derived peptides.
In cells, MOTS-c inhibits the folate cycle, a set of reactions that supplies building blocks for new DNA, and this leads to activation of AMPK, an enzyme that acts as the cell's energy sensor. The stress-signalling idea comes from Kim et al. (2018): when cultured cells were deprived of glucose, MOTS-c moved from the cytoplasm into the nucleus and altered the activity of genes involved in the stress response, including antioxidant genes. In plain terms, a peptide made by the mitochondria appears to travel to the nucleus and switch on defences when fuel runs short. Whether that happens to the same extent in a whole animal, or in people, is a separate question.
Two lines of evidence need to be kept apart: studies of the peptide the body makes, and studies in which the peptide was administered.
Administered MOTS-c has been studied in mice. Lee et al. (2015) reported that injected MOTS-c prevented high-fat-diet-induced obesity and insulin resistance, and age-dependent insulin resistance, with skeletal muscle as the apparent target tissue. Reynolds et al. (2021) gave MOTS-c to young, middle-aged and old mice and measured treadmill performance, muscle gene expression and, in a late-life intermittent regimen, physical capacity. Both are rodent studies; several authors declare consulting and shareholding interests in a company developing MOTS-c analogues.
Naturally occurring MOTS-c has been measured in people. Cataldo et al. (2018) measured plasma MOTS-c in ten lean and ten obese adults; concentrations were similar between groups, and correlated with insulin-resistance indices only in lean participants. von Walden et al. (2021) randomised 30 subjects to endurance exercise, resistance exercise or rest and found circulating MOTS-c showed only a trend to rise after endurance exercise. Reynolds et al. also reported that exercise increased endogenous MOTS-c in human muscle and blood. These are measurements of a native signal, not trials of a treatment.
This note did not identify a peer-reviewed randomised trial of administered MOTS-c in people.
The mouse findings used injected peptide at doses and schedules that have no established human equivalent, and results in cells and rodents are not proof of the same effect in people. Human data describe how much MOTS-c circulates and when it changes, not what happens when it is supplied. Assays for the peptide differ between laboratories, which complicates comparison of reported concentrations. Its nuclear role has been shown under glucose restriction in cultured cells; how that translates to tissue in a living animal, and whether the same pathway is engaged by exogenous peptide, remains open.
MOTS-c is not an approved medicine in Australia. No regulator-approved MOTS-c medicine was identified in any jurisdiction for this note.
Sources and status checked 2026-09-22
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