Key takeaways
- MOTS-c is a 16-amino-acid peptide encoded within the mitochondrial MT-RNR1 (12S rRNA) gene, discovered in 2015.
- It's linked to AMPK activation and metabolic regulation, and moves into the nucleus under metabolic stress.
- Research covers insulin sensitivity, exercise physiology and ageing, almost entirely in preclinical models.
In this guide
- What is MOTS-c?
- Mitochondrial-derived peptides
- How it's thought to work
- Research areas
- Related research
- FAQ
What is MOTS-c?
MOTS-c stands for mitochondrial open reading frame of the 12S rRNA type-c. It's a 16-amino-acid peptide with the sequence MRWQEMGYIFYPRKLR and a molecular weight of 2,174.62 g/mol.
It was discovered in 2015 by researchers at the University of Southern California, who found a short open reading frame hidden inside the mitochondrial gene for 12S ribosomal RNA (Lee et al., Cell Metabolism, 2015).
Why mitochondrial-derived peptides matter
Mitochondria are best known as the cell's power plants, but they have their own small genome. Discovering that this genome encodes signalling peptides changed how researchers think about mitochondria: not just as energy producers, but as active signalling organelles that send messages to the rest of the cell and to other tissues. MOTS-c, along with humanin, is one of the best-studied examples.
How MOTS-c is thought to work
AMPK and the folate cycle
The discovery study linked MOTS-c to inhibition of the folate cycle, leading to accumulation of AICAR, a natural activator of AMP-activated protein kinase (AMPK). AMPK is a master regulator of cellular energy balance that switches on when energy is low.
Moving into the nucleus
A later study reported that under metabolic stress, MOTS-c moves into the cell nucleus and helps regulate genes involved in the antioxidant response (Kim et al., Cell Metabolism, 2018). This makes it a direct line of communication from mitochondria to the nuclear genome.
What the research has examined
Metabolism and insulin sensitivity
The discovery paper reported that MOTS-c targets skeletal muscle and improved insulin sensitivity and prevented diet-induced obesity in mouse models.
Exercise physiology
A 2021 study described MOTS-c as exercise-induced: its levels rose with exercise in humans, and it improved physical performance in young, middle-aged and older mice (Reynolds et al., Nature Communications, 2021). This has made it a subject of interest as a potential "exercise mimetic" in research.
Ageing
Because mitochondrial function declines with age, MOTS-c is studied in models of age-related metabolic and physical decline.
These are preclinical findings. MOTS-c is not an approved medicine, and it is named among unauthorized peptides in Health Canada's 2026 advisory.
Related research
MOTS-c sits alongside other compounds studied in mitochondrial and cellular-energy research, including SS-31, which targets the inner mitochondrial membrane, and NAD+, the coenzyme at the centre of energy metabolism.
Frequently asked questions
What is MOTS-c?
MOTS-c is a 16-amino-acid peptide encoded by mitochondrial DNA, within the MT-RNR1 (12S rRNA) gene. It was discovered in 2015 and is studied in metabolism, exercise physiology and ageing research.
What makes MOTS-c different from other peptides?
Most peptides are encoded by nuclear DNA. MOTS-c is encoded by mitochondrial DNA, so it's studied as a signal through which mitochondria communicate with the rest of the cell.
How does MOTS-c affect AMPK?
The discovery study linked MOTS-c to inhibition of the folate cycle and accumulation of AICAR, which activates AMP-activated protein kinase (AMPK), a central regulator of cellular energy balance.
Is MOTS-c linked to exercise?
Research has reported that MOTS-c levels rise with exercise and that it improved physical performance in mice of different ages (Reynolds et al., 2021).
References
- Lee C, et al. The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance. Cell Metab. 2015;21(3):443–454.
- Kim KH, et al. The mitochondrial-encoded peptide MOTS-c translocates to the nucleus to regulate nuclear gene expression in response to metabolic stress. Cell Metab. 2018;28(3):516–524.
- Reynolds JC, et al. MOTS-c is an exercise-induced mitochondrial-encoded regulator of age-dependent physical decline and muscle homeostasis. Nat Commun. 2021;12:470.
