Mitochondria · MOTS-c
MOTS-c: a peptide encoded in mitochondrial DNA
October 18, 2026 · 2 min read · Models: Mouse, Cell culture
MOTS-c is a 16-amino-acid peptide encoded within the mitochondrial 12S rRNA gene. Cell and mouse studies link it to the folate cycle, AMPK activation and skeletal-muscle metabolism, and show it can move to the nucleus under metabolic stress.
A summary of published research for scientific reference. It is not medical advice and does not describe or endorse use in humans or animals. Findings from cell culture and animal models often do not carry over to other systems.
A short open reading frame in mitochondrial DNA
The mitochondrial genome was long thought to encode only 13 proteins, along with rRNAs and tRNAs. Short open reading frames within mitochondrial rRNA genes changed that picture. Humanin was found first, then the small humanin-like peptides, then MOTS-c, described by Lee and colleagues in Cell Metabolism (2015).
Metabolic signaling
In the 2015 study, MOTS-c inhibited the folate cycle and de novo purine synthesis. That led to accumulation of the AMP analog AICAR and activation of AMPK. Experiments in a high-fat-diet mouse model identified skeletal muscle as a primary target tissue.
Kim and colleagues (Cell Metabolism, 2018) showed that MOTS-c moves to the nucleus during metabolic stress. There it interacts with antioxidant-response transcription factors, which suggests mitochondria can signal to nuclear gene expression through encoded peptides.
Endogenous levels
Reynolds and colleagues (Nature Communications, 2021) measured endogenous MOTS-c in skeletal muscle and plasma and reported that its levels change with exercise. The same study examined muscle gene expression and physical measures in aged mice.
Open questions
How a mitochondrially encoded peptide is translated (mitochondrial or cytosolic ribosomes) and exported is not fully resolved. Assays for endogenous MOTS-c vary between laboratories, which complicates comparisons across studies.
References
- Lee C, Zeng J, Drew BG, 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, Son JM, Benayoun BA, Lee C. 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, Lai RW, Woodhead JST, et al. MOTS-c is an exercise-induced mitochondrial-encoded regulator of age-dependent physical decline and muscle homeostasis. Nat Commun. 2021;12:470.