MOTS-C is a 16-amino acid peptide encoded by the mitochondrial genome — not the nuclear genome — discovered in 2015 by Lee et al. in Cell Metabolism. It belongs to a newly characterised class of mitochondrial-derived peptides (MDPs) and is dubbed a 'mitokine' due to its endocrine-like signalling role. Circulating MOTS-C is elevated by exercise and declines with age, positioning it as a key subject in longevity and metabolic biology research.
MOTS-C's discovery overturned a long-held assumption: that the mitochondrial genome encodes only 13 protein-coding genes. The identification of functional short open reading frames (sORFs) in mitochondrial ribosomal RNA sequences revealed a new category of bioactive peptides with endocrine-like functions — mitokines.
Circulating MOTS-C levels vary meaningfully across physiological and pathological states. Studies have documented lower MOTS-C in patients with type 2 diabetes, coronary endothelial dysfunction, obese children, and gestational diabetes — suggesting an endogenous protective role in metabolic homeostasis. In healthy humans, acute exercise induces MOTS-C expression in skeletal muscle and releases it into systemic circulation.
MOTS-C's primary metabolic action occurs through activation of AMP-activated protein kinase (AMPK) — a master metabolic sensor activated when cellular energy (ATP) is low. AMPK activation by MOTS-C promotes glucose uptake in skeletal muscle via GLUT4 translocation, increases fatty acid oxidation, and inhibits de novo lipid synthesis.
MOTS-C has also been shown to directly inhibit the folate-methionine cycle, elevating AICAR — an endogenous AMPK activator — in a mechanism with structural similarities to methotrexate's biochemistry. Under metabolic stress, MOTS-C translocates from mitochondria into the cell nucleus in an AMPK-dependent manner, binding ARE-regulated transcription factors and modulating nuclear gene expression to improve cellular stress resistance and mitochondrial biogenesis.
A 2021 Nature Communications study (Reynolds et al.) demonstrated MOTS-C treatment significantly enhanced physical performance in young, middle-aged, and old mice. Late-life intermittent treatment (3×/week from 23.5 months) was associated with differences in physical capacity measures in that study. MOTS-C gene polymorphisms have also been associated with human lifespan in genetic epidemiology studies.
Pancreatic islet research (Nature 2025) showed MOTS-C prevents β-cell senescence via AMPK/mTOR pathway modulation, reducing pancreatic islet senescence and improving glucose intolerance in diabetic mouse models.
MOTS-C has been studied in cardiac structure and function models, with data suggesting activity through the NRG1-ErbB4 pathway in preclinical settings. Functional enrichment analysis reported activity in angiogenesis, inflammation, and apoptosis pathway markers in cardiac cell culture models.
Exogenous MOTS-C treatment in type 2 diabetic rat hearts (Frontiers in Physiology, 2025) showed differences in mitochondrial respiration markers, fasted blood glucose levels, and left ventricular wall thickness measurements in that preclinical model.