MOTS-c — questions, answered plainly.

MOTS-c is a 16-residue peptide encoded within the open reading frame of the mitochondrial 12S rRNA. It was discovered in 2015 (Lee et al., Cell Metabolism, PMID 25738459) and is referenced as a mitochondrial-derived peptide regulating metabolic homeostasis in cell and mouse models.

Most peptides are encoded by nuclear DNA. MOTS-c is encoded by mitochondrial DNA — specifically by an open reading frame within the 12S rRNA gene. This makes it part of a distinct class of mitochondrially-derived peptides (MDPs).

No controlled human clinical trials are cited on this profile. All three cited primary studies use mouse and cell models. Observational human studies of endogenous MOTS-c levels exist in the wider literature but are not cited here as primary evidence.

AMP-activated protein kinase (AMPK) is a central cellular energy sensor. Lee et al. 2015 reported that MOTS-c activated AMPK in skeletal muscle in mouse models — a key part of the proposed mechanism by which the peptide promotes metabolic homeostasis.

Kim et al. 2018 (Cell Metabolism, PMID 29983246) reported that MOTS-c translocates from mitochondria to the nucleus under metabolic stress and interacts with NRF2 to regulate antioxidant gene expression — extending the proposed mechanism beyond cytoplasmic AMPK signalling.

Kumagai et al. 2021 (Am J Physiol Endocrinol Metab, PMID 33554779) reported that MOTS-c was associated with reduced myostatin expression and muscle atrophy signalling via the CK2-PTEN-mTORC2-AKT-FOXO1 pathway in skeletal muscle cell models with in vivo mouse correlates.

All currently cited primary studies are preclinical (mouse and cell models). MOTS-c is a relatively recently discovered peptide (2015), and independent replication across research groups is still accumulating. No PubMed-indexed controlled human clinical trials are cited on this profile.