MOTS-c Research: A Peptide Encoded in Mitochondrial DNA

Published September 26, 2026 · ROVIQ Research

Most proteins and peptides in a cell are encoded in the nucleus. Mitochondria, though, carry a small genome of their own, and in the last two decades researchers have found short stretches of mitochondrial DNA that encode small signalling peptides. MOTS-c is one of them. This overview summarizes what the published research reports about it, and at what level of evidence. Almost all of it is cell culture and mouse work.

What MOTS-c is

MOTS-c ("mitochondrial open reading frame of the 12S rRNA-c") is a 16-amino-acid peptide. It is encoded by a short open reading frame inside the mitochondrial 12S ribosomal RNA gene (Lee et al., 2015). It belongs to a small family of mitochondrial-derived peptides (MDPs). A 2020 review counts eight identified so far: MOTS-c in the 12S rRNA gene, and humanin plus six small humanin-like peptides in the 16S rRNA gene (Merry et al., 2020).

Discovery and cellular mechanism (cells and mice)

The 2015 study that first described MOTS-c reported that its cellular actions inhibit the folate cycle and the de novo purine synthesis tethered to it, leading to activation of AMPK, a central cellular energy sensor. Skeletal muscle appeared to be its primary target organ (Lee et al., 2015). In mouse experiments, the same study reported that MOTS-c treatment prevented insulin resistance associated with age and with a high-fat diet, and prevented diet-induced weight gain (Lee et al., 2015).

A mitochondrial peptide that reaches the nucleus (cell culture)

A 2018 study examined where MOTS-c goes inside the cell. In cultured human cell lines under metabolic stress, such as glucose restriction, MOTS-c moved into the nucleus in an AMPK-dependent manner. There it regulated a broad range of genes, including genes with antioxidant response elements, and interacted with stress-responsive transcription factors such as NRF2 (Kim et al., 2018). The authors present this as evidence that the mitochondrial genome can directly influence nuclear gene expression, communication that had been thought to run mostly the other way (Kim et al., 2018).

Exercise and physical capacity (mice), and endogenous levels (humans)

A 2021 study reported that MOTS-c treatment improved measures of physical performance in young, middle-aged and old mice, and that treatment started late in life increased physical capacity in old mice (Reynolds et al., 2021). The same paper reported a separate human finding: exercise increased the body's own (endogenous) MOTS-c, both in skeletal muscle and in circulation (Reynolds et al., 2021).

Where the field stands

A 2020 review of mitochondrial-derived peptides summarizes the pattern. Circulating MDP levels are associated with metabolic conditions and aging, muscle MDP expression rises under mitochondrial stress such as exercise, and treating rodents with MDPs including MOTS-c has improved insulin sensitivity in several models. The same review is explicit that "it remains to be fully determined" whether these properties can be turned into therapies (Merry et al., 2020).

One more thing a careful reader should know: the foundational MOTS-c papers cited here come largely from one research group, and authors of each disclosed consulting or shareholding relationships with CohBar, Inc. Disclosed interests don't invalidate research, but independent replication is what turns a promising line of work into an established one.