MOTS-c: The 16-Amino-Acid Peptide Encoded in Mitochondrial DNA, and What the Key Studies Measured

MOTS-c is a peptide with an unusual address: it is encoded in mitochondrial DNA, in a short open reading frame within the gene for the 12S ribosomal RNA (Lee 2015). This Vial Post explainer covers how it was found, what the defining papers actually measured, who did that work, and where the peptide stands with the FDA.

Nothing below is guidance on use in people or animals. The Vial Post covers MOTS-c strictly as a subject of laboratory and literature research.

Quick Facts

• Name: MOTS-c, short for "mitochondrial open reading frame of the 12S rRNA-c" (Lee 2015).
• Length and sequence: 16 amino acids (Lee 2015). PubChem lists the human peptide as H-MRWQEMGYIFYPRKLR-OH (PubChem CID 146675088).
• Formula and mass: C101H152N28O22S2, molecular weight 2174.6 g/mol; CAS 1627580-64-6 (PubChem).
• Family: a mitochondrial-derived peptide (MDP), the group of bioactive peptides produced from short open reading frames in mitochondrial DNA (Reynolds 2021).
• Regulatory note: FDA places MOTs-C among bulk substances whose compounding nominations were withdrawn, and says it has not identified any human exposure data on drug products containing it (FDA bulk substances page).

How It Was Found

The search started from an earlier discovery. Humanin, a signaling peptide encoded by a short open reading frame (sORF) in mitochondrial DNA, suggested that more such sORFs might exist. In 2015, Lee and colleagues at the University of Southern California reported one within the mitochondrial 12S rRNA, encoding the 16-amino-acid peptide they named MOTS-c (Lee 2015).

What the Founding Paper Proposed

The 2015 paper set out the model most later work builds on (Lee 2015):

• Main target tissue: skeletal muscle appeared to be the peptide's primary target organ.
• Cellular mechanism: MOTS-c's actions inhibited the folate cycle and the de novo purine biosynthesis tied to it, which led to activation of AMPK.
• Animal work: the authors studied the peptide in mice under high-fat-diet and aging conditions. Their results are reported in the paper itself and are not summarized here as effects.

From Mitochondria to the Nucleus

A 2018 follow-up from the same laboratory addressed an open question: whether anything encoded in mitochondrial DNA actively controls the nuclear genome (Kim 2018). The group reported that:

• MOTS-c translocates to the nucleus after metabolic stress, in a manner that depends on AMPK.
• In the nucleus it regulated a broad range of genes in response to glucose restriction, including genes with antioxidant response elements (ARE).
• It interacted with ARE-regulating transcription factors such as NFE2L2/NRF2.

The authors read this as evidence that the mitochondrial and nuclear genomes encode factors that regulate each other (Kim 2018).

The Exercise Study, Read Closely

A 2021 Nature Communications paper extended the work to exercise (Reynolds 2021). Its human component was small and observational:

• Who: 10 sedentary, healthy young men (24.5 ± 3.7 years) exercising on a stationary bicycle. Muscle and plasma samples were taken before, during (plasma only) and after exercise, and after a 4-hour rest.
• Muscle: relative endogenous MOTS-c levels, measured by Western blot, rose 11.9-fold after exercise and stayed raised after 4 hours, with a trend back toward baseline.
• Plasma: relative circulating levels, measured by ELISA, rose 1.6-fold during and 1.5-fold after exercise, and returned to baseline after 4 hours of rest.

The rest of the paper was done in mice and cultured muscle cells. It examined physical performance at three ages (2, 12 and 22 months), nuclear gene regulation, skeletal-muscle metabolism and myoblast responses to metabolic stress (Reynolds 2021). In short, the study measured the body's own MOTS-c rising with exercise. It did not test giving the peptide to people.

Who Did the Research

The three papers discussed here share authors from the same research group, and their disclosures matter when weighing the findings:

• C. Lee is an author on all three papers discussed here (Lee 2015; Kim 2018; Reynolds 2021).
• The 2018 paper discloses that C. Lee was a consultant for and shareholder of CohBar, Inc. (Kim 2018).
• The 2021 paper discloses that P. Cohen and C. Lee were consultants and shareholders of CohBar, Inc. (Reynolds 2021).

Independent replication by unaffiliated groups is the natural next test for any finding that rests largely on one laboratory.

Regulatory Status

FDA's page on bulk drug substances that may present significant safety risks lists MOTs-C in the "nominated but withdrawn" group, made up of substances previously in category 2 of the interim compounding policies whose nominations were withdrawn. FDA writes that compounded drugs containing MOTs-C may pose a significant risk of immunogenicity for certain routes of administration and may raise complexities with peptide-related impurities and API characterization. FDA also says it lacks important information on safety issues, including whether MOTs-C would cause harm if given to humans (FDA bulk substances page, content current as of 04/22/2026).

For the wider policy background, see our news report on the interim compounding policy.

Questions Readers Ask

Is MOTS-c made by mitochondria? It is encoded in mitochondrial DNA, in a short open reading frame within the 12S rRNA gene (Lee 2015).

How long is MOTS-c? 16 amino acids (Lee 2015); PubChem gives the sequence MRWQEMGYIFYPRKLR (PubChem).

Has MOTS-c been tested in people? The 2021 study measured naturally occurring MOTS-c in 10 exercising volunteers; it did not give them the peptide (Reynolds 2021). FDA says it has not identified human exposure data on drug products containing MOTs-C (FDA bulk substances page).

Handling in the Lab

MOTS-c is usually supplied as a lyophilized powder. Typical peptide practice applies: store it cold (commonly -20 degrees C), dry and away from light, prepare solutions only when needed, and avoid repeated freeze-thaw cycles. Confirm identity and purity against the batch Certificate of Analysis.

For research and educational use only. This article is not medical advice and does not describe dosing or human use.