MOTS-c Research Primer: A Mitochondrial-Encoded Peptide After the 2026 PCAC Review

• ·MOTS-c is a 16-amino-acid peptide encoded within the mitochondrial genome, in the 12S rRNA region.[1]
• ·Foundational mouse work in Cell Metabolism (2015) linked it to skeletal muscle metabolism and AMPK activation.[1]
• ·Later studies reported that it can translocate to the nucleus under metabolic stress,[2] and that exercise induces it in human skeletal muscle and circulation.[3]
• ·In July 2026 the FDA's Pharmacy Compounding Advisory Committee (PCAC) voted 7 in favor, 5 against, with 2 abstentions, to recommend MOTS-c for the 503A bulks list. It remains unapproved.[4]

Most proteins in a mitochondrion are encoded in the nucleus. Mitochondrial DNA was long thought to encode only 13 proteins plus the RNAs needed to make them. "Mitochondrial-derived peptides" challenged that view: short open reading frames within mitochondrial genes that appear to produce bioactive peptides.

MOTS-c (mitochondrial open reading frame of the 12S rRNA type-c) was described by Lee and colleagues in 2015.[1] Its identity data:

• ·Sequence. MRWQEMGYIFYPRKLR.
• ·Length. 16 residues.
• ·Molecular weight. 2174.6 g/mol (C₁₀₁H₁₅₂N₂₈O₂₂S₂).
• ·Encoded in. The mitochondrial MT-RNR1 (12S rRNA) region.
• ·Related peptides. Humanin and the SHLPs, other mitochondrial-derived peptides.

Research Material

Amino Acid Sequence

Chemical Structure

Four papers carry most of the weight in this literature:

• ·Lee et al., Cell Metabolism 2015. The founding study reported that MOTS-c acts primarily on skeletal muscle, where it inhibited the folate cycle, raised levels of the metabolite AICAR, and activated AMP-activated protein kinase (AMPK).[1] In mice on a high-fat diet, administration was associated with prevention of diet-induced obesity and insulin resistance.[1] An accompanying commentary described it as a mitochondrially encoded hormone.[7]
• ·Kim et al., Cell Metabolism 2018. Under metabolic stress, MOTS-c moved from the cytoplasm into the nucleus in an AMPK-dependent manner, where it interacted with stress-responsive transcription factors such as NRF2 and regulated nuclear genes, including those with antioxidant response elements.[2] That positions it as a possible mitochondria-to-nucleus signal.
• ·Reynolds et al., Nature Communications 2021. Exercise induced endogenous MOTS-c in human skeletal muscle and in circulation, and late-life treatment of aged mice was associated with improved physical capacity measures.[3]
• ·Lee, Kim and Cohen, Free Radical Biology & Medicine 2016. An earlier review summarized MOTS-c as a regulator of muscle and fat metabolism and laid out open questions about its receptor and transport.[5]

• ·Receptor. No cell-surface receptor has been definitively identified.[5]
• ·Origin. Whether circulating MOTS-c is produced in mitochondria, how it exits, and how it is regulated remain active questions.[5]
• ·Species translation. Most mechanistic evidence comes from mice and cell lines.
• ·Assay consistency. Circulating levels reported across studies vary with assay method, which complicates comparison.

MOTS-c was removed from FDA Category 2 in April 2026, after its nomination was withdrawn; removal alone did not make it eligible for compounding.[6]

On 23 and 24 July 2026 the FDA's Pharmacy Compounding Advisory Committee reviewed MOTS-c for inclusion on the Section 503A Bulk Drug Substances List, alongside BPC-157, KPV, TB-500, MOTS-c, Epitalon and Semax. FDA staff had recommended against inclusion for every substance under review, citing insufficient characterization, little or no human effectiveness evidence, and inadequate human safety data. The committee voted in favor anyway. The vote was 7 in favor, 5 against, 2 abstentions.

Of the six recommendations, MOTS-c's was the only one in which the votes in favor (7) did not outnumber the votes against and abstentions combined (5 and 2).[4] FDA rulemaking would be required before any change in compounding status. The full breakdown is in our July 2026 PCAC post. What the vote does not do, per the FDA's meeting materials and the current 503A list:[8][9][10]

• ·It is non-binding. The committee advises, it does not decide. No final FDA determination has been issued and none of the six peptides appears in 21 CFR 216.23.
• ·It requires a further step. Addition to the 503A Bulks List requires formal action by the Secretary of Health and Human Services, which had not occurred as of publication.
• ·It does not make the compound an FDA-approved drug, and it establishes nothing about efficacy.
• ·It does not legitimize research-chemical retail. A compounding-list decision concerns licensed pharmacists preparing patient-specific prescriptions under Section 503A, which is a different channel entirely from research material sold in vials.

MOTS-c contains methionine and tryptophan, both oxidation-prone. Minimize air exposure after reconstitution, aliquot promptly, and avoid repeated freeze-thaw. The Peptide Calculator includes an aliquot split and cold-storage planner, and our shipping and storage guide covers the rest.

Each MOTS-c lot is tested by Janoshik Analytical before sale, and the certificate is published as the laboratory reported it, verifiable on Janoshik's own site. Batch, HPLC purity and measured content are read live from the batch record below; the buttons under the certificate switch between strengths. Every lot is listed on the certificates of analysis page.

Published Certificate

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10mg20mg40mg45mg

Batch

MOTS-CA-26A-02

Purity (HPLC)

98.683%

Measured content

11.20 mglabeled 10 mg

Laboratory

Janoshik

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MOTS-c

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