MOTs-C: how it got to PCAC

Background

MOTs-C — also rendered MOTS-c — is a 16-amino-acid mitochondrial-derived peptide encoded within the 12S rRNA open reading frame of the mitochondrial genome (Lee et al. 2015, Cell Metab). Unlike most peptides considered by the Pharmacy Compounding Advisory Committee, MOTs-C is an endogenous human peptide identified from a sequence inside human mitochondrial DNA, not a synthetic fragment of a larger protein. Despite its endogenous origin, MOTs-C has no FDA-approved indication and no marketing authorization in any major jurisdiction. It is among the seven peptides scheduled for PCAC review on July 23, 2026.

Discovery

The MOTs-C peptide was first characterized by Lee and colleagues at the University of Southern California’s Leonard Davis School of Gerontology in a 2015 paper in Cell Metabolism. The authors reported that intraperitoneal administration of synthetic MOTs-C in mice attenuated diet-induced obesity and insulin resistance, and they outlined a mechanistic model in which the peptide signals through the AMPK pathway in skeletal muscle.

The PubChem compound record (CID 146675088) lists the peptide’s molecular formula and aggregates synonyms and references (PubChem MOTs-C entry).

Subsequent literature

A 2022 review by Mohtashami and colleagues at the University of California Irvine summarized the MOTs-C literature through that year, surveying preclinical reports across diabetes, cardiovascular disease, osteoporosis, postmenopausal obesity, and Alzheimer’s disease models (Mohtashami et al. 2022, Int J Mol Sci). The authors noted that MOTs-C serum levels in humans decline with age and observed a hormonal-like signaling pattern across multiple tissues. They concluded that no clinically validated therapeutic application of MOTs-C had been established at the time of writing, and that the existing literature was dominated by animal and cell-culture work.

Subsequent published research, indexed in PubMed through 2025, has continued to be predominantly preclinical. Some observational studies have measured serum MOTs-C concentrations in human cohorts (for example, in cardiac surgery and obstructive sleep apnea populations), but no controlled human trial of MOTs-C as a therapeutic intervention has been completed and published as of the cited literature.

Regulatory journey

There is no FDA-approved drug product containing MOTs-C as an active ingredient. No public NDA or BLA filing for MOTs-C is recorded in FDA’s databases. ClinicalTrials.gov, as of the cited literature, does not register an interventional trial of MOTs-C with a U.S. sponsor and an active IND.

In the U.S. compounding context, MOTs-C was nominated for inclusion on the 503A bulks list during FDA’s evaluation of bulk drug substances under the agency’s interim 503A policy. In 2023, FDA placed MOTs-C in Category 2 — the category for substances that “may present significant safety risks” and that may not be compounded under section 503A pending further review (FDA Category 2 reference). The agency’s stated concerns echoed those it described for other peptides on the list: peptide identity and purity, immunogenicity risk, and the absence of human clinical data.

In April 2026, FDA announced that the original MOTs-C nomination had been withdrawn and that, on the basis of a new nomination, the substance would be reconsidered at the July 23, 2026 PCAC meeting (FDA July 23-24, 2026 PCAC announcement). STAT News reported that the meeting was scheduled in the context of public statements from senior HHS leadership advocating broader access to compounded peptides (STAT News, April 15, 2026).

What the July 23, 2026 meeting will consider

The July 2026 PCAC docket asks committee members to vote on whether MOTs-C (free base and acetate) should be included on the 503A bulks list. The FDA briefing document — expected to be posted to the meeting’s web page two business days before the meeting — will present FDA review staff’s evaluation of the substance against the agency’s standard 503A criteria: chemical and physical characterization, safety, effectiveness, historical use in compounding, and an FDA staff recommendation. Public comments may be filed in docket FDA-2025-N-6895 through July 22, 2026.

Coverage notes

The MOTs-C literature is heavily skewed toward animal and cell-culture work, with no large controlled human trial completed. The peptide’s endogenous status — it is encoded within human mitochondrial DNA — does not, on its own, establish that exogenous synthetic MOTs-C is safe or effective at therapeutic doses; that question is what FDA review staff will be asked to characterize at the July 2026 meeting. This page will be updated after July 23, 2026 with the released briefing document, FDA staff recommendation, and committee vote.