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SpartaLabs Research · June 17, 2026

MOTS-c: Discovery and Regulatory History

MOTS-c was identified in 2015 through systematic interrogation of mitochondrial open reading frames at the University of Southern California. This article traces the peptide's discovery, the scientific lineage that enabled it, and its subsequent research and regulatory context. Educational reference.

mots-cmitochondrial-derived-peptidediscovery-historymdp

Introduction

MOTS-c entered the published scientific record in March 2015 when Lee and colleagues at the University of Southern California (USC) reported the identification and initial characterization of a 16-amino-acid peptide encoded within the mitochondrial 12S ribosomal RNA gene (MT-RNR1) [1]. Its discovery was the product of a research trajectory that began more than a decade earlier with the identification of humanin—the first mitochondrially encoded bioactive peptide—and was enabled by advances in bioinformatics screening of the mitochondrial genome for previously uncharacterized open reading frames. A companion account of the peptide's chemistry and current regulatory status appears in the MOTS-c research overview.

Discovery Period: The Mitochondrial-Derived Peptide Lineage

The conceptual foundation for MOTS-c's discovery was established by the identification of humanin in 2001. Hashimoto and colleagues, working in the laboratory of Ikuo Nishimoto, screened a cDNA library constructed from the preserved cerebral cortex of an Alzheimer's disease patient and identified a 75-base-pair sequence encoding a 24-amino-acid peptide that suppressed neuronal apoptosis induced by familial Alzheimer's disease-associated proteins. This sequence mapped to the 16S ribosomal RNA region (MT-RNR2) of the mitochondrial genome [2]. The discovery, reported in the Proceedings of the National Academy of Sciences in 2001, established for the first time that rRNA-encoding regions of mitochondrial DNA contained protein-coding open reading frames producing biologically active peptides.

Humanin research expanded throughout the 2000s, with studies documenting its expression in various tissues, its circulating presence in human plasma, and age-related changes in endogenous levels. Pinchas Cohen's group at USC contributed to characterization of humanin's cytoprotective signaling properties and, in doing so, developed both the methodological tools and the conceptual framework for systematically asking whether other rRNA-encoding regions of mitochondrial DNA harbored additional functional peptide-coding sequences.

Early Research: Identification of MOTS-c

By the early 2010s, improved bioinformatics tools allowed researchers to scan open reading frames within non-protein-coding genomic regions with greater efficiency. The USC group, led by Changhan Lee within the Cohen laboratory, applied this approach to the 12S rRNA region (MT-RNR1) of the human mitochondrial genome and identified a 75-base-pair ORF encoding a 16-amino-acid peptide. The peptide was synthesized, characterized biochemically, and its endogenous expression confirmed via mass spectrometry in human plasma and cell lines. The team designated it MOTS-c—mitochondrial open reading frame of the 12S rRNA-c—using the "type-c" suffix to distinguish it from other ORFs in the same genomic region [1].

The 2015 Cell Metabolism paper by Lee, Zeng, Drew, Sallam, Martin-Montalvo, Wan, Kim, Mehta, Hevener, de Cabo, and Cohen presented the peptide's amino acid sequence (MRWQEMGYIFYPRKLR), its conservation across 14 mammalian species, its AMPK-activating mechanism via folate cycle inhibition and AICAR accumulation, and metabolic findings in rodent models [1]. The publication was accompanied by a companion commentary and generated immediate scientific interest in the idea that the mitochondrial genome—long studied primarily for its role in oxidative phosphorylation—encoded a class of signaling molecules with systemic reach.

Expansion of the MDP Research Field

Following the 2015 publication, research on mitochondrial-derived peptides expanded substantially. In 2016, the Cohen group described a family of six small humanin-like peptides (SHLPs 1–6) encoded in the MT-RNR2 region, extending the MDP class further. Together, humanin, MOTS-c, and the SHLPs established a coherent framework for the concept that mitochondria communicate with other cellular compartments and with distant tissues through secreted peptide products of the organellar genome.

Independent laboratories in Japan, China, South Korea, and Europe began publishing on MOTS-c beginning in 2016–2017, examining circulating levels in aging cohorts, associations with genetic variants in the MT-RNR1 gene, and potential roles in specific disease models. A 2015 letter in Aging Cell by Fuku and colleagues noted that variants in the MT-RNR1 region had previously been associated with longevity in Japanese centenarian cohorts, raising the hypothesis that endogenous MOTS-c levels or signaling efficacy might be relevant to population-level variation in aging trajectories—an area that subsequent genetic studies have continued to investigate [3].

The 2018 Cell Metabolism paper by Kim, Son, Benayoun, and Lee added a new dimension by demonstrating MOTS-c's capacity for nuclear translocation and direct participation in nuclear gene regulation under metabolic stress [4]. This finding positioned MOTS-c as a mitochondrial-nuclear retrograde messenger—a molecule through which the mitochondrial genome could directly influence nuclear transcriptional responses—and attracted sustained attention from researchers working on organellar communication.

Regulatory Milestones

MOTS-c's regulatory history reflects its position as a compound under active scientific development. No New Drug Application (NDA) or Biologics License Application (BLA) for MOTS-c has been filed with the FDA as of the date of this article; the compound is at a preclinical characterization stage with human observational data accumulating and interventional research as a logical next horizon. It is currently sold by research-use-only vendors consistent with this stage of development.

In 2024, the World Anti-Doping Agency (WADA) added MOTS-c to its Prohibited List under category S4.4 (Metabolic Modulators, AMPK activators subcategory), effective at all times in and out of competition for athletes subject to WADA rules. The WADA listing constitutes regulatory recognition of the peptide's biological characterization as an AMPK pathway modulator and reflects the scientific community's assessment of its activity in that pathway.

Current Research Landscape

As of the mid-2020s, the MOTS-c literature encompasses several dozen peer-reviewed publications spanning cell biology, rodent physiology, human observational studies, and review articles. Key themes include the characterization of the CK2 binding interaction reported by Zhu and colleagues in 2024 [5]—which identified the strongest human genetic evidence to date connecting MOTS-c biology to musculoskeletal metabolic endpoints—as well as studies in models of inflammatory tissue injury, including the 2024 Antioxidants publication on radiation pneumonitis [6].

A 2023 review in the Journal of Translational Medicine by Wan and colleagues provided a comprehensive synthesis of the mechanistic and translational state of knowledge, characterizing the field as having established a rich preclinical foundation across stress response, metabolic regulation, and aging-related research contexts [7]. The trajectory of the MOTS-c literature—from a single-group discovery paper in 2015 to an internationally distributed research effort across dozens of laboratories—reflects the scientific community's assessment of the peptide as a productive subject for continued investigation.

Research on whether endogenous MOTS-c levels are causally related to metabolic health outcomes—and how that relationship informs the design of interventional studies—represents the field's most productive near-term research direction. Glutathione is another compound in the mitochondrial metabolic cluster with a distinct but intersecting research lineage; the glutathione research overview provides contextual background on antioxidant signaling in the same broad research space.

References

  1. Lee C, Zeng J, Drew BG, Sallam T, Martin-Montalvo A, Wan J, Kim SJ, Mehta H, Hevener AL, de Cabo R, Cohen P. The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance. Cell Metab. 2015 Mar 3;21(3):443–454. doi: 10.1016/j.cmet.2015.02.009. PMID: 25738459. https://pubmed.ncbi.nlm.nih.gov/25738459/

  2. Hashimoto Y, Niikura T, Tajima H, Yasukawa T, Sudo H, Ito Y, Kita Y, Kawasumi M, Kouyama K, Doyu M, Sobue G, Koide T, Tsuji S, Lang J, Kurokawa K, Nishimoto I. A rescue factor abolishing neuronal cell death by a wide spectrum of familial Alzheimer's disease genes and Abeta. Proc Natl Acad Sci U S A. 2001 May 22;98(11):6336–6341. doi: 10.1073/pnas.101133498. PMID: 11371646. https://pubmed.ncbi.nlm.nih.gov/11371646/

  3. Fuku N, Pareja-Galeano H, Zempo H, Alis R, Arai Y, Lucia A, Hirose N. The mitochondrial-derived peptide MOTS-c: a player in exceptional longevity? Aging Cell. 2015 Dec;14(6):921–923. doi: 10.1111/acel.12389. PMID: 26332820. https://pubmed.ncbi.nlm.nih.gov/26332820/

  4. Kim KH, Son JM, Benayoun BA, Lee C. The mitochondrial-encoded peptide MOTS-c translocates to the nucleus to regulate nuclear gene expression in response to metabolic stress. Cell Metab. 2018 Sep 4;28(3):516–524.e7. doi: 10.1016/j.cmet.2018.06.015. PMID: 29983246. https://pubmed.ncbi.nlm.nih.gov/29983246/

  5. Zhu Z, Qian M, Joly JH, Lu R, Mehta HH, Cohen P, Lee C. MOTS-c modulates skeletal muscle function by directly binding and activating CK2. iScience. 2024 Oct 19;27(11):111215. doi: 10.1016/j.isci.2024.111215. PMID: 39559755. https://pubmed.ncbi.nlm.nih.gov/39559755/

  6. Zhang Y, Huang J, Zhang Y, Jiang F, Li S, He S, Sun J, Chen D, Tong Y, Pang Q, Wu Y. The mitochondrial-derived peptide MOTS-c alleviates radiation pneumonitis via an Nrf2-dependent mechanism. Antioxidants (Basel). 2024 May 17;13(5):613. doi: 10.3390/antiox13050613. PMID: 38790718. https://pubmed.ncbi.nlm.nih.gov/38790718/

  7. Wan W, Zhang L, Lin Y, Rao X, Wang X, Hua F, Ying J. Mitochondria-derived peptide MOTS-c: effects and mechanisms related to stress, metabolism and aging. J Transl Med. 2023 Jan 20;21(1):36. doi: 10.1186/s12967-023-03885-2. PMID: 36670507. https://pubmed.ncbi.nlm.nih.gov/36670507/

Frequently asked questions

  • When was MOTS-c discovered?

    MOTS-c was first described in a March 2015 publication in Cell Metabolism by Lee, Zeng, Drew, Sallam, and colleagues at the University of Southern California. The discovery arose from systematic bioinformatics screening of the mitochondrial 12S ribosomal RNA gene (MT-RNR1) for previously uncharacterized open reading frames.

  • Who discovered MOTS-c?

    MOTS-c was identified by Changhan Lee working within the laboratory of Pinchas Cohen at the Leonard Davis School of Gerontology, University of Southern California. The research built on the group's prior work characterizing humanin and its cytoprotective signaling properties.

  • What is humanin and how does it relate to MOTS-c?

    Humanin is a 24-amino-acid peptide encoded in the MT-RNR2 region of mitochondrial DNA, first described in 2001. It was the founding member of the mitochondrial-derived peptide (MDP) class. MOTS-c, encoded in the MT-RNR1 region, extended that class with a distinct peptide from a different rRNA-encoding region with different signaling properties.

  • What is the WADA regulatory history of MOTS-c?

    In 2024, the World Anti-Doping Agency added MOTS-c to its Prohibited List under category S4.4 (Metabolic Modulators, AMPK activators subcategory), effective at all times for athletes subject to WADA rules. This represented the first major regulatory milestone for the compound, reflecting scientific recognition of its biological characterization.