MOTS-cresearch overview.

Overview

MOTS-c stands for mitochondrial open reading frame of the 12S rRNA type-c. Lee et al. (2015) reported a short open reading frame within the mitochondrial 12S rRNA gene that encodes a 16-amino-acid peptide, and studied it in cultured cells and mice ¹. It belongs to a small group of mitochondrial-derived peptides, alongside humanin, that are encoded in mitochondrial DNA rather than the nuclear genome ^1,6.

Most of the primary literature comes from a small number of linked groups, centred on the University of Southern California, and many papers share authors ^1,2,3,4,5,6.

MOTS-c is listed by the US Anti-Doping Agency as prohibited at all times under section S4 of the World Anti-Doping Agency Prohibited List, as an activator of AMP-activated protein kinase (AMPK) ⁷.

Structure and chemistry

Met-Arg-Trp-Gln-Glu-Met-Gly-Tyr-Ile-Phe-Tyr-Pro-Arg-Lys-Leu-Arg (MRWQEMGYIFYPRKLR). Molecular formula C101H152N28O22S2, molecular weight 2174.6 g/mol, CAS 1627580-64-6. It is a linear peptide of L-amino acids.

Three arginines and one lysine give it a net positive charge at neutral pH, and it contains two methionines, which can oxidise to the sulfoxide during handling and storage. Because it is encoded in mitochondrial DNA, its sequence can vary with mitochondrial haplotype. Zempo et al. (2021) studied one such variant, m.1382A>C, which changes lysine 14 to glutamine (K14Q) ⁴.

Mechanisms investigated

No cell-surface receptor for MOTS-c has been identified. The studies below measured intracellular signalling, gene expression and peptide levels.

• Folate cycle and AMPK. In cultured cells, Lee et al. (2015) reported that MOTS-c inhibited the folate cycle and the de novo purine synthesis linked to it, followed by AMPK activation. In mice they measured insulin sensitivity in models of diet-induced and age-dependent insulin resistance ¹.
• Nuclear translocation. Kim et al. (2018) reported that under metabolic stress, including glucose restriction, MOTS-c moved from the cytoplasm to the nucleus in an AMPK-dependent way. There it was associated with changes in a broad set of genes, including those with antioxidant response elements, and interacted with transcription factors such as NRF2 ².
• Levels after exercise. Reynolds et al. (2021) reported higher MOTS-c in human plasma and tissue after exercise. They also studied mice aged 2, 12 and 22 months given the peptide, using physical capacity tests and nuclear gene-expression measures ³.
• Genetic variant. Zempo et al. (2021) studied the m.1382A>C (K14Q) variant, which is specific to East Asian populations. In a meta-analysis of three cohorts (27,527 people), men but not women carrying the C allele had a higher prevalence of type 2 diabetes. In male mice, the K14Q form did not reproduce the glucose-tolerance changes they measured with the common form ⁴.
• Tissue expression. D’Souza et al. (2020) measured MOTS-c in plasma and tissue biopsies from young, middle-aged and older men. Plasma levels were lower with age, while tissue expression was about 1.5-fold higher in the two older groups and was associated with markers of slow-type fibres ⁵.

Research areas

• Discovery, folate cycle and AMPK signalling (in vitro and animal) ¹
• Nuclear translocation and gene regulation under metabolic stress (in vitro) ²
• Exercise-related changes in plasma and tissue levels (human and animal) ³
• The m.1382A>C (K14Q) variant in three population cohorts (human, genetic association) ⁴
• Plasma and tissue levels across age groups in men (human) ⁵
• Mitonuclear signalling (review) ⁶

Limits of the evidence

The literature is young, dating from 2015, and comes largely from one research network with overlapping authors ^1,2,3,4,5,6. Independent replication is limited.

Human data are observational: peptide levels measured in blood or tissue, and a genetic association study ^3,4,5. This summary did not identify published controlled trials of MOTS-c given to people.

Measuring an endogenous peptide at low concentrations depends on the assay, and studies have used different methods. Mouse findings depend on the model, diet, age and timing used, and should not be assumed to carry over to other designs.

OzPept’s MOTS-c is a research chemical, not a medicine, and is not for human use.

Key studies

1. 2015Animal

   Discovery, folate cycle and AMPK signalling ¹

2. 2018In vitro

   Nuclear translocation under metabolic stress ²

3. 2019Review

   MOTS-c as a mitochondrial-encoded regulator of the nucleus ⁶

4. 2020Human

   Tissue expression in younger and older men ⁵

5. 2021Human

   Plasma and tissue levels after exercise ³

6. 2021Human

   K14Q variant in three population cohorts ⁴

Questions

References

1. Lee C, Zeng J, Drew BG, Sallam T, Martin-Montalvo A, Wan J, et al. The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance. Cell Metab. 2015;21(3):443-454. Source
2. 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;28(3):516-524.e7. Source
3. Reynolds JC, Lai RW, Woodhead JST, Joly JH, Mitchell CJ, Cameron-Smith D, et al. MOTS-c is an exercise-induced mitochondrial-encoded regulator of age-dependent physical decline and muscle homeostasis. Nat Commun. 2021;12(1):470. Source
4. Zempo H, Kim SJ, Fuku N, Nishida Y, Higaki Y, Wan J, et al. A pro-diabetogenic mtDNA polymorphism in the mitochondrial-derived peptide, MOTS-c. Aging (Albany NY). 2021;13(2):1692-1717. Source
5. D’Souza RF, Woodhead JST, Hedges CP, Zeng N, Wan J, Kumagai H, et al. Increased expression of the mitochondrial derived peptide, MOTS-c, in skeletal muscle of healthy aging men is associated with myofiber composition. Aging (Albany NY). 2020;12(6):5244-5258. Source
6. Benayoun BA, Lee C. MOTS-c: a mitochondrial-encoded regulator of the nucleus. Bioessays. 2019;41(9):e1900046. Source
7. US Anti-Doping Agency. What is the MOTS-c peptide? Spirit of Sport. Accessed October 2026. Source