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The Mitochondrial-Derived Peptide MOTS-c Promotes Metabolic Homeostasis and Reduces Obesity and Insulin Resistance
Open accessAbstract
Mitochondria are known to be functional organelles, but their role as a signaling unit is increasingly being appreciated. The identification of a short open reading frame (sORF) in the mitochondrial DNA (mtDNA) that encodes a signaling peptide, humanin, suggests the possible existence of additional sORFs in the mtDNA. Here we report a sORF within the mitochondrial 12S rRNA encoding a 16-amino-acid peptide named MOTS-c (mitochondrial open reading frame of the 12S rRNA-c) that regulates insulin sensitivity and metabolic homeostasis. Its primary target organ appears to be the skeletal muscle, and its cellular actions inhibit the folate cycle and its tethered de novo purine biosynthesis, leading to AMPK activation. MOTS-c treatment in mice prevented age-dependent and high-fat-diet-induced insulin resistance, as well as diet-induced obesity. These results suggest that mitochondria may actively regulate metabolic homeostasis at the cellular and organismal level via peptides encoded within their genome.
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“whilst recent studies have demonstrated that MOTS-c may also exert protective effects against diet-induced obesity and insulin resistance by altering skeletal muscle gene expression related to metabolism and inflammation”
From Exercise-Induced Muscle–Fat Crosstalk: Molecular Mediators and Their Pharmacological Modulation for the Maintenance of Metabolic Flexibility in Aging (2025) · cites this paper as [117]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Mitochondrial-derived peptides such as MOTS-c may further promote fatigue resistance and enhance muscle strength by activating key metabolic pathways and supporting mitochondrial health”
From Exercise-Induced Muscle–Fat Crosstalk: Molecular Mediators and Their Pharmacological Modulation for the Maintenance of Metabolic Flexibility in Aging (2025) · cites this paper as [117]
Experimental — accuracy not yet measuredIn the citing paper
“The mitochondrial open reading frame of the 12S rRNA-c (MOTS-c) is a bioactive mitochondrial-derived peptide shown to activate the AMPK pathway and modulate metabolic homeostasis [193].”
From AMPK, Mitochondrial Function, and Cardiovascular Disease (2020) · cites this paper as [193]
In the citing paper
“Interestingly, treatment with MOTS-C in mice prevent agedependent and high-fat diet induced insulin resistance and obesity indicating an important role of mitochondria in the control of fat metabolism probably producing prolongevity effects (Fuku et al., 2015; Lee et al., 2015).”
From Mitochondrial Activity and Dynamics Changes Regarding Metabolism in Ageing and Obesity (2017) · cites this paper as Lee et al., 2015
In the citing paper
“treatment with MOTS-C in mice prevent agedependent and high-fat diet induced insulin resistance and obesity indicating an important role of mitochondria in the control of fat metabolism probably producing prolongevity effects (Fuku et al., 2015; Lee et al., 2015).”
From Mitochondrial Activity and Dynamics Changes Regarding Metabolism in Ageing and Obesity (2017) · cites this paper as Lee et al., 2015
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“Interestingly, treatment with MOTS-C in mice prevent agedependent and high-fat diet induced insulin resistance and obesity indicating an important role of mitochondria in the control of fat metabolism probably producing prolongevity effects (Fuku et al., 2015; Lee et al., 2015).”
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“One of these MDPs, mitochondrial ORF of the 12S ribosomal RNA type-c (MOTS-c), activates similar signaling pathways as exercise and, when administered exogenously, promotes exercise-like adaptations (Lee et al., 2015; Kim et al., 2018).”
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MOTS-c peptide increases survival and decreases bacterial load in mice infected with MRSA
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Martinez, T. F., Lyons‐Abbott, S., Bookout, A. L., de Souza, E. V., Donaldson, C. J., Vaughan, J. M., Lau, C. J., Abramov, A., Baquero, A. F., Baquero, K. C., et al. (2023) · Cell Metabolism · doi:10.1016/j.cmet.2022.12.004 · Cited by 79
Metadata
- Authors
- Lee, C., Zeng, J., Drew, B. G., Sallam, T., Martin-Montalvo, A., Wan, J., Kim, S.-J., Mehta, H., Hevener, A. L., de Cabo, R., & Cohen, P.
- Affiliations
- University of Southern California (US)
- University of California, Los Angeles (US)
- Corresponding author
- Lee, Changhan
- Cohen, Pinchas
- ORCID
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2015-03
- Volume
- 21
- Issue
- 3
- Pages
- 443-454
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC4350682
- OpenAlex
- W2160343816
- Cited by
- 715
- References
- 62
- Citations by year
- 2026: 61 · 2025: 77 · 2024: 104 · 2023: 97 · 2022: 59 · 2021: 67 · 2020: 68 · 2019: 55 · 2018: 45 · 2017: 27 · 2016: 40 · 2015: 15
- FWCI
- 18.37
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (UL1TR000130, 7r01ag034430-05)
- National Institute on Aging (1R01AG 034430, # R01AG034430)
- National Institute of General Medical Sciences (R01GM090311)
- National Institute of Diabetes and Digestive and Kidney Diseases (NIH DK063491, P30DK063491)
- National Institute of Environmental Health Sciences (R01ES020812)
- National Center for Advancing Translational Sciences
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Health Sciences › Medicine › Physiology (medical) › Adipose Tissue and Metabolism
- Keywords
- MOTS-c, mitochondrial peptides, 12S rRNA, small open reading frames, mitochondrial DNA, metabolic homeostasis, insulin resistance, obesity, AMPK activation, folate cycle, de novo purine synthesis, skeletal muscle, mitochondrial signaling
- MeSH terms
- Animals, Cell Line, DNA, Mitochondrial, HeLa Cells, Homeostasis, Humans, Insulin, Insulin Resistance, Male, Mice, Inbred C57BL, Mice, Inbred ICR, Mitochondria, Obesity, Peptides, Signal Transduction, Muscle, Skeletal, Cell Line, Tumor, Mice, AMP-Activated Protein Kinases, HEK293 Cells, Diet, High-Fat
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