Mitochondrial-derived peptides in energy metabolism
Open accessAbstract
Mitochondrial-derived peptides (MDPs) are small bioactive peptides encoded by short open-reading frames (sORF) in mitochondrial DNA that do not necessarily have traditional hallmarks of protein-coding genes. To date, eight MDPs have been identified, all of which have been shown to have various cyto- or metaboloprotective properties. The 12S ribosomal RNA ( MT-RNR1) gene harbors the sequence for MOTS-c, whereas the other seven MDPs [humanin and small humanin-like peptides (SHLP) 1–6] are encoded by the 16S ribosomal RNA gene. Here, we review the evidence that endogenous MDPs are sensitive to changes in metabolism, showing that metabolic conditions like obesity, diabetes, and aging are associated with lower circulating MDPs, whereas in humans muscle MDP expression is upregulated in response to stress that perturbs the mitochondria like exercise, some mtDNA mutation-associated diseases, and healthy aging, which potentially suggests a tissue-specific response aimed at restoring cellular or mitochondrial homeostasis. Consistent with this, treatment of rodents with humanin, MOTS-c, and SHLP2 can enhance insulin sensitivity and offer protection against a range of age-associated metabolic disorders. Furthermore, assessing how mtDNA variants alter the functions of MDPs is beginning to provide evidence that MDPs are metabolic signal transducers in humans. Taken together, MDPs appear to form an important aspect of a retrograde signaling network that communicates mitochondrial status with the wider cell and to distal tissues to modulate adaptative responses to metabolic stress. It remains to be fully determined whether the metaboloprotective properties of MDPs can be harnessed into therapies for metabolic disease.
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Exercise has been shown to increase the expression of Humanin and SHLP6, exerting anti-inflammatory, insulin-sensitizing, and metabolic regulatory effects.
“In humans, exercise has been shown to increase the expression of Humanin and SHLP6, exerting anti-inflammatory, insulin-sensitizing, and metabolic regulatory effects [77,78].”
From Exercise-Induced Myokines in Obesity-Related Metabolic Disorders and Cardiovascular Protection: A Narrative Review (2026) · cites this paper as [78]
The Introduction reports increased humanin in muscle and plasma after acute high-intensity exercise in young men, and says plasma SHLP6 concentration responds to exercise. It does not establish that SHLP6 expression increases or that exercise-induced changes in these peptides exert anti-inflammatory or insulin-sensitizing effects in humans. Its discussion of improved insulin sensitivity concerns humanin and other peptides administered to rodents. (LLM, conf=0.87)
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- Authors
- Merry, T. L., Chan, A., Woodhead, J. S. T., Reynolds, J. C., Kumagai, H., Kim, S.-J., & Lee, C.
- Affiliations
- University of Auckland (NZ)
- University of Southern California (US)
- Corresponding author
- Merry, Troy L.
- Venue
- American Journal of Physiology-Endocrinology and Metabolism
- Publisher
- American Physiological Society
- Published
- 2020-10-01
- Volume
- 319
- Issue
- 4
- Pages
- E659-E666
- ISSN
- 0193-1849 (ISSN-L)
- 1522-1555
- PMC
- PMC7750512
- OpenAlex
- W3048794145
- Cited by
- 141
- References
- 60
- Citations by year
- 2026: 14 · 2025: 27 · 2024: 33 · 2023: 27 · 2022: 18 · 2021: 21 · 2020: 1
- FWCI
- 1.60
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- American Journal of Physiology-Endocrinology and Metabolism (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Rutherford Discover Fellowship (RDF-15-UOA-020)
- NIA (R01AG052258)
- Hanson-Thorell Family (N/A)
- American Federation for Aging Research (N/A)
- Ellison Medical Foundation (N/A)
- Royal Society of New Zealand | Marsden Fund (16-UOA-313)
- 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 › Adipose Tissue and Metabolism
- Keywords
- mitochondrial peptides, small open reading frames, mitochondrial DNA, humanin, MOTS-c, 16S rRNA gene, obesity, diabetes mellitus, aging, insulin sensitivity, mitochondrial homeostasis, mitochondrial DNA mutations, retrograde signaling, physical activity, metabolic stress, muscle
- MeSH terms
- Animals, Energy Metabolism, Humans, Mitochondria, Peptides, Mitochondrial Proteins
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