Low-dose rapamycin extends lifespan in a mouse model of mtDNA depletion syndrome
Open accessAbstract
Mitochondrial disorders affecting oxidative phosphorylation (OxPhos) are caused by mutations in both the nuclear and mitochondrial genomes. One promising candidate for treatment is the drug rapamycin, which has been shown to extend lifespan in multiple animal models, and which was previously shown to ameliorate mitochondrial disease in a knock-out mouse model lacking a nuclear-encoded gene specifying an OxPhos structural subunit (Ndufs4). In that model, relatively high-dose intraperitoneal rapamycin extended lifespan and improved markers of neurological disease, via an unknown mechanism. Here, we administered low-dose oral rapamycin to a knock-in (KI) mouse model of authentic mtDNA disease, specifically, progressive mtDNA depletion syndrome, resulting from a mutation in the mitochondrial nucleotide salvage enzyme thymidine kinase 2 (TK2). Importantly, low-dose oral rapamycin was sufficient to extend Tk2KI/KI mouse lifespan significantly, and did so in the absence of detectable improvements in mitochondrial dysfunction. We found no evidence that rapamycin increased survival by acting through canonical pathways, including mitochondrial autophagy. However, transcriptomics and metabolomics analyses uncovered systemic metabolic changes pointing to a potential 'rapamycin metabolic signature.' These changes also implied that rapamycin may have enabled the Tk2KI/KI mice to utilize alternative energy reserves, and possibly triggered indirect signaling events that modified mortality through developmental reprogramming. From a therapeutic standpoint, our results support the possibility that low-dose rapamycin, while not targeting the underlying mtDNA defect, could represent a crucial therapy for the treatment of mtDNA-driven, and some nuclear DNA-driven, mitochondrial diseases.
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A low dose of rapamycin extended lifespan in a mouse model of mtDNA depletion syndrome.
“Additionally, a low dose of rapamycin extended lifespan in a mouse model of mtDNA depletion syndrome38.”
From Mitochondrial and metabolic dysfunction in ageing and age-related diseases (2022) · cites this paper as [38]
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Mitochondrial and metabolic dysfunction in ageing and age-related diseases
Amorim, J. A., Coppotelli, G., Rolo, A. P., Palmeira, C. M., Ross, J. M., & Sinclair, D. A. (2022) · Nature Reviews Endocrinology · doi:10.1038/s41574-021-00626-7 · Cited by 990 · see citing works
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- Authors
- Siegmund, S. E., Yang, H., Sharma, R., Javors, M., Skinner, O., Mootha, V., Hirano, M., & Schon, E. A.
- Affiliations
- Massachusetts General Hospital (US)
- The University of Texas at San Antonio (US)
- Columbia University Irving Medical Center (US)
- Corresponding author
- Schon, Eric A
- ORCID
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2017-09-01
- Volume
- 26
- Issue
- 23
- Pages
- 4588-4605
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- PMC
- PMC5886265
- OpenAlex
- W2753910921
- Cited by
- 92
- References
- 72
- Citations by year
- 2026: 7 · 2025: 9 · 2024: 6 · 2023: 5 · 2022: 14 · 2021: 14 · 2020: 12 · 2019: 13 · 2018: 11
- FWCI
- 4.02
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc
- Locations
- Human Molecular Genetics (publishedVersion, cc-by-nc)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Funders
- U.S. Department of Defense (W911F-15-1-0169)
- Howard Hughes Medical Institute
- National Institutes of Health (AG013319)
- National Institute on Aging (P30AG013319, U01AG022307, P30AG044271)
- National Institute of Neurological Disorders and Stroke (F30NS093798)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (P01HD080642)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Keywords
- rapamycin, mtDNA depletion syndrome, thymidine kinase 2, mitochondrial disease, lifespan extension, mitophagy, oxidative phosphorylation, developmental reprogramming, metabolic reprogramming, knock-in mice
- MeSH terms
- Animals, Autophagy, Disease Models, Animal, DNA, Mitochondrial, Dose-Response Relationship, Drug, Female, Male, Mitochondria, Mutation, Oxidative Phosphorylation, Syndrome, Thymidine Kinase, Signal Transduction, Sirolimus, Mitochondrial Diseases, Electron Transport Complex I, Mice, Gene Knock-In Techniques
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