ArticleHuman molecular genetics2017
Low-dose rapamycin extends lifespan in a mouse model of mtDNA depletion syndrome.
Article in Human molecular genetics, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 57 papers.
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Who cites it
57 citing papers in PubMed, 89 citations in OpenAlex.
- Primary Mitochondrial-Disorders-Associated Nephropathy in Adulthood.Kidney international reports · 2026Review
- Activation of the protective arm of renin-angiotensin system enhances mitochondrial turnover improving respiration and decreasing integrated stress response in a human Complex III deficiency model.bioRxiv : the preprint server for biology · 2026Article
- 4,5-dihydroxyhexanoic acid is a robust circulating and urine marker of mitochondrial disease and its severity.bioRxiv : the preprint server for biology · 2026Article
- Distinct signaling mechanisms and proteome phenotypes are elicited by compartment-specific genetic defects of copper homeostasis.bioRxiv : the preprint server for biology · 2026Article
- Preclinical evaluation of candidate "kill or cure" strategies to treat MFN2-related lipodystrophy.Molecular medicine (Cambridge, Mass.) · 2025Article
- Rapamycin reveals neuropeptide Y as a regulator of senescence and inflammatory pathways in arthritis.Neuropeptides · 2025Article
- Exploring the Mechanisms and Therapeutic Approaches of Mitochondrial Dysfunction in Alzheimer's Disease: An Educational Literature Review.Molecular neurobiology · 2025Review
- Article
- Effects of Long-term low-dose intermittent rapamycin administration on glucose metabolism and immune system of SAMP8 and SAMR1 mice.Frontiers in immunology · 2025Article
- Article
- Biomarkers in Thyroid Cancer: Emerging Opportunities from Non-Coding RNAs and Mitochondrial Space.International journal of molecular sciences · 2024Review
- Pathways controlling neurotoxicity and proteostasis in mitochondrial complex I deficiency.Human molecular genetics · 2024Article
- Geroprotector drugs and exercise: friends or foes on healthy longevity?BMC biology · 2023Review
- Neurological Phenotypes in Mouse Models of Mitochondrial Disease and Relevance to Human Neuropathology.International journal of molecular sciences · 2023Review
- Targeting the biology of aging with mTOR inhibitors.Nature aging · 2023Review
- Autophagy inducer rapamycin treatment reduces IFN-I-mediated Inflammation and improves anti-HIV-1 T cell response in vivo.JCI insight · 2022Article
- Epigenetic regulation of aging: implications for interventions of aging and diseases.Signal transduction and targeted therapy · 2022Review
- Rapamycin treatment early in life reprograms aging: hyperfunction theory and clinical practice.Aging · 2022Article
- Peripheral tissular analysis of rapamycin's effect as a neuroprotective agent in vivo.Naunyn-Schmiedeberg's archives of pharmacology · 2022Article
- Rapamycin treatment during development extends life span and health span of male mice andScience advances · 2022Article
Corrections and comments
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Authors and funding
8 authors at 3 institutions in 1 country.
Funding
Abstract
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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