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Published on: August 27, 2019
Low-dose rapamycin extends lifespan in a mouse model of mtDNA depletion syndrome
Stephanie E Siegmund1, Hua Yang2, Rohit Sharma3
1Department of Cellular, Molecular and Biophysical Studies.
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.
Insights
Low-dose oral rapamycin extended lifespan in mice with mitochondrial DNA disease, independent of direct mitochondrial improvements. This suggests rapamycin may offer a novel therapeutic strategy for mitochondrial disorders.
Area of Science:
- Mitochondrial biology
- Genetics
- Pharmacology
Background:
- Mitochondrial disorders, caused by nuclear or mitochondrial DNA mutations, impact oxidative phosphorylation (OxPhos).
- Rapamycin shows promise in extending lifespan and ameliorating mitochondrial disease in mouse models.
- Previous studies used high-dose rapamycin in nuclear gene defects; this study investigates low-dose oral rapamycin in a mitochondrial DNA disease model.
Purpose of the Study:
- To investigate the efficacy of low-dose oral rapamycin in a mouse model of mitochondrial DNA depletion syndrome due to a thymidine kinase 2 (TK2) mutation.
- To explore the mechanisms by which rapamycin might extend lifespan in this context, independent of direct mitochondrial function.
- To identify potential therapeutic applications of rapamycin for mitochondrial diseases.
Main Methods:
- Administration of low-dose oral rapamycin to knock-in (KI) mice with a mutation in the thymidine kinase 2 (TK2) gene.
- Assessment of lifespan extension and markers of mitochondrial dysfunction.
- Transcriptomic and metabolomic analyses to uncover underlying mechanisms.
- Investigation of canonical pathways such as mitochondrial autophagy.
Main Results:
- Low-dose oral rapamycin significantly extended the lifespan of Tk2KI/KI mice.
- Lifespan extension occurred without detectable improvements in mitochondrial dysfunction.
- Rapamycin did not appear to act through canonical pathways like mitochondrial autophagy.
- Systemic metabolic changes, a potential 'rapamycin metabolic signature,' were observed, suggesting alternative energy utilization and indirect signaling.
Conclusions:
- Low-dose oral rapamycin can extend lifespan in a mouse model of mitochondrial DNA disease.
- The therapeutic effect may be mediated by systemic metabolic reprogramming rather than direct correction of mitochondrial defects.
- Rapamycin holds potential as a therapeutic agent for mitochondrial diseases, even without targeting the primary genetic defect.
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