An X-chromosome linked mouse model ( Ndufa1 S55A ) for systemic partial Complex I deficiency for studying predisposition to neurodegeneration and other diseases

Kim, Chul; Potluri, Prasanth; Khalil, Ahmed; Gaut, Daria; McManus, Meagan J.; Compton, Shannon; Wallace, Douglas C.; Yadava, Nagendra

doi:10.1016/j.neuint.2017.05.003

Cited by 7 publications

(1 citation statement)

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“…We investigated the brain and liver RNA expression and metabolite profiles of treated and untreated WT and TK2 mice sacrificed after disease manifestation. Metabolomics analysis was conducted in plasma as well, because of the traditional role of certain plasma metabolite levels in diagnosing mitochondrial disease ( 48 , 49 ).…”

Section: Resultsmentioning

confidence: 99%

Low-dose rapamycin extends lifespan in a mouse model of mtDNA depletion syndrome

Siegmund

Yang²,

Sharma

et al. 2017

Human Molecular Genetics

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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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Section: Resultsmentioning

confidence: 99%