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.