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

Stephanie E. Siegmund, Hua Yang, Rohit Sharma, Martin A Javors, Owen Skinner, Vamsi Mootha, Michio Hirano, Eric A. Schon

Research output: Contribution to journalArticle

20 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)4588-4605
Number of pages18
JournalHuman Molecular Genetics
Volume26
Issue number23
DOIs
StatePublished - Dec 1 2017
Externally publishedYes

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Sirolimus
Mitochondrial DNA
Mitochondrial Diseases
Oxidative Phosphorylation
Mutation
Metabolomics
Mitochondrial Genome
Autophagy
Therapeutics
Knockout Mice
Nucleotides
Animal Models
Mortality
DNA
Enzymes
Pharmaceutical Preparations
Genes

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Siegmund, S. E., Yang, H., Sharma, R., Javors, M. A., Skinner, O., Mootha, V., ... Schon, E. A. (2017). Low-dose rapamycin extends lifespan in a mouse model of mtDNA depletion syndrome. Human Molecular Genetics, 26(23), 4588-4605. https://doi.org/10.1093/hmg/ddx341

Low-dose rapamycin extends lifespan in a mouse model of mtDNA depletion syndrome. / Siegmund, Stephanie E.; Yang, Hua; Sharma, Rohit; Javors, Martin A; Skinner, Owen; Mootha, Vamsi; Hirano, Michio; Schon, Eric A.

In: Human Molecular Genetics, Vol. 26, No. 23, 01.12.2017, p. 4588-4605.

Research output: Contribution to journalArticle

Siegmund, SE, Yang, H, Sharma, R, Javors, MA, Skinner, O, Mootha, V, Hirano, M & Schon, EA 2017, 'Low-dose rapamycin extends lifespan in a mouse model of mtDNA depletion syndrome', Human Molecular Genetics, vol. 26, no. 23, pp. 4588-4605. https://doi.org/10.1093/hmg/ddx341
Siegmund, Stephanie E. ; Yang, Hua ; Sharma, Rohit ; Javors, Martin A ; Skinner, Owen ; Mootha, Vamsi ; Hirano, Michio ; Schon, Eric A. / Low-dose rapamycin extends lifespan in a mouse model of mtDNA depletion syndrome. In: Human Molecular Genetics. 2017 ; Vol. 26, No. 23. pp. 4588-4605.
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