PMID- 28973153
OWN - NLM
STAT- MEDLINE
DCOM- 20180524
LR  - 20191210
IS  - 1460-2083 (Electronic)
IS  - 0964-6906 (Print)
IS  - 0964-6906 (Linking)
VI  - 26
IP  - 23
DP  - 2017 Dec 1
TI  - Low-dose rapamycin extends lifespan in a mouse model of mtDNA depletion syndrome.
PG  - 4588-4605
LID - 10.1093/hmg/ddx341 [doi]
AB  - 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.
CI  - (c) The Author 2017. Published by Oxford University Press.
FAU - Siegmund, Stephanie E
AU  - Siegmund SE
AD  - Department of Cellular, Molecular and Biophysical Studies.
FAU - Yang, Hua
AU  - Yang H
AD  - Department of Neurology.
FAU - Sharma, Rohit
AU  - Sharma R
AD  - Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 
      02114, USA.
FAU - Javors, Martin
AU  - Javors M
AD  - Department of Psychiatry, University of Texas, San Antonio, TX 78229, USA.
FAU - Skinner, Owen
AU  - Skinner O
AD  - Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 
      02114, USA.
FAU - Mootha, Vamsi
AU  - Mootha V
AD  - Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 
      02114, USA.
FAU - Hirano, Michio
AU  - Hirano M
AD  - Department of Neurology.
FAU - Schon, Eric A
AU  - Schon EA
AD  - Department of Neurology.
AD  - Department of Genetics and Development, Columbia University Medical Center, New 
      York, NY 10032, USA.
LA  - eng
GR  - F30 NS093798/NS/NINDS NIH HHS/United States
GR  - P01 HD080642/HD/NICHD NIH HHS/United States
GR  - P30 AG013319/AG/NIA NIH HHS/United States
GR  - U01 AG022307/AG/NIA NIH HHS/United States
PT  - Journal Article
PL  - England
TA  - Hum Mol Genet
JT  - Human molecular genetics
JID - 9208958
RN  - 0 (DNA, Mitochondrial)
RN  - EC 2.7.1.- (thymidine kinase 2)
RN  - EC 2.7.1.21 (Thymidine Kinase)
RN  - EC 7.1.1.2 (Electron Transport Complex I)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Animals
MH  - Autophagy/drug effects/genetics
MH  - DNA, Mitochondrial/*genetics/metabolism
MH  - Disease Models, Animal
MH  - Dose-Response Relationship, Drug
MH  - Electron Transport Complex I/metabolism
MH  - Female
MH  - Gene Knock-In Techniques
MH  - Male
MH  - Mice
MH  - Mitochondria/metabolism
MH  - Mitochondrial Diseases/*drug therapy/*genetics/pathology
MH  - Mutation
MH  - Oxidative Phosphorylation/drug effects
MH  - Signal Transduction
MH  - Sirolimus/*pharmacology
MH  - Syndrome
MH  - Thymidine Kinase/genetics/metabolism
PMC - PMC5886265
EDAT- 2017/10/04 06:00
MHDA- 2018/05/25 06:00
PMCR- 2017/09/01
CRDT- 2017/10/04 06:00
PHST- 2017/06/09 00:00 [received]
PHST- 2017/08/24 00:00 [accepted]
PHST- 2017/10/04 06:00 [pubmed]
PHST- 2018/05/25 06:00 [medline]
PHST- 2017/10/04 06:00 [entrez]
PHST- 2017/09/01 00:00 [pmc-release]
AID - 4101876 [pii]
AID - ddx341 [pii]
AID - 10.1093/hmg/ddx341 [doi]
PST - ppublish
SO  - Hum Mol Genet. 2017 Dec 1;26(23):4588-4605. doi: 10.1093/hmg/ddx341.