PMID- 24231806
OWN - NLM
STAT- MEDLINE
DCOM- 20140108
LR  - 20240503
IS  - 1095-9203 (Electronic)
IS  - 0036-8075 (Print)
IS  - 0036-8075 (Linking)
VI  - 342
IP  - 6165
DP  - 2013 Dec 20
TI  - mTOR inhibition alleviates mitochondrial disease in a mouse model of Leigh 
      syndrome.
PG  - 1524-8
LID - 10.1126/science.1244360 [doi]
AB  - Mitochondrial dysfunction contributes to numerous health problems, including 
      neurological and muscular degeneration, cardiomyopathies, cancer, diabetes, and 
      pathologies of aging. Severe mitochondrial defects can result in childhood 
      disorders such as Leigh syndrome, for which there are no effective therapies. We 
      found that rapamycin, a specific inhibitor of the mechanistic target of rapamycin 
      (mTOR) signaling pathway, robustly enhances survival and attenuates disease 
      progression in a mouse model of Leigh syndrome. Administration of rapamycin to 
      these mice, which are deficient in the mitochondrial respiratory chain subunit 
      Ndufs4 [NADH dehydrogenase (ubiquinone) Fe-S protein 4], delays onset of 
      neurological symptoms, reduces neuroinflammation, and prevents brain lesions. 
      Although the precise mechanism of rescue remains to be determined, rapamycin 
      induces a metabolic shift toward amino acid catabolism and away from glycolysis, 
      alleviating the buildup of glycolytic intermediates. This therapeutic strategy 
      may prove relevant for a broad range of mitochondrial diseases.
FAU - Johnson, Simon C
AU  - Johnson SC
AD  - Department of Pathology, University of Washington, Seattle, WA 98195, USA.
FAU - Yanos, Melana E
AU  - Yanos ME
FAU - Kayser, Ernst-Bernhard
AU  - Kayser EB
FAU - Quintana, Albert
AU  - Quintana A
FAU - Sangesland, Maya
AU  - Sangesland M
FAU - Castanza, Anthony
AU  - Castanza A
FAU - Uhde, Lauren
AU  - Uhde L
FAU - Hui, Jessica
AU  - Hui J
FAU - Wall, Valerie Z
AU  - Wall VZ
FAU - Gagnidze, Arni
AU  - Gagnidze A
FAU - Oh, Kelly
AU  - Oh K
FAU - Wasko, Brian M
AU  - Wasko BM
FAU - Ramos, Fresnida J
AU  - Ramos FJ
FAU - Palmiter, Richard D
AU  - Palmiter RD
FAU - Rabinovitch, Peter S
AU  - Rabinovitch PS
FAU - Morgan, Philip G
AU  - Morgan PG
FAU - Sedensky, Margaret M
AU  - Sedensky MM
FAU - Kaeberlein, Matt
AU  - Kaeberlein M
LA  - eng
GR  - T32AG000057/AG/NIA NIH HHS/United States
GR  - P01 AG001751/AG/NIA NIH HHS/United States
GR  - T32ES007032/ES/NIEHS NIH HHS/United States
GR  - T32 AG000057/AG/NIA NIH HHS/United States
GR  - R01 AG039390/AG/NIA NIH HHS/United States
GR  - T32 ES007032/ES/NIEHS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20131114
PL  - United States
TA  - Science
JT  - Science (New York, N.Y.)
JID - 0404511
RN  - 0 (Multiprotein Complexes)
RN  - 0 (Ndufs4 protein, mouse)
RN  - 0 (Neuroprotective Agents)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 7.1.1.2 (Electron Transport Complex I)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
CIN - Nat Rev Neurol. 2014 Jan;10(1):2. PMID: 24296657
CIN - Science. 2013 Dec 20;342(6165):1453-4. PMID: 24357304
MH  - Animals
MH  - Brain/drug effects/enzymology/pathology
MH  - Disease Models, Animal
MH  - Electron Transport Complex I/genetics/metabolism
MH  - Glycolysis/drug effects
MH  - Leigh Disease/*drug therapy/genetics/pathology
MH  - Mechanistic Target of Rapamycin Complex 1
MH  - Mice
MH  - Mice, Knockout
MH  - Mice, Mutant Strains
MH  - Mitochondria/drug effects/enzymology
MH  - Mitochondrial Diseases/*drug therapy/genetics/pathology
MH  - *Molecular Targeted Therapy
MH  - Multiprotein Complexes/*antagonists & inhibitors
MH  - Neuroprotective Agents/*therapeutic use
MH  - Sirolimus/*therapeutic use
MH  - TOR Serine-Threonine Kinases/*antagonists & inhibitors
PMC - PMC4055856
MID - NIHMS584331
EDAT- 2013/11/16 06:00
MHDA- 2014/01/09 06:00
PMCR- 2014/06/20
CRDT- 2013/11/16 06:00
PHST- 2013/11/16 06:00 [entrez]
PHST- 2013/11/16 06:00 [pubmed]
PHST- 2014/01/09 06:00 [medline]
PHST- 2014/06/20 00:00 [pmc-release]
AID - science.1244360 [pii]
AID - 10.1126/science.1244360 [doi]
PST - ppublish
SO  - Science. 2013 Dec 20;342(6165):1524-8. doi: 10.1126/science.1244360. Epub 2013 
      Nov 14.