Publication Date:
2013-11-16
Description:
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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4055856/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4055856/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Johnson, Simon C -- Yanos, Melana E -- Kayser, Ernst-Bernhard -- Quintana, Albert -- Sangesland, Maya -- Castanza, Anthony -- Uhde, Lauren -- Hui, Jessica -- Wall, Valerie Z -- Gagnidze, Arni -- Oh, Kelly -- Wasko, Brian M -- Ramos, Fresnida J -- Palmiter, Richard D -- Rabinovitch, Peter S -- Morgan, Philip G -- Sedensky, Margaret M -- Kaeberlein, Matt -- R01 AG039390/AG/NIA NIH HHS/ -- T32 AG000057/AG/NIA NIH HHS/ -- T32 ES007032/ES/NIEHS NIH HHS/ -- T32AG000057/AG/NIA NIH HHS/ -- T32ES007032/ES/NIEHS NIH HHS/ -- New York, N.Y. -- Science. 2013 Dec 20;342(6165):1524-8. doi: 10.1126/science.1244360. Epub 2013 Nov 14.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pathology, University of Washington, Seattle, WA 98195, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24231806" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Brain/drug effects/enzymology/pathology
;
Disease Models, Animal
;
Electron Transport Complex I/genetics/metabolism
;
Glycolysis/drug effects
;
Leigh Disease/*drug therapy/genetics/pathology
;
Mice
;
Mice, Knockout
;
Mice, Mutant Strains
;
Mitochondria/drug effects/enzymology
;
Mitochondrial Diseases/*drug therapy/genetics/pathology
;
*Molecular Targeted Therapy
;
Multiprotein Complexes/*antagonists & inhibitors
;
Neuroprotective Agents/*therapeutic use
;
Sirolimus/*therapeutic use
;
TOR Serine-Threonine Kinases/*antagonists & inhibitors
Print ISSN:
0036-8075
Electronic ISSN:
1095-9203
Topics:
Biology
,
Chemistry and Pharmacology
,
Computer Science
,
Medicine
,
Natural Sciences in General
,
Physics
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