mTOR inhibition alleviates mitochondrial disease in a mouse model of Leigh syndrome

Simon C. Johnson, Melana E. Yanos, Ernst-Bernhard Kayser, Albert Quintana, Maya Sangesland, Anthony Castanza, Lauren Uhde, Jessica Hui, Valerie Z Wall, Arni Gagnidze, Kelly Oh, Brian M Wasko, Fresnida J Ramos, Richard D Palmiter, Peter S Rabinovitch, Philip G Morgan, Margaret M Sedensky, Matt Kaeberlein*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

417 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1524-8
Number of pages5
JournalScience
Volume342
Issue number6165
Early online date14 Nov 2013
DOIs
Publication statusPublished - 20 Dec 2013
Externally publishedYes

Keywords

  • Animals
  • Brain/drug effects
  • Disease Models, Animal
  • Electron Transport Complex I/genetics
  • Glycolysis/drug effects
  • Leigh Disease/drug therapy
  • Mechanistic Target of Rapamycin Complex 1
  • Mice
  • Mice, Knockout
  • Mice, Mutant Strains
  • Mitochondria/drug effects
  • Mitochondrial Diseases/drug therapy
  • Molecular Targeted Therapy
  • Multiprotein Complexes/antagonists & inhibitors
  • Neuroprotective Agents/therapeutic use
  • Sirolimus/therapeutic use
  • TOR Serine-Threonine Kinases/antagonists & inhibitors

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