title: Alleviation of neuronal energy deficiency by mTOR inhibition as a treatment for mitochondria-related neurodegeneration.
abstract: mTOR inhibition is beneficial in neurodegenerative disease models and its effects are often attributable to the modulation of autophagy and anti-apoptosis. Here, we report a neglected but important bioenergetic effect of mTOR inhibition in neurons. mTOR inhibition by rapamycin significantly preserves neuronal ATP levels, particularly when oxidative phosphorylation is impaired, such as in neurons treated with mitochondrial inhibitors, or in neurons derived from maternally inherited Leigh syndrome (MILS) patient iPS cells with ATP synthase deficiency. Rapamycin treatment significantly improves the resistance of MILS neurons to glutamate toxicity. Surprisingly, in mitochondrially defective neurons, but not neuroprogenitor cells, ribosomal S6 and S6 kinase phosphorylation increased over time, despite activation of AMPK, which is often linked to mTOR inhibition. A rapamycin-induced decrease in protein synthesis, a major energy-consuming process, may account for its ATP-saving effect. We propose that a mild reduction in protein synthesis may have the potential to treat mitochondria-related neurodegeneration.
authors.affiliation: Molecular and Cell Biology Laboratory, Salk Institute for Biological Studies, La Jolla, United States.
authors.forename: Xinde
authors.initials: X
authors.lastname: Zheng
authors.affiliation: Laboratory of Genetics, Salk Institute for Biological Studies, La Jolla, United States.
authors.forename: Leah
authors.initials: L
authors.lastname: Boyer
authors.affiliation: Molecular and Cell Biology Laboratory, Salk Institute for Biological Studies, La Jolla, United States.
authors.forename: Mingji
authors.initials: M
authors.lastname: Jin
authors.affiliation: Laboratory of Genetics, Salk Institute for Biological Studies, La Jolla, United States.
authors.forename: Yongsung
authors.initials: Y
authors.lastname: Kim
authors.affiliation: Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, United States.
authors.forename: Weiwei
authors.initials: W
authors.lastname: Fan
authors.affiliation: Laboratory of Genetics, Salk Institute for Biological Studies, La Jolla, United States.
authors.forename: Cedric
authors.identifier: 0000-0001-8321-0852
authors.initials: C
authors.lastname: Bardy
authors.affiliation: Stem Cell Core, Salk Institute for Biological Studies, La Jolla, United States.
authors.forename: Travis
authors.initials: T
authors.lastname: Berggren
authors.affiliation: Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, United States.|Howard Hughes Medical Institute, Salk Institute for Biological Studies, La Jolla, United States.
authors.forename: Ronald M
authors.initials: RM
authors.lastname: Evans
authors.affiliation: Laboratory of Genetics, Salk Institute for Biological Studies, La Jolla, United States.
authors.forename: Fred H
authors.initials: FH
authors.lastname: Gage
authors.affiliation: Molecular and Cell Biology Laboratory, Salk Institute for Biological Studies, La Jolla, United States.
authors.forename: Tony
authors.identifier: 0000-0002-7691-6993
authors.initials: T
authors.lastname: Hunter
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D002478:Cells, Cultured; D006801:Humans; D008928:Mitochondria / Q000378:metabolism*; D019636:Neurodegenerative Diseases / Q000473:pathology*; D009474:Neurons / Q000187:drug effects* / Q000502:physiology*; D018696:Neuroprotective Agents / Q000378:metabolism; D014176:Protein Biosynthesis / Q000187:drug effects; D020123:Sirolimus / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*
chemical_list: D018696:Neuroprotective Agents; D000255:Adenosine Triphosphate; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
keywords: ATP; human; human biology; iPS disease modeling; maternally inherited Leigh syndrome; medicine; mitochondria; rapamycin