Format

Send to

Choose Destination
Elife. 2016 Mar 23;5. pii: e13378. doi: 10.7554/eLife.13378.

Alleviation of neuronal energy deficiency by mTOR inhibition as a treatment for mitochondria-related neurodegeneration.

Author information

1
Molecular and Cell Biology Laboratory, Salk Institute for Biological Studies, La Jolla, United States.
2
Laboratory of Genetics, Salk Institute for Biological Studies, La Jolla, United States.
3
Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, United States.
4
Stem Cell Core, Salk Institute for Biological Studies, La Jolla, United States.
5
Howard Hughes Medical Institute, Salk Institute for Biological Studies, La Jolla, United States.

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.

KEYWORDS:

ATP; human; human biology; iPS disease modeling; maternally inherited Leigh syndrome; medicine; mitochondria; rapamycin

PMID:
27008180
PMCID:
PMC4846388
DOI:
10.7554/eLife.13378
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for eLife Sciences Publications, Ltd Icon for PubMed Central
Loading ...
Support Center