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

被引:94
|
作者
Zheng, Xinde [1 ]
Boyer, Leah [2 ]
Jin, Mingji [1 ]
Kim, Yongsung [2 ]
Fan, Weiwei [3 ]
Bardy, Cedric [2 ]
Berggren, Travis [4 ]
Evans, Ronald M. [3 ,5 ]
Gage, Fred H. [2 ]
Hunter, Tony [1 ]
机构
[1] Salk Inst Biol Studies, Mol & Cell Biol Lab, 10010 N Torrey Pines Rd, La Jolla, CA 92037 USA
[2] Salk Inst Biol Studies, Genet Lab, 10010 N Torrey Pines Rd, La Jolla, CA 92037 USA
[3] Salk Inst Biol Studies, Gene Express Lab, 10010 N Torrey Pines Rd, La Jolla, CA 92037 USA
[4] Salk Inst Biol Studies, Stem Cell Core, 10010 N Torrey Pines Rd, La Jolla, CA 92037 USA
[5] Salk Inst Biol Studies, Howard Hughes Med Inst, 10010 N Torrey Pines Rd, La Jolla, CA 92037 USA
来源
ELIFE | 2016年 / 5卷
基金
美国国家卫生研究院;
关键词
PLURIPOTENT STEM-CELLS; P70; S6; KINASE; ATPASE; 6; GENE; PARKINSONS-DISEASE; ALZHEIMERS-DISEASE; MAMMALIAN TARGET; PROTEIN-KINASE; LEIGH-SYNDROME; OXIDATIVE STRESS; ALPHA-SYNUCLEIN;
D O I
10.7554/eLife.13378
中图分类号
Q [生物科学];
学科分类号
07 ; 0710 ; 09 ;
摘要
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.
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页数:23
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