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.