Activated mTORC1 promotes long-term cone survival in retinitis pigmentosa mice
Aditya Venkatesh, … , Markus A. Rüegg, Claudio Punzo
Aditya Venkatesh, … , Markus A. Rüegg, Claudio Punzo
Published April 1, 2015; First published March 23, 2015
Citation Information: J Clin Invest. 2015;125(4):1446-1458. https://doi.org/10.1172/JCI79766.
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Categories: Research Article Genetics Neuroscience Ophthalmology

Activated mTORC1 promotes long-term cone survival in retinitis pigmentosa mice

Abstract

Retinitis pigmentosa (RP) is an inherited photoreceptor degenerative disorder that results in blindness. The disease is often caused by mutations in genes that are specific to rod photoreceptors; however, blindness results from the secondary loss of cones by a still unknown mechanism. Here, we demonstrated that the mammalian target of rapamycin complex 1 (mTORC1) is required to slow the progression of cone death during disease and that constitutive activation of mTORC1 in cones is sufficient to maintain cone function and promote long-term cone survival. Activation of mTORC1 in cones enhanced glucose uptake, retention, and utilization, leading to increased levels of the key metabolite NADPH. Moreover, cone death was delayed in the absence of the NADPH-sensitive cell death protease caspase 2, supporting the contribution of reduced NADPH in promoting cone death. Constitutive activation of mTORC1 preserved cones in 2 mouse models of RP, suggesting that the secondary loss of cones is caused mainly by metabolic deficits and is independent of a specific rod-associated mutation. Together, the results of this study address a longstanding question in the field and suggest that activating mTORC1 in cones has therapeutic potential to prolong vision in RP.

Authors

Aditya Venkatesh, Shan Ma, Yun Z. Le, Michael N. Hall, Markus A. Rüegg, Claudio Punzo

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Figure 1

Schematic representation of the insulin/mTOR pathway.

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Schematic representation of the insulin/mTOR pathway. Upon insulin or gr...
Upon insulin or growth factor binding, phosphosinositide 3-kinase (PI3K) increases the concentration of the second messenger PIP3, a reaction that is reversed by PTEN. Increased PIP3 levels promote mTORC2 and PDK1 activity. Both mTORC2 and PDK1 phosphorylate AKT on Ser473 and Thr308, respectively. While phosphorylation on both sites increases AKT activity, phosphorylation on Thr308 is sufficient to promote AKT activity toward TSC. Activated AKT phosphorylates the TSC protein tuberin (TSC2), which releases the inhibitory function of the TSC1/TSC2 complex on mTORC1, resulting in increased mTORC1 activity. Activated mTORC1 phosphorylates and thereby activates its target ribosomal protein S6 kinase (S6K). S6K negatively feeds back to growth factor receptors by phosphorylation of the insulin receptor substrate (IRS), which prevents overactivation of the pathway. Activated S6K can also phosphorylate RICTOR, which is part of the mTORC2 complex. Phosphorylation of RICTOR by S6K reduces mTORC2-mediated activation of AKT. mTORC1 controls mainly progrowth processes, while mTORC2 and AKT regulate many prosurvival and apoptotic processes.