Improving metabolism prolongs cone cell survival

Retinitis pigmentosa (RP) is an inherited degenerative eye disease that results from the presence of mutations in rod-associated genes. Cone cells, which mediate day light vision, also progressively degrade in RP; however, the mechanisms that mediate loss of these cells are not completely understood. In RP, dying cones exhibit signs of starvation, suggesting metabolic dysfunction in these cells. In this episode, Claudio Punzo and Aditya Venkatesh present their work, which demonstrates that constitutive activation of the metabolic regulator mTORC1 prolongs cone survival and maintains cone function in murine models of RP. The results of this study support further exploration of strategies to improve metabolic function for maintaining cone function in RP.

Published March 23, 2015, by The JCI

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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 March 23, 2015
Citation Information: J Clin Invest. 2015;125(4):1446-1458. https://doi.org/10.1172/JCI79766.
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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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