UMMS Affiliation

Department of Ophthalmology

Date

6-1-2015

Document Type

Article

Subjects

Animals; Cell Survival; Diabetic Retinopathy; Disease Models, Animal; Electroretinography; Eye Proteins; Immunosuppressive Agents; Mice; Mice, Inbred C57BL; Multiprotein Complexes; Phosphatidylinositol 3-Kinases; Retinal Cone Photoreceptor Cells; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

Disciplines

Cellular and Molecular Physiology | Eye Diseases | Ophthalmology

Abstract

Cones are the primary photoreceptor (PR) cells responsible for vision in humans. They are metabolically highly active requiring phosphoinositide 3-kinase (PI3K) activity for long-term survival. One of the downstream targets of PI3K is the kinase mammalian target of rapamycin (mTOR), which is a key regulator of cell metabolism and growth, integrating nutrient availability and growth factor signals. Both PI3K and mTOR are part of the insulin/mTOR signaling pathway, however if mTOR is required for long-term PR survival remains unknown. This is of particular interest since deregulation of this pathway in diabetes results in reduced PR function before the onset of any clinical signs of diabetic retinopathy. mTOR is found in two distinct complexes (mTORC1 and mTORC2) that are characterized by their unique accessory proteins RAPTOR and RICTOR respectively. mTORC1 regulates mainly cell metabolism in response to nutrient availability and growth factor signals, while mTORC2 regulates pro-survival mechanisms in response to growth factors. Here we analyze the effect on cones of loss of mTORC1, mTORC2 and simultaneous loss of mTORC1 and mTORC2. Interestingly, neither loss of mTORC1 nor mTORC2 affects cone function or survival at one year of age. However, outer and inner segment morphology is affected upon loss of either complex. In contrast, concurrent loss of mTORC1 and mTORC2 leads to a reduction in cone function without affecting cone viability. The data indicates that PI3K mediated pro-survival signals diverge upstream of both mTOR complexes in cones, suggesting that they are independent of mTOR activity. Furthermore, the data may help explain why PR function is reduced in diabetes, which can lead to deregulation of both mTOR complexes simultaneously. Finally, although mTOR is a key regulator of cell metabolism, and PRs are metabolically highly active, the data suggests that the role of mTOR in regulating the metabolic transcriptome in healthy cones is minimal.

Rights and Permissions

Citation: Exp Eye Res. 2015 Jun;135:1-13. doi: 10.1016/j.exer.2015.04.006. Epub 2015 Apr 14. Link to article on publisher's site

DOI of Published Version

10.1016/j.exer.2015.04.006

Comments

© 2015 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Related Resources

Link to Article in PubMed

Keywords

Cone survival, Diabetic retinopathy, Neuroprotective, PI3K, Photoreceptors, Retinitis pigmentosa, Visual function, mTOR

Journal Title

Experimental eye research

PubMed ID

25887293

Creative Commons License

Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.

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