Hypoxia-induced metabolic stress in retinal pigment epithelial cells is sufficient to induce photoreceptor degeneration

  1. Toshihide Kurihara
  2. Peter D Westenskow
  3. Marin L Gantner
  4. Yoshihiko Usui
  5. Andrew Schultz
  6. Stephen Bravo
  7. Edith Aguilar
  8. Carli Wittgrove
  9. Mollie SH Friedlander
  10. Liliana P Paris
  11. Emily Chew
  12. Gary Siuzdak
  13. Martin Friedlander  Is a corresponding author
  1. Keio University School of Medicine, Japan
  2. The Scripps Research Institute, United States
  3. The Lowy Medical Research Institute, United States
  4. Tokyo Medical University Hospital, Japan
  5. National Institutes of Health, United States
  6. The Scripps Research institute, United States

Abstract

Photoreceptors are the most numerous and metabolically demanding cells in the retina. Their primary nutrient source is the choriocapillaris, and both the choriocapillaris and photoreceptors require trophic and functional support from retinal pigment epithelium (RPE) cells. Defects in RPE, photoreceptors, and the choriocapillaris are characteristic of age-related macular degeneration (AMD), a common vision-threatening disease. RPE dysfunction or death is a primary event in AMD, but the combination(s) of cellular stresses that affect the function and survival of RPE are incompletely understood. Here, using mouse models in which hypoxia can be genetically triggered in RPE, we show that hypoxia-induced metabolic stress alone leads to photoreceptor atrophy. Glucose and lipid metabolism are radically altered in hypoxic RPE cells; these changes impact nutrient availability for the sensory retina and promote progressive photoreceptor degeneration. Understanding the molecular pathways that control these responses may provide important clues about AMD pathogenesis and inform future therapies.

Article and author information

Author details

  1. Toshihide Kurihara

    Department of Ophthalmology, Keio University School of Medicine, Tokyo, Japan
    Competing interests
    The authors declare that no competing interests exist.
  2. Peter D Westenskow

    Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Marin L Gantner

    The Lowy Medical Research Institute, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Yoshihiko Usui

    Department of Ophthalmology, Tokyo Medical University Hospital, Tokyo, Japan
    Competing interests
    The authors declare that no competing interests exist.
  5. Andrew Schultz

    Center for Metabolomics, The Scripps Research Institute, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Stephen Bravo

    Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Edith Aguilar

    Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Carli Wittgrove

    Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Mollie SH Friedlander

    Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Liliana P Paris

    Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Emily Chew

    National Eye Institute, National Institutes of Health, Bethesda, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Gary Siuzdak

    Center for Metabolomics, The Scripps Research Institute, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  13. Martin Friedlander

    Department of Cell and Molecular Biology, The Scripps Research institute, La Jolla, United States
    For correspondence
    friedlan@scripps.edu
    Competing interests
    The authors declare that no competing interests exist.

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (#08-0045-3) of the Scripps Research Institute. All surgery was performed under isofluorane and/or ketamine/xylazine anesthesia, and every effort was made to minimize suffering.

Copyright

This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

Metrics

  • 5,606
    views
  • 1,329
    downloads
  • 168
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Toshihide Kurihara
  2. Peter D Westenskow
  3. Marin L Gantner
  4. Yoshihiko Usui
  5. Andrew Schultz
  6. Stephen Bravo
  7. Edith Aguilar
  8. Carli Wittgrove
  9. Mollie SH Friedlander
  10. Liliana P Paris
  11. Emily Chew
  12. Gary Siuzdak
  13. Martin Friedlander
(2016)
Hypoxia-induced metabolic stress in retinal pigment epithelial cells is sufficient to induce photoreceptor degeneration
eLife 5:e14319.
https://doi.org/10.7554/eLife.14319

Share this article

https://doi.org/10.7554/eLife.14319

Further reading

    1. Cell Biology
    2. Genetics and Genomics
    Keva Li, Nicholas Tolman ... UK Biobank Eye and Vision Consortium
    Research Article

    A glaucoma polygenic risk score (PRS) can effectively identify disease risk, but some individuals with high PRS do not develop glaucoma. Factors contributing to this resilience remain unclear. Using 4,658 glaucoma cases and 113,040 controls in a cross-sectional study of the UK Biobank, we investigated whether plasma metabolites enhanced glaucoma prediction and if a metabolomic signature of resilience in high-genetic-risk individuals existed. Logistic regression models incorporating 168 NMR-based metabolites into PRS-based glaucoma assessments were developed, with multiple comparison corrections applied. While metabolites weakly predicted glaucoma (Area Under the Curve = 0.579), they offered marginal prediction improvement in PRS-only-based models (p=0.004). We identified a metabolomic signature associated with resilience in the top glaucoma PRS decile, with elevated glycolysis-related metabolites—lactate (p=8.8E-12), pyruvate (p=1.9E-10), and citrate (p=0.02)—linked to reduced glaucoma prevalence. These metabolites combined significantly modified the PRS-glaucoma relationship (Pinteraction = 0.011). Higher total resilience metabolite levels within the highest PRS quartile corresponded to lower glaucoma prevalence (Odds Ratiohighest vs. lowest total resilience metabolite quartile=0.71, 95% Confidence Interval = 0.64–0.80). As pyruvate is a foundational metabolite linking glycolysis to tricarboxylic acid cycle metabolism and ATP generation, we pursued experimental validation for this putative resilience biomarker in a human-relevant Mus musculus glaucoma model. Dietary pyruvate mitigated elevated intraocular pressure (p=0.002) and optic nerve damage (p<0.0003) in Lmx1bV265D mice. These findings highlight the protective role of pyruvate-related metabolism against glaucoma and suggest potential avenues for therapeutic intervention.

    1. Cell Biology
    2. Immunology and Inflammation
    Alejandro Rosell, Agata Adelajda Krygowska ... Esther Castellano Sanchez
    Research Article

    Macrophages are crucial in the body’s inflammatory response, with tightly regulated functions for optimal immune system performance. Our study reveals that the RAS–p110α signalling pathway, known for its involvement in various biological processes and tumourigenesis, regulates two vital aspects of the inflammatory response in macrophages: the initial monocyte movement and later-stage lysosomal function. Disrupting this pathway, either in a mouse model or through drug intervention, hampers the inflammatory response, leading to delayed resolution and the development of more severe acute inflammatory reactions in live models. This discovery uncovers a previously unknown role of the p110α isoform in immune regulation within macrophages, offering insight into the complex mechanisms governing their function during inflammation and opening new avenues for modulating inflammatory responses.