Abstract

Here we report multiple lines of evidence for a comprehensive model of energy metabolism in the vertebrate eye. Metabolic flux, locations of key enzymes, and our finding that glucose enters mouse and zebrafish retinas mostly through photoreceptors support a conceptually new model for retinal metabolism. In this model, glucose from the choroidal blood passes through the retinal pigment epithelium to the retina where photoreceptors convert it to lactate. Photoreceptors then export the lactate as fuel for the retinal pigment epithelium and for neighboring Müller glial cells. We used human retinal epithelial cells to show that lactate can suppress consumption of glucose by the retinal pigment epithelium. Suppression of glucose consumption in the retinal pigment epithelium can increase the amount of glucose that reaches the retina. This framework for understanding metabolic relationships in the vertebrate retina provides new insights into the underlying causes of retinal disease and age-related vision loss.

Article and author information

Author details

  1. Mark A Kanow

    Department of Biochemistry, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Michelle M Giarmarco

    Department of Biochemistry, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3344-4268
  3. Connor SR Jankowski

    Department of Biochemistry, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Kristine Tsantilas

    Department of Biochemistry, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Abbi L Engel

    Department of Biochemistry, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Jianhai Du

    Department of Ophthalmology, West Virginia University, Morgantown, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Jonathan D Linton

    Department of Biochemistry, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Christopher C Farnsworth

    Department of Biochemistry, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Stephanie R Sloat

    Department of Biochemistry, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Austin Rountree

    Department of Medicine, UW Diabetes Institute, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Ian R Sweet

    Department of Medicine, UW Diabetes Institute, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Ken J Lindsay

    Department of Biochemistry, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  13. Edward D Parker

    Department of Ophthalmology, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  14. Susan E Brockerhoff

    Department of Biochemistry, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  15. Martin Sadilek

    Department of Chemistry, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  16. Jennifer R Chao

    Department of Ophthalmology, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6859-5552
  17. James B Hurley

    Department of Biochemistry, University of Washington, Seattle, United States
    For correspondence
    jbhhh@uw.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7754-0705

Funding

National Eye Institute (EY06641)

  • James B Hurley

National Eye Institute (EY017863)

  • James B Hurley

National Eye Institute (EY026030)

  • Jianhai Du
  • Jennifer R Chao

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All animal research was authorized by the University of Washington Institutional Animal Care and Use Committee.

Copyright

© 2017, Kanow et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 8,512
    views
  • 1,339
    downloads
  • 281
    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. Mark A Kanow
  2. Michelle M Giarmarco
  3. Connor SR Jankowski
  4. Kristine Tsantilas
  5. Abbi L Engel
  6. Jianhai Du
  7. Jonathan D Linton
  8. Christopher C Farnsworth
  9. Stephanie R Sloat
  10. Austin Rountree
  11. Ian R Sweet
  12. Ken J Lindsay
  13. Edward D Parker
  14. Susan E Brockerhoff
  15. Martin Sadilek
  16. Jennifer R Chao
  17. James B Hurley
(2017)
Biochemical adaptations of the retina and retinal pigment epithelium support a metabolic ecosystem in the vertebrate eye
eLife 6:e28899.
https://doi.org/10.7554/eLife.28899

Share this article

https://doi.org/10.7554/eLife.28899

Further reading

    1. Biochemistry and Chemical Biology
    2. Structural Biology and Molecular Biophysics
    Jie Luo, Jeff Ranish
    Tools and Resources

    Dynamic conformational and structural changes in proteins and protein complexes play a central and ubiquitous role in the regulation of protein function, yet it is very challenging to study these changes, especially for large protein complexes, under physiological conditions. Here, we introduce a novel isobaric crosslinker, Qlinker, for studying conformational and structural changes in proteins and protein complexes using quantitative crosslinking mass spectrometry. Qlinkers are small and simple, amine-reactive molecules with an optimal extended distance of ~10 Å, which use MS2 reporter ions for relative quantification of Qlinker-modified peptides derived from different samples. We synthesized the 2-plex Q2linker and showed that the Q2linker can provide quantitative crosslinking data that pinpoints key conformational and structural changes in biosensors, binary and ternary complexes composed of the general transcription factors TBP, TFIIA, and TFIIB, and RNA polymerase II complexes.

    1. Biochemistry and Chemical Biology
    2. Stem Cells and Regenerative Medicine
    Alejandro J Brenes, Eva Griesser ... Angus I Lamond
    Research Article

    Human induced pluripotent stem cells (hiPSCs) have great potential to be used as alternatives to embryonic stem cells (hESCs) in regenerative medicine and disease modelling. In this study, we characterise the proteomes of multiple hiPSC and hESC lines derived from independent donors and find that while they express a near-identical set of proteins, they show consistent quantitative differences in the abundance of a subset of proteins. hiPSCs have increased total protein content, while maintaining a comparable cell cycle profile to hESCs, with increased abundance of cytoplasmic and mitochondrial proteins required to sustain high growth rates, including nutrient transporters and metabolic proteins. Prominent changes detected in proteins involved in mitochondrial metabolism correlated with enhanced mitochondrial potential, shown using high-resolution respirometry. hiPSCs also produced higher levels of secreted proteins, including growth factors and proteins involved in the inhibition of the immune system. The data indicate that reprogramming of fibroblasts to hiPSCs produces important differences in cytoplasmic and mitochondrial proteins compared to hESCs, with consequences affecting growth and metabolism. This study improves our understanding of the molecular differences between hiPSCs and hESCs, with implications for potential risks and benefits for their use in future disease modelling and therapeutic applications.