Mouse Tmem135 mutation reveals a mechanism involving mitochondrial dynamics that leads to age-dependent retinal pathologies

  1. Wei-Hua Lee
  2. Hitoshi Higuchi
  3. Sakae Ikeda
  4. Erica L Macke
  5. Tetsuya Takimoto
  6. Bikash R Pattnaik
  7. Che Liu
  8. Li-Fang Chu
  9. Sandra M Siepka
  10. Kathleen J Krentz
  11. C Dustin Rubinstein
  12. Robert F Kalejta
  13. James A Thomson
  14. Robert F Mullins
  15. Joseph S Takahashi
  16. Lawrence Pinto
  17. Akihiro Ikeda  Is a corresponding author
  1. University of Wisconsin-Madison, United States
  2. Okayama University Hospital, Japan
  3. Morgridge Institute for Research, United States
  4. Northwestern University, United States
  5. University of Iowa, United States
  6. Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, United States

Abstract

While aging process is central to the pathogenesis of age-dependent diseases, it is poorly understood at the molecular level. We identified a mouse mutant with accelerated aging in the retina as well as pathologies observed in age-dependent retinal diseases, suggesting that the responsible gene regulates retinal aging, and its impairment results in age-dependent disease. We determined that a mutation in the transmembrane 135 (Tmem135) is responsible for these phenotypes. We observed localization of TMEM135 on mitochondria, and imbalance of mitochondrial fission and fusion in mutant Tmem135 as well as Tmem135 overexpressing cells, indicating that TMEM135 is involved in the regulation of mitochondrial dynamics. Additionally, mutant retina showed higher sensitivity to oxidative stress. These results suggest that the regulation of mitochondrial dynamics through TMEM135 is critical for protection from environmental stress and controlling the progression of retinal aging. Our study identified TMEM135 as a critical link between aging and age-dependent diseases.

Article and author information

Author details

  1. Wei-Hua Lee

    Department of Medical Genetics, University of Wisconsin-Madison, Madison, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8032-0279
  2. Hitoshi Higuchi

    Department of Dental Anesthesiology, Okayama University Hospital, Okayama, Japan
    Competing interests
    No competing interests declared.
  3. Sakae Ikeda

    Department of Medical Genetics, University of Wisconsin-Madison, Madison, United States
    Competing interests
    No competing interests declared.
  4. Erica L Macke

    Department of Medical Genetics, University of Wisconsin-Madison, Madison, United States
    Competing interests
    No competing interests declared.
  5. Tetsuya Takimoto

    Department of Medical Genetics, University of Wisconsin-Madison, Madison, United States
    Competing interests
    No competing interests declared.
  6. Bikash R Pattnaik

    McPherson Eye Research Institute, University of Wisconsin-Madison, Madison, United States
    Competing interests
    No competing interests declared.
  7. Che Liu

    Institute for Molecular Virology, University of Wisconsin-Madison, Madison, United States
    Competing interests
    No competing interests declared.
  8. Li-Fang Chu

    Morgridge Institute for Research, Madison, United States
    Competing interests
    No competing interests declared.
  9. Sandra M Siepka

    The Chemistry of Life Processes Institute, Northwestern University, Evanston, United States
    Competing interests
    No competing interests declared.
  10. Kathleen J Krentz

    Transgenic Mouse Facility, Biotechnology Center, University of Wisconsin-Madison, Madison, United States
    Competing interests
    No competing interests declared.
  11. C Dustin Rubinstein

    Translational Genomics Facility, Biotechnology Center, University of Wisconsin-Madison, Madison, United States
    Competing interests
    No competing interests declared.
  12. Robert F Kalejta

    Institute for Molecular Virology, University of Wisconsin-Madison, Madison, United States
    Competing interests
    No competing interests declared.
  13. James A Thomson

    Morgridge Institute for Research, Madison, United States
    Competing interests
    No competing interests declared.
  14. Robert F Mullins

    Department of Ophthalmology and Visual, University of Iowa, Iowa City, United States
    Competing interests
    No competing interests declared.
  15. Joseph S Takahashi

    Department of Neuroscience, Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    Joseph S Takahashi, Reviewing editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0384-8878
  16. Lawrence Pinto

    Department of Neurobiology, Northwestern University, Evanston, United States
    Competing interests
    No competing interests declared.
  17. Akihiro Ikeda

    Department of Medical Genetics, University of Wisconsin-Madison, Madison, United States
    For correspondence
    aikeda@wisc.edu
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8440-3891

Funding

National Institutes of Health (R21 EY023061, R01 EY022086)

  • Akihiro Ikeda

Retina Research Foundation (Professorship)

  • Akihiro Ikeda

Howard Hughes Medical Institute

  • Joseph S Takahashi

National Institutes of Health (U01 MH61915)

  • Joseph S Takahashi

National Institutes of Health (P30 845 EY016665, P30 HD003352)

  • Akihiro Ikeda

National Institutes of Health (T32 GM007133)

  • Erica L Macke

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 experiments were performed in accordance with the National Institute of Health Guide for the Care and Use of Laboratory Animals and were approved by the Animal Care and Use Committee (IACUC) protocols (M01771) at the University of Wisconsin-Madison.

Reviewing Editor

  1. Jeremy Nathans, Johns Hopkins University School of Medicine, United States

Publication history

  1. Received: July 1, 2016
  2. Accepted: October 25, 2016
  3. Accepted Manuscript published: November 15, 2016 (version 1)
  4. Version of Record published: November 21, 2016 (version 2)

Copyright

© 2016, Lee 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.

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  1. Wei-Hua Lee
  2. Hitoshi Higuchi
  3. Sakae Ikeda
  4. Erica L Macke
  5. Tetsuya Takimoto
  6. Bikash R Pattnaik
  7. Che Liu
  8. Li-Fang Chu
  9. Sandra M Siepka
  10. Kathleen J Krentz
  11. C Dustin Rubinstein
  12. Robert F Kalejta
  13. James A Thomson
  14. Robert F Mullins
  15. Joseph S Takahashi
  16. Lawrence Pinto
  17. Akihiro Ikeda
(2016)
Mouse Tmem135 mutation reveals a mechanism involving mitochondrial dynamics that leads to age-dependent retinal pathologies
eLife 5:e19264.
https://doi.org/10.7554/eLife.19264

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