1. Cell Biology
  2. Neuroscience
Download icon

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
Research Article
  • Cited 22
  • Views 2,785
  • Annotations
Cite this article as: eLife 2016;5:e19264 doi: 10.7554/eLife.19264

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.

Metrics

  • 2,785
    Page views
  • 453
    Downloads
  • 22
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, Scopus, PubMed Central.

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)

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

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

Further reading

    1. Biochemistry and Chemical Biology
    2. Cell Biology
    Haibin Yang et al.
    Research Article Updated

    Communications between actin filaments and integrin-mediated focal adhesion (FA) are crucial for cell adhesion and migration. As a core platform to organize FA proteins, the tripartite ILK/PINCH/Parvin (IPP) complex interacts with actin filaments to regulate the cytoskeleton-FA crosstalk. Rsu1, a Ras suppressor, is enriched in FA through PINCH1 and plays important roles in regulating F-actin structures. Here, we solved crystal structures of the Rsu1/PINCH1 complex, in which the leucine-rich-repeats of Rsu1 form a solenoid structure to tightly associate with the C-terminal region of PINCH1. Further structural analysis uncovered that the interaction between Rsu1 and PINCH1 blocks the IPP-mediated F-actin bundling by disrupting the binding of PINCH1 to actin. Consistently, overexpressing Rsu1 in HeLa cells impairs stress fiber formation and cell spreading. Together, our findings demonstrated that Rsu1 is critical for tuning the communication between F-actin and FA by interacting with the IPP complex and negatively modulating the F-actin bundling.

    1. Cell Biology
    2. Chromosomes and Gene Expression
    Qiuying Liu et al.
    Research Article Updated

    The regulation of stem cell fate is poorly understood. Genetic studies in Caenorhabditis elegans lead to the hypothesis that a conserved cytoplasmic double-negative feedback loop consisting of the RNA-binding protein Trim71 and the let-7 microRNA controls the pluripotency and differentiation of stem cells. Although let-7-microRNA-mediated inhibition of Trim71 promotes differentiation, whether and how Trim71 regulates pluripotency and inhibits the let-7 microRNA are still unknown. Here, we show that Trim71 represses Ago2 mRNA translation in mouse embryonic stem cells. Blocking this repression leads to a specific post-transcriptional increase of mature let-7 microRNAs, resulting in let-7-dependent stemness defects and accelerated differentiation in the stem cells. These results not only support the Trim71-let-7-microRNA bi-stable switch model in controlling stem cell fate, but also reveal that repressing the conserved pro-differentiation let-7 microRNAs at the mature microRNA level by Ago2 availability is critical to maintaining pluripotency.