1. Cell Biology
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Function of hTim8a in Complex IV assembly in neuronal cells provides insight into pathomechanism underlying Mohr-Tranebjærg syndrome

  1. Yilin Kang
  2. Alexander J Anderson
  3. Thomas Daniel Jackson
  4. Catherine S Palmer
  5. David P De Souza
  6. Kenji M Fujihara
  7. Tegan Stait
  8. Ann E Frazier
  9. Nicholas J Clemons
  10. Deidreia Tull
  11. David R Thorburn
  12. Malcolm J McConville
  13. Michael T Ryan
  14. David A Stroud
  15. Diana Stojanovski  Is a corresponding author
  1. The University of Melbourne, Australia
  2. Peter MacCallum Cancer Centre, Australia
  3. Murdoch Children's Research Institute, Australia
  4. Monash University, Australia
Research Article
  • Cited 14
  • Views 1,558
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Cite this article as: eLife 2019;8:e48828 doi: 10.7554/eLife.48828

Abstract

Human Tim8a and Tim8b are members of an intermembrane space chaperone network, known as the small TIM family. Mutations in TIMM8A cause a neurodegenerative disease, Mohr-Tranebjærg syndrome (MTS), which is characterised by sensorineural hearing loss, dystonia and blindness. Nothing is known about the function of hTim8a in neuronal cells or how mutation of this protein leads to a neurodegenerative disease. We show that hTim8a is required for the assembly of Complex IV in neurons, which is mediated through a transient interaction with Complex IV assembly factors, in particular the copper chaperone COX17. Complex IV assembly defects resulting from loss of hTim8a leads to oxidative stress and changes to key apoptotic regulators, including cytochrome c and Bax, which primes cells for death. Alleviation of oxidative stress by Vitamin E rescues cells from apoptotic vulnerability. We hypothesise that enhanced sensitivity of neuronal cells to apoptosis is the underlying mechanism of MTS.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files. Source data files have been provided for Figure 1 (Table 1); Figure 2 (Table 2) and Figure 3 (Table 3. 4 and 5).

Article and author information

Author details

  1. Yilin Kang

    Department of Biochemistry and Molecular Biology, The University of Melbourne, Melbourne, Australia
    Competing interests
    The authors declare that no competing interests exist.
  2. Alexander J Anderson

    Department of Biochemistry and Molecular Biology, The University of Melbourne, Melbourne, Australia
    Competing interests
    The authors declare that no competing interests exist.
  3. Thomas Daniel Jackson

    Department of Biochemistry and Molecular Biology, The University of Melbourne, Melbourne, Australia
    Competing interests
    The authors declare that no competing interests exist.
  4. Catherine S Palmer

    Department of Biochemistry and Molecular Biology, The University of Melbourne, Melbourne, Australia
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5124-2400
  5. David P De Souza

    Metabolomics Australia, The Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Melbourne, Australia
    Competing interests
    The authors declare that no competing interests exist.
  6. Kenji M Fujihara

    Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, Australia
    Competing interests
    The authors declare that no competing interests exist.
  7. Tegan Stait

    Royal Children's Hospital, Murdoch Children's Research Institute, Melbourne, Australia
    Competing interests
    The authors declare that no competing interests exist.
  8. Ann E Frazier

    Royal Children's Hospital, Murdoch Children's Research Institute, Melbourne, Australia
    Competing interests
    The authors declare that no competing interests exist.
  9. Nicholas J Clemons

    Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, Australia
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9283-9978
  10. Deidreia Tull

    Metabolomics Australia, The Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Melbourne, Australia
    Competing interests
    The authors declare that no competing interests exist.
  11. David R Thorburn

    Royal Children's Hospital, Murdoch Children's Research Institute, Melbourne, Australia
    Competing interests
    The authors declare that no competing interests exist.
  12. Malcolm J McConville

    Metabolomics Australia, The Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Melbourne, Australia
    Competing interests
    The authors declare that no competing interests exist.
  13. Michael T Ryan

    Department of Biochemistry and Molecular Biology, Monash University, Melbourne, Australia
    Competing interests
    The authors declare that no competing interests exist.
  14. David A Stroud

    Department of Biochemistry and Molecular Biology, The University of Melbourne, Melbourne, Australia
    Competing interests
    The authors declare that no competing interests exist.
  15. Diana Stojanovski

    Department of Biochemistry and Molecular Biology, The University of Melbourne, Melbourne, Australia
    For correspondence
    d.stojanovski@unimelb.edu.au
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0199-3222

Funding

Australian Research Council (DP170101249)

  • Diana Stojanovski

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

Reviewing Editor

  1. Agnieszka Chacinska, University of Warsaw, Poland

Publication history

  1. Received: May 28, 2019
  2. Accepted: November 4, 2019
  3. Accepted Manuscript published: November 4, 2019 (version 1)
  4. Version of Record published: November 18, 2019 (version 2)
  5. Version of Record updated: March 18, 2020 (version 3)

Copyright

© 2019, Kang 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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