Augmenter of Liver Regeneration regulates cellular iron homeostatis by modulating mitochondrial transport of ATP-binding cassette B8

Abstract

Chronic loss of Augmenter of Liver Regeneration (ALR) results in mitochondrial myopathy with cataracts, however, the mechanism for this disorder remains unclear. Here, we demonstrate that loss of ALR, a principal component of the MIA40/ALR protein import pathway, results in impaired cytosolic Fe/S cluster biogenesis in mammalian cells. Mechanistically, MIA40/ALR facilitates the mitochondrial import of ATP binding cassette (ABC)-B8, an inner mitochondrial membrane protein required for cytoplasmic Fe/S cluster maturation, through physical interaction with ABCB8. Downregulation of ALR impairs mitochondrial ABCB8 import, reduces cytoplasmic Fe/S cluster maturation, and increases cellular iron through the iron regulatory protein-iron response element system. Our finding provides a mechanistic link between MIA40/ALR import machinery and cytosolic Fe/S cluster maturation through the mitochondrial import of ABCB8, and offers a potential explanation for the pathology seen in patients with ALR mutations.

Data availability

There are no sequencing or structural data generated in the manuscript. All data generated and analyzed during this study are included in the manuscript and supporting files.

Article and author information

Author details

  1. Hsiang-Chun Chang

    Feinberg Cardiovascular Research Inst, Northwestern University, Chicago, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9201-4500
  2. Jason Solomon Shapiro

    Feinberg Cardiovascular Research Inst, Northwestern University, Chicago, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0880-3142
  3. Xinghang Jiang

    Feinberg Cardiovascular Research Inst, Northwestern University, Chicago, United States
    Competing interests
    No competing interests declared.
  4. Grant Senyei

    Feinberg Cardiovascular Research Inst, Northwestern University, Chicago, United States
    Competing interests
    No competing interests declared.
  5. Teruki Sato

    Feinberg Cardiovascular Research Inst, Northwestern University, Chicago, United States
    Competing interests
    No competing interests declared.
  6. Justin Geier

    Feinberg Cardiovascular Research Institute, Northwestern University, Chicago, United States
    Competing interests
    No competing interests declared.
  7. Konrad T Sawicki

    Feinberg Cardiovascular Research Inst, Northwestern University, Chicago, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2124-0081
  8. Hossein Ardehali

    Feinberg Cardiovascular Research Institute, Northwestern University, Chicago, United States
    For correspondence
    h-ardehali@northwestern.edu
    Competing interests
    Hossein Ardehali, Reviewing editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7662-0551

Funding

NIH Office of the Director (NIH R01 HL127646,R01 HL140973,and R01 HL138982)

  • Hossein Ardehali

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

Reviewing Editor

  1. Carlos Isales, Medical College of Georgia at Augusta University, United States

Version history

  1. Received: November 25, 2020
  2. Accepted: April 6, 2021
  3. Accepted Manuscript published: April 9, 2021 (version 1)
  4. Version of Record published: April 19, 2021 (version 2)

Copyright

© 2021, Chang 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. Hsiang-Chun Chang
  2. Jason Solomon Shapiro
  3. Xinghang Jiang
  4. Grant Senyei
  5. Teruki Sato
  6. Justin Geier
  7. Konrad T Sawicki
  8. Hossein Ardehali
(2021)
Augmenter of Liver Regeneration regulates cellular iron homeostatis by modulating mitochondrial transport of ATP-binding cassette B8
eLife 10:e65158.
https://doi.org/10.7554/eLife.65158

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https://doi.org/10.7554/eLife.65158

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