Augmenter of Liver Regeneration regulates cellular iron homeostatis by modulating mitochondrial transport of ATP-binding cassette B8
- Northwestern University, United States
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
Jason Solomon Shapiro
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.
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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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
