Augmenter of liver regeneration regulates cellular iron homeostasis by modulating mitochondrial transport of atp-binding cassette b8

Hsiang Chun Chang; Jason Solomon Shapiro; Xinghang Jiang; Grant Senyei; Teruki Sato; Justin Geier; Konrad T. Sawicki; Hossein Ardehali

doi:10.7554/ELIFE.65158

Augmenter of liver regeneration regulates cellular iron homeostasis by modulating mitochondrial transport of atp-binding cassette b8

Hsiang Chun Chang, Jason Solomon Shapiro, Xinghang Jiang, Grant Senyei, Teruki Sato, Justin Geier, Konrad T. Sawicki, Hossein Ardehali^*

^*Corresponding author for this work

Medicine, Cardiology Division

Research output: Contribution to journal › Article › peer-review

4 Scopus citations

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 thus 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.

Original language	English (US)
Article number	e65158
Journal	eLife
Volume	10
DOIs	https://doi.org/10.7554/ELIFE.65158
State	Published - 2021

ASJC Scopus subject areas

Biochemistry, Genetics and Molecular Biology(all)
Immunology and Microbiology(all)
Neuroscience(all)

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10.7554/ELIFE.65158

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@article{b586562cf3534cddbc3dae7c8d1d4d8a,

title = "Augmenter of liver regeneration regulates cellular iron homeostasis 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 thus 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.",

author = "Chang, {Hsiang Chun} and Shapiro, {Jason Solomon} and Xinghang Jiang and Grant Senyei and Teruki Sato and Justin Geier and Sawicki, {Konrad T.} and Hossein Ardehali",

note = "Funding Information: We would like to thank Drs. Roland Lill, Barry Paw, Tracey Rouault, and Celeste Simon for sharing reagents. We would also like to thank technical help from Chunlei Chen. H-CC is supported by American Heart Association12PRE12030002 and NIHT32 GM008152. HA is supported by NIHR01 HL127646, R01 HL140973, and R01 HL138982. Funding Information: We would like to thank Drs. Roland Lill, Barry Paw, Tracey Rouault, and Celeste Simon for sharing reagents. We would also like to thank technical help from Chunlei Chen. H-CC is supported by American Heart Association 12PRE12030002 and NIH T32 GM008152. HA is supported by NIH R01 HL127646, R01 HL140973, and R01 HL138982. Publisher Copyright: {\textcopyright} Chang et al.",

year = "2021",

doi = "10.7554/ELIFE.65158",

language = "English (US)",

volume = "10",

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issn = "2050-084X",

publisher = "eLife Sciences Publications",

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T1 - Augmenter of liver regeneration regulates cellular iron homeostasis by modulating mitochondrial transport of atp-binding cassette b8

AU - Chang, Hsiang Chun

AU - Shapiro, Jason Solomon

AU - Jiang, Xinghang

AU - Senyei, Grant

AU - Sato, Teruki

AU - Geier, Justin

AU - Sawicki, Konrad T.

AU - Ardehali, Hossein

N1 - Funding Information: We would like to thank Drs. Roland Lill, Barry Paw, Tracey Rouault, and Celeste Simon for sharing reagents. We would also like to thank technical help from Chunlei Chen. H-CC is supported by American Heart Association12PRE12030002 and NIHT32 GM008152. HA is supported by NIHR01 HL127646, R01 HL140973, and R01 HL138982. Funding Information: We would like to thank Drs. Roland Lill, Barry Paw, Tracey Rouault, and Celeste Simon for sharing reagents. We would also like to thank technical help from Chunlei Chen. H-CC is supported by American Heart Association 12PRE12030002 and NIH T32 GM008152. HA is supported by NIH R01 HL127646, R01 HL140973, and R01 HL138982. Publisher Copyright: © Chang et al.

PY - 2021

Y1 - 2021

N2 - 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 thus 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.

AB - 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 thus 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.

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Augmenter of liver regeneration regulates cellular iron homeostasis by modulating mitochondrial transport of atp-binding cassette b8

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