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bioRxiv · 10.1101/2020.11.30.403295

Augmenter of Liver Regeneration Regulates Cellular Iron by Modulating Mitochondrial Transport of ATP-Binding Cassette B8

Ardehali, H.·Chang, H.-C.·Shapiro, J. S.·Jiang, X.·Senyei, G.·Sato, T.·Sawicki, K.
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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.

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Ardehali, H., Chang, H.-C., Shapiro, J. S., Jiang, X., Senyei, G., Sato, T., Sawicki, K.. 2020-11-30. Augmenter of Liver Regeneration Regulates Cellular Iron by Modulating Mitochondrial Transport of ATP-Binding Cassette B8. https://doi.org/10.1101/2020.11.30.403295

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