Biogenesis and functions of mammalian iron-sulfur proteins in the regulation of iron homeostasis and pivotal metabolic pathways

Abstract

Fe-S cofactors are composed of iron and inorganic sulfur in various stoichiometries. A complex assembly pathway conducts their initial synthesis and subsequent binding to recipient proteins. In this minireview, we discuss how discovery of the role of the mammalian cytosolic aconitase, known as iron regulatory protein 1 (IRP1), led to the characterization of the function of its Fe-S cluster in sensing and regulating cellular iron homeostasis. Moreover, we present an overview of recent studies that have provided insights into the mechanism of Fe-S cluster transfer to recipient Fe-S proteins. Discovery of a regulatory role for an iron-sulfur cluster in iron regulatory protein 1Interest in understanding how mammalian cells regulated iron uptake and distribution in the 1980s led to the discovery of a post-transcriptional regulatory mechanism, which was found to be crucial for cellular and systemic iron homeostasis in vertebrates. It was known that the expression of a major iron storage protein, ferritin (Ft), 2 was primarily regulated at the translational rather than transcriptional level (1, 2). However, it was not possible to dissect how ferritin levels were controlled under different conditions of iron availability until the genes encoding H and L ferritin were cloned in 1984 (2). At that time, gel-shift assays were commonly used to demonstrate direct binding of specific transcription factors to DNA sequences. A similar approach revealed that one or more cytosolic proteins were bound to the 5Ј-untranslated (5Ј-UTR) region of ferritin transcripts in mammalian cells (3-5). Moreover, it appeared that the binding factors reflected the iron status of the cell, as ferritin translation and gel-shift binding activity were reduced in cells that were iron-deficient, while conversely increasing in cells that were iron-loaded. The region of the ferritin transcripts responsible for mediating translational regulation was identified and subsequently named the IRE, for iron-responsive element. The IRE was defined through mutagenesis and sequence homology as a short stem-loop structure located near the 5Ј-end of the ferritin transcript. Intensive efforts to identify cytosolic factors that bound to the IRE resulted in cloning of two major cytosolic regulatory proteins, iron regulatory proteins 1 and 2 (IRP1 and IRP2) (5). It was immediately apparent, upon inspection of its primary amino acid sequence, that IRP1 was remarkably similar to mitochondrial aconitase, which was a well-characterized Fe-S protein. A cubane [Fe 4 -S 4 ] cluster in the IRP1 active-site cleft was known to be critical for the reversible aconitase-mediated conversion of citrate to isocitrate (6), which is essential for cholesterol and fatty acid metabolism, as citrate is the substrate of ATP-citrate lyase, which generates acetyl-coenzyme A utilized for cholesterol and lipid biosynthesis. Additionally, citrate has important regulatory roles in glycolysis and fatty acid synthesis and oxidation (7). Isocitrate is also metabolized by the cytosolic NADP-dependent iso...

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PTBP1 acts as a dominant repressor of the aberrant tissue‐specific splicing of ISCU in hereditary myopathy with lactic acidosis

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