Glycogen branching enzyme controls cellular iron homeostasis via Iron Regulatory Protein 1 and mitoNEET

Abstract

Iron Regulatory Protein 1 (IRP1) is a bifunctional cytosolic iron sensor. When iron levels are normal, IRP1 harbours an iron-sulphur cluster (holo-IRP1), an enzyme with aconitase activity. When iron levels fall, IRP1 loses the cluster (apo-IRP1) and binds to iron-responsive elements (IREs) in messenger RNAs (mRNAs) encoding proteins involved in cellular iron uptake, distribution, and storage. Here we show that mutations in the Drosophila 1,4-Alpha-Glucan Branching Enzyme (AGBE) gene cause porphyria. AGBE was hitherto only linked to glycogen metabolism and a fatal human disorder known as glycogen storage disease type IV. AGBE binds specifically to holo-IRP1 and to mitoNEET, a protein capable of repairing IRP1 iron-sulphur clusters. This interaction ensures nuclear translocation of holo-IRP1 and downregulation of iron-dependent processes, demonstrating that holo-IRP1 functions not just as an aconitase, but throttles target gene expression in anticipation of declining iron requirements.

Systematic Surveys of Iron Homeostasis Mechanisms reveal Ferritin Superfamily and Nucleotide Surveillance Regulation to be Modified by PINK1 Absence

“…When the ISC are not available for IRP1/IRP2 or are damaged, the mRNA for Tfrc will be stabilized to increase iron import, while repression of mRNA translation will occur for ferritin heavy and light subunits to maximize iron liberation [101]. Some repair of IRP1 can occur via the [2Fe-2S] clusters of CISD1/CISD2, which protect the cells from ferroptosis [120,121].…”

Systematic Surveys of Iron Homeostasis Mechanisms Reveal Ferritin Superfamily and Nucleotide Surveillance Regulation to be Modified by PINK1 Absence

“…When the ISC are not available for IRP1/IRP2 or are damaged, the mRNA for Tfrc will be stabilized to increase iron import, while repression of mRNA translation will occur for ferritin heavy and light subunits to maximize iron liberation [ 95 ]. Some repair of IRP1 can occur via the [2Fe-2S] clusters of CISD1/CISD2, which protect the cells from ferroptosis [ 114 , 115 ].…”

Regulatory Connections between Iron and Glucose Metabolism

“…Further evidence is provided by data obtained in a Drosophila melanogaster model. A genetic screen using drosophila larvae revealed that IRP-1A physically and genetically interacts with AGBE (1,4-alpha-glucan branching enzyme), which catalyzes the addition of branches to growing glycogen during glycogen synthesis [ 124 ]. The physical interaction is preserved between human IRP1 and GBE1, the orthologs of drosophila IRP-1A and AGBE, respectively.…”

“…Huynh et al demonstrated that AGBE promotes nuclear translocation of IRP-1A, where Cisd2 maintains its 4Fe-4S cluster [ 124 ]. This occurs in the prothoracic gland of drosophila larvae, a tissue with high iron requirements.…”

“…Conversely, under iron deficiency, AGBE gets dissociated from IRP-1A and becomes active, favoring storage of glucose into glycogen (or catabolism via glycolysis to lactate). While the IRP-1A/AGBE interaction was identified using the prothoracic gland of drosophila larvae, proteomic studies using whole drosophila larvae showed that IRP-1A also interacts with glycogen synthase, a key enzyme of glycogen synthesis [ 124 ]. These data provide further evidence for a coordinate regulation of iron and glucose metabolism in the drosophila model.…”