Iron-sulfur cluster deficiency can be sensed by IRP2 and regulates iron homeostasis and sensitivity to ferroptosis independent of IRP1 and FBXL5

Abstract

Intracellular iron levels are strictly regulated to support homeostasis and avoid iron-mediated ROS production. Loss of iron-sulfur cluster (ISC) synthesis can increase iron loading and promote cell death by ferroptosis. Iron-responsive element-binding proteins IRP1 and IRP2 posttranscriptionally regulate iron homeostasis. IRP1 binding to target mRNAs is competitively regulated by ISC occupancy. However, IRP2 is principally thought to be regulated at the protein level via E3 ubiquitin ligase FBXL5–mediated degradation. Here, we show that ISC synthesis suppression can activate IRP2 and promote ferroptosis sensitivity via a previously unidentified mechanism. At tissue-level O2 concentrations, ISC deficiency enhances IRP2 binding to target mRNAs independent of IRP1, FBXL5, and changes in IRP2 protein level. Deletion of both IRP1 and IRP2 abolishes the iron-starvation response, preventing its activation by ISC synthesis inhibition. These findings will inform strategies to manipulate ferroptosis sensitivity and help illuminate the mechanism underlying ISC biosynthesis disorders, such as Friedreich’s ataxia.

ISCA2 inhibition decreases HIF and induces ferroptosis in clear cell renal carcinoma

“…3H, S3B ). Intriguingly, shRNA knockdown of NFS1, a sulfur donor in ISC biogenesis, also induces IRP2 and TFRC and depletes FTH1, sensitizing cells to ferroptosis (effects on HIF were not investigated) reminiscent of that seen in our current study [65]. Since NFS1 contributes to the maturation of both cytosolic and mitochondrial Fe-S proteins (unlike ISCA1, ISCA2 and IBA57 that are believed to contribute only to mitochondrial [4Fe-4S] assembly), our findings suggest that ISCA2 may play an earlier role in ISC assembly than previously thought [44, 66].…”

miR-29a-3p in Exosomes from Heme Oxygenase-1 Modified Bone Marrow Mesenchymal Stem Cells Alleviates Steatotic Liver Ischemia-Reperfusion Injury in Rats by Suppressing Ferroptosis via Iron Responsive Element Binding Protein 2

“…When ferroptosis occurs, the level of IREB2 mRNA increases and aggravates ferroptosis. Knockdown of IREB2 can reduce ferroptosis [ 11 , 20 ]. Therefore, ferroptosis in steatotic liver IRI is likely to be related to the abnormal expression of IREB2 .…”

“…When ferroptosis occurs, its mRNA expression increases and promotes the occurrence of ferroptosis. Knocking down IREB 2 can reduce the occurrence of ferroptosis [ 11 , 20 ]. Studies have shown that spinal cord injury in rats involves ferroptosis and is accompanied by an increase in Ireb2 mRNA [ 31 ].…”

“…It regulates the translation of FTH1 mRNA (encoding ferritin H, which mediates the storage of intracellular iron) and the stability of TFR1 mRNA (encoding transferrin receptor 1, which mediates cellular iron transport) through posttranscriptional regulatory mechanisms and plays a central role in cellular iron homeostasis [ 18 , 19 ]. IREB2 has been proven to be a marker gene for ferroptosis [ 11 , 20 ]. However, the effects of IREB2 on ferroptosis of steatotic liver IRI are unclear.…”

The Role of Iron in Cancer Progression

“…ISC are made up of iron and sulfur ions to form [1Fe-0S], [2Fe-2S], [3Fe-4S] and [4Fe-4S] clusters (6,119). Suppressing ISC synthesis can activate IRP2 and promote ferroptosis sensitivity (120); in line with this finding, insufficient ISC maintenance has been shown to robustly activate the iron-starvation response and trigger ferroptosis (121). Notably, inorganic sulfur is first produced from the cysteine by the cysteine desulfurase NFS1 and ISC is formed on the ISC assembly enzyme (ISCU) with the help of frataxin (FXN) (122),Which was indicated to be localized in the mitochondrial matrix and participated in the biosynthesis of ISC and FXN deficiency accelerates erastin-activated ferroptosis (123).…”