The role of mitochondria in cellular iron–sulfur protein biogenesis and iron metabolism

Abstract

Mitochondria play a key role in iron metabolism in that they synthesize heme, assemble iron-sulfur (Fe/S) proteins, and participate in cellular iron regulation. Here, we review the latter two topics and their intimate connection. The mitochondrial Fe/S cluster (ISC) assembly machinery consists of 17 proteins that operate in three major steps of the maturation process. First, the cysteine desulfurase complex Nfs1-Isd11 as the sulfur donor cooperates with ferredoxin-ferredoxin reductase acting as an electron transfer chain, and frataxin to synthesize an [2Fe-2S] cluster on the scaffold protein Isu1. Second, the cluster is released from Isu1 and transferred toward apoproteins with the help of a dedicated Hsp70 chaperone system and the glutaredoxin Grx5. Finally, various specialized ISC components assist in the generation of [4Fe-4S] clusters and cluster insertion into specific target apoproteins. Functional defects of the core ISC assembly machinery are signaled to cytosolic or nuclear iron regulatory systems resulting in increased cellular iron acquisition and mitochondrial iron accumulation. In fungi, regulation is achieved by iron-responsive transcription factors controlling the expression of genes involved in iron uptake and intracellular distribution. They are assisted by cytosolic multidomain glutaredoxins which use a bound Fe/S cluster as iron sensor and additionally perform an essential role in intracellular iron delivery to target metalloproteins. In mammalian cells, the iron regulatory proteins IRP1, an Fe/S protein, and IRP2 act in a post-transcriptional fashion to adjust the cellular needs for iron. Thus, Fe/S protein biogenesis and cellular iron metabolism are tightly linked to coordinate iron supply and utilization. This article is part of a Special Issue entitled: Cell Biology of Metals.

Architecture of the Yeast Mitochondrial Iron-Sulfur Cluster Assembly Machinery

“…However, a protein docking study further suggested that Yfh1 binding would only be possible with the flexible loop of Nfs1 positioned inside the cysteine substrate-binding site rather than in proximity of the Fe-S cluster assembly site. This implies that iron and sulfur donation would have to occur sequentially and that sulfur donation would require the displacement of Yfh1 from the Fe-S cluster assembly complex (17), which is in contrast with the general consensus that Fe-S cluster assembly requires the simultaneous binding of the scaffold to both the cysteine desulfurase and the iron donor (1,2).…”

“…In yeast and animal cells, mitochondria assemble Fe-S clusters autonomously, whereas other cellular compartments depend on precursors and/or signals generated by mitochondria (2). A complete loss of mitochondrial Fe-S cluster synthesis is therefore lethal, while partial defects typically result in mitochondrial dysfunction, multiple Fe-S enzyme deficits throughout the cell, and global iron imbalance (1).…”

Architecture of the Human Mitochondrial Iron-Sulfur Cluster Assembly Machinery

“…1-2, and b, pp. [1][2][3][4][5][6][7][8], or between monomers from two adjacent trimers (supplemental Table S2 24 complex. A-F, to visualize the structure of the entire complex, the simulated half of the structure was aligned with itself into the EM density map of the refined 3D model.…”

Interaction with Cfd1 Increases the Kinetic Lability of FeS on the Nbp35 Scaffold

“…The compartmental nature of the eukaryotic cell coupled with the variety and ubiquitous distribution of iron-sulfur (FeS) proteins necessitates multiple systems to ensure efficient FeS protein maturation throughout the cell. All FeS cluster biogenesis in the eukaryotic cell requires the activity of the mitochondrial iron-sulfur cluster (ISC) 5 assembly system (2). Although small amounts of some components of the ISC system have been detected in the cytoplasm of animal cells (3)(4)(5), most cytosolic and nuclear FeS proteins require the action of a cytosolic iron sulfur cluster assembly (CIA) system for their maturation (1, 6 -10).…”

“…The CIA system is restricted to the cytoplasm and consists of six core proteins, in yeast called Cfd1, Nbp35, Nar1, Cia1, Dre2, and Tah18 (1, 6 -11). CIA is linked to the ISC system through a yet undefined product that is exported out of mitochondria via the ISC export system (2,12).…”