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Mitochondria are essential in most eukaryotes and are involved in numerous biological functions including ATP production, cofactor biosyntheses, apoptosis, lipid synthesis, and steroid metabolism. Work over the past two decades has uncovered the biogenesis of cellular iron-sulfur (Fe/S) proteins as the essential and minimal function of mitochondria. This process is catalyzed by the bacteria-derived iron-sulfur cluster assembly (ISC) machinery and has been dissected into three major steps: de novo synthesis of a [2Fe-2S] cluster on a scaffold protein; Hsp70 chaperone–mediated trafficking of the cluster and insertion into [2Fe-2S] target apoproteins; and catalytic conversion of the [2Fe-2S] into a [4Fe-4S] cluster and subsequent insertion into recipient apoproteins. ISC components of the first two steps are also required for biogenesis of numerous essential cytosolic and nuclear Fe/S proteins, explaining the essentiality of mitochondria. This review summarizes the molecular mechanisms underlying the ISC protein–mediated maturation of mitochondrial Fe/S proteins and the importance for human disease.
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Download Supplemental Material, including Supplemental Figure 1, Supplemental Tables 1-3, and Supplemental References (PDF). Updated 6/17/20.
Supplemental Video 1: Model of the human dodecameric core ISC complex comprising NFS1 (yellow and orange), ISD11 (magenta and purple), ACP1 (green), ISCU2 (blue), FXN (slate grey) and FDX2 (red). The model is based on the cryo-EM structure of NFS1-ISD11-ACP1- ISCU2-FXN (pdb: 6NZU), the crystal structure of FDX2 (pdb: 2Y5C, unpublished), and NMR data revealing the interaction site for yeast Isu1 on yeast Yah1 (5, 6). Pyridoxal phosphate (PLP) of NFS1 and acyl-phosphopantetheine (PPA) of ACP1 are depicted as spheres.
Supplemental Video 2: Hypothetical movement of the conserved Cys-loop of NFS1. Morphing was done by UCSF Chimera (7) based on several loop intermediates in NFS1 or related bacterial SufS structures (loop “inside” and “outside”; Boniecki, Freibert et al., unpublished; (8, 9)). Color code is as in Supplemental video 1. The conserved Cys381 residue of human NFS1 receives a persulfide in its “inside” position when Cys381 is located close to the pyridoxal phosphate (PLP) moiety (shown as spheres) of NFS1. Subsequently, the Cysloop undergoes large conformational rearrangements, and Cys381 contacts ISCU2 at the NFS1 surface for persulfide transfer to ISCU2.
Supplemental Video 3: Binding sites for HSPA9 and HSC20 on ISCU2 are inaccessible when ISCU2 is bound to NFS1-FXN with the core ISC complex. The video was generated on the basis of the cryo-EM structure pdb: 6NZU (10). The HSPA9 binding site (131LPPVK135) is depicted in orange, and the HSC20 binding site (L63, V72, F93) is shown in green (see also Figure 5). The conserved Cys and His residues (sticks and balls) constitute the active center of ISCU2. NFS1 (yellow) and FXN (dark slate grey) are represented as surface model. The HSPA9 binding site is largely occupied by FXN, while the HSC20 binding site is almost fully covered by the C-terminus of NFS1.