Iron–sulfur cluster biogenesis and trafficking in mitochondria

Abstract

The biogenesis of iron-sulfur (Fe/S) proteins in eukaryotes is a multistage, multicompartment process that is essential for a broad range of cellular functions, including genome maintenance, protein translation, energy conversion, and the antiviral response. Genetic and cell biological studies over almost 2 decades have revealed some 30 proteins involved in the synthesis of cellular [2Fe-2S] and [4Fe-4S] clusters and their incorporation into numerous apoproteins. Mechanistic aspects of Fe/S protein biogenesis continue to be elucidated by biochemical and ultrastructural investigations. Here, we review recent developments in the pursuit of constructing a comprehensive model of Fe/S protein assembly in the mitochondrion. Ubiquitous iron-sulfur clusters and their synthesis: an overviewIron-sulfur (Fe/S) 2 clusters are inorganic cofactors that are essential for the proper functioning of virtually all biological cells (1). The chemical versatility of these clusters is utilized in fundamental life processes such as energy production, metabolic conversions, DNA maintenance, gene expression regulation, protein translation, and the antiviral response ( Fig. 1) (2-4). In eukaryotes, Fe/S proteins are found in or associated with the mitochondrion, endoplasmic reticulum, cytosol, and the nucleus. These cofactors participate in electron transfer reactions, Lewis acid catalysis, transfer of sulfur atoms, or facilitating structural roles (5, 6). Although the activities of some Fe/S proteins are dispensable for cell survival under certain conditions, for example fungal Fe/S enzymes in the metabolism of amino acids, others such as Fe/S proteins involved in DNA maintenance or protein translation are essential for cell viability (Fig. 1). The growing number of diseases that implicate Fe/S proteins or their assembly factors illustrates the essentiality of the various functions of these protein cofactors (7-9). The phenotypes associated with these "Fe/S diseases" and the in vivo work in model systems such as Saccharomyces cerevisiae and human cell culture have led to a mechanistic model of eukaryotic Fe/S protein biogenesis, in which the sequence of events required for proper synthesis and trafficking of Fe/S clusters has been elucidated (2). This model has been invaluable to diagnosing new mitochondrial disorders, and its continued advancement will enhance the ability for early diagnosis (10 -13). The focus of this review will be on the latest developments of the functional and mechanistic aspects that have advanced the model of mitochondrial Fe/S protein biogenesis.Cells typically maintain a strict balance of iron and sulfide ion concentrations due to their damaging redox reactions when present in excess (14, 15). The cell also uses a complex biosynthetic system to ensure that the sometimes redox-sensitive and labile Fe/S clusters are assembled correctly, trafficked to specific target apoproteins, and remain protected during these processes. This cellular control is exemplified by the 18 known "Fe/S cluster assembly" (ISC) proteins...

Intracellular iron and heme trafficking and metabolism in developing erythroblasts

“…11 Once iron is taken up by the cell, iron can be targeted to the mitochondria for heme and iron-sulfur cluster biosynthesis. 12–15 Within the mitochondrion, the metabolic processes associated with iron uptake and hematopoiesis are interdependent and facilitated by a network of enzymes, including δ-aminolevulinic acid-synthase (ALAS, EC 2.3.1.37) and ferrochelatase (FECH, EC 4.99.1.1). Recently, novel mechanisms associated with iron uptake and heme metabolism have been identified, which can further our understanding of the biochemical properties of erythroid development.…”

“…12–15 Iron that is not utilized for heme or iron-sulfur cluster assembly is stored within mitochondrial ferritin (mitoferritin). 52 Both cytosolic ferritin 53 and mitoferritin 54 mediated mineralization of iron minimize the production of potentially harmful hydrogen peroxide.…”

Robust Production, Crystallization, Structure Determination, and Analysis of [Fe–S] Proteins: Uncovering Control of Electron Shuttling and Gating in the Respiratory Metabolism of Molybdopterin Guanine Dinucleotide Enzymes

“…The maturation and insertion of [Fe–S] clusters into apo-target proteins require mitochondrial ISC assembly machinery that contains scaffold protein IscU, cysteine desulfurase (Nfs1), accessory protein Isd11, activator/iron donor Frataxin, and Ferredoxin (Agar et al, 2000; Colin et al, 2013; Cory et al, 2017; Johnson et al, 2005; Lill, 2009; Pandey et al, 2013; Raulfs, O’Carroll, Santos Dos, Unciuleac, & Dean, 2008; Schmucker et al, 2011; Tsai & Barondeau, 2010; Webert et al, 2014; Yoon & Cowan, 2003; Zheng, Cash, Flint, & Dean, 1998). [Fe–S] clusters are assembled in mitochondrial and cytosolic machineries (Braymer & Lill, 2017; Bridwell-Rabb, Fox, Tsai, Winn, & Barondeau, 2014; Lill et al, 2006), and clusters are transferred to apo-target proteins aided by chaperones HscA/HscB upon maturation (Bonomi, Iametti, Morleo, Ta, & Vickery, 2011; Chandramouli & Johnson, 2006; Fox, Chakrabarti, McCormick, Lindahl, & Barondeau, 2015; Fox, Das, Chakrabarti, Lindahl, & Barondeau, 2015; Uzarska, Dutkiewicz, Freibert, Lill, & Muhlenhoff, 2013; Vranish et al, 2015). Defects in Fe–S cluster assembly and maturation lead to multiple human diseases and protein dysfunctions (Rouault, 2015; Stehling, Wilbrecht, & Lill, 2014) that encompass many processes including metabolism, DNA maintenance, Fe–S cluster assembly machineries, respiratory chain metabolism, ribosome function, and tRNA modification (Andreini, Banci, & Rosato, 2016).…”

Iron metabolism in erythroid cells and patients with congenital sideroblastic anemia

“…In eukaryotic cells, ISC is synthesized in mitochondria and cytosol, although the de novo synthesis of ISC is initiated only in mitochondria [12]. It was suggested that approximately 30 proteins are involved in the machinery [13]. In human mitochondria, proteins including ISCU, NFU, ISCA and GLRX5 provide the scaffold for assembling the ISC; the complex of ISCS and ISD11 supplies sulfur; and frataxin (FXN) might provide the iron for initial ISC formation [14].…”