The role of mitochondria and the CIA machinery in the maturation of cytosolic and nuclear iron–sulfur proteins

Lill, Roland; Dutkiewicz, Rafał; Freibert, Sven‐Andreas; Heidenreich, Torsten; Mascarenhas, Judita; Netz, Daili J. A.; Paul, Viktoria Désirée; Pierik, Antonio J.; Richter, Nadine; Stümpfig, Martin; Srinivasan, Vasundara; Stehling, Oliver; Mühlenhoff, Ulrich

doi:10.1016/j.ejcb.2015.05.002

Cited by 161 publications

(181 citation statements)

References 132 publications

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“…Iron ions are similarly needed for the de novo synthesis or repair of iron-sulfur clusters in the cytosol. Much progress has been made using genetic, proteomic, and biochemical approaches to identify components of the machinery that distributes [4Fe-4S] clusters in the cytosol (52). HEK293 cells lacking PCBP1 or PCBP2 exhibit loss of activity in cytosolic aconitase (19), an enzyme with a labile [4Fe-4S] cluster.…”

Section: Iron-sulfur Cluster Trafficking Via Glutaredoxin-bola Complexesmentioning

confidence: 99%

Cytosolic iron chaperones: Proteins delivering iron cofactors in the cytosol of mammalian cells

Philpott

Ryu

Frey

et al. 2017

Journal of Biological Chemistry

105

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Eukaryotic cells contain hundreds of metalloproteins that are supported by intracellular systems coordinating the uptake and distribution of metal cofactors. Iron cofactors include heme, iron-sulfur clusters, and simple iron ions. Poly(rC)-binding proteins are multifunctional adaptors that serve as iron ion chaperones in the cytosolic/nuclear compartment, binding iron at import and delivering it to enzymes, for storage (ferritin) and export (ferroportin). Ferritin iron is mobilized by autophagy through the cargo receptor, nuclear co-activator 4. The monothiol glutaredoxin Glrx3 and BolA2 function as a [2Fe-2S] chaperone complex. These proteins form a core system of cytosolic iron cofactor chaperones in mammalian cells.High-throughput approaches to elucidating the roles of metals in biology are in their infancy, yet they have yielded some surprising results (1, 2). Based on the findings from three species of prokaryotes (3), metalloproteins make up one-third of the cellular proteome. Of these, only half have been previously identified as metalloproteins. Iron and zinc are the most abundant metals in eukaryotic cells, and new iron-containing proteins continue to be identified in mammalian cells (4 -6).Because of the extent and complexity of the metalloproteome, cells require a distribution system for metal cofactors. Iron cofactors in the form of simple ionic iron, iron-sulfur clusters, and heme need to be taken up, assembled, and synthesized, respectively, before delivery to their recipient apoproteins, which localize to nearly every compartment of the cell. Mitochondria are the ultimate sites of heme synthesis and the initial sites of iron-sulfur cluster assembly. Nevertheless, heme, ironsulfur clusters, and iron ions are required cofactors in the cytosol and nucleus as well. This review will focus on recent studies examining the trafficking of cytosolic iron cofactors and the function of cytosolic chaperone proteins in mammalian cells. Poly r(C)-binding proteins are iron chaperones for iron transportersThe term metallochaperone is used to describe a metal-binding protein that mediates the transfer of the bound metal to a recipient apoprotein via a metal-mediated protein-protein interaction (7). Metallochaperones with specificity for iron, copper, and possibly zinc have been identified in eukaryotes (8 -11). Poly r(C)-binding proteins (PCBPs) 2 are a family of four multifunctional adaptor proteins that bind iron, singlestranded nucleic acids, and proteins, altering the fates of each of these ligands (12-16). PCBP1 and PCBP2 were initially identified as RNA-binding proteins called HN-RNP E1 and E2 or ␣CP-1 and -2. In their RNA-binding capacity, they affect the splicing, polyadenylation, processing, translation, and stability of many RNA species with cells. PCBP1 was later identified as an iron chaperone for ferritin (11), the major iron storage protein found in most eukaryotes (17). PCBP1 and PCBP2 can bind ferrous iron in vitro in a 3:1 Fe/PCBP stoichiometric ratio with low micromolar affinity, similar to the ...

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Section: Iron-sulfur Cluster Trafficking Via Glutaredoxin-bola Complexesmentioning

confidence: 99%

Cytosolic iron chaperones: Proteins delivering iron cofactors in the cytosol of mammalian cells

Philpott

Ryu

Frey

et al. 2017

Journal of Biological Chemistry

105

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“…Iron-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.…”

Section: Ubiquitous Iron-sulfur Clusters and Their Synthesis: An Overmentioning

confidence: 99%

“…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)(3)(4). In eukaryotes, Fe/S proteins are found in or associated with the mitochondrion, endoplasmic reticulum, cytosol, and the nucleus.…”

Section: Ubiquitous Iron-sulfur Clusters and Their Synthesis: An Overmentioning

confidence: 99%

“…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)(8)(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).…”

Section: Ubiquitous Iron-sulfur Clusters and Their Synthesis: An Overmentioning

confidence: 99%

“…This cellular control is exemplified by the 18 known "Fe/S cluster assembly" (ISC) proteins involved in the proper biogenesis and trafficking of clusters in mitochondria and the 11 known "cytosolic Fe/S protein assembly" (CIA) proteins responsible for synthesis, trafficking, and insertion of clusters in the cytosol and nucleus (Figs. 1 and 2) (2,16). Mitochondria or the evolutionarily derived hydrogenosomes and mitosomes appear to be essential for biogenesis of all cellular Fe/S proteins (7,17,18).…”

Section: Ubiquitous Iron-sulfur Clusters and Their Synthesis: An Overmentioning

confidence: 99%

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Iron–sulfur cluster biogenesis and trafficking in mitochondria

Braymer

Lill

2017

Journal of Biological Chemistry

Self Cite

320

293

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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...

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Cytosolic iron–sulfur cluster transfer—a proposed kinetic pathway for reconstitution of glutaredoxin 3

2016

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Iron-sulfur clusters are ubiquitously conserved and play essential cellular roles. The mechanism of Fe-S cluster biogenesis involves multiple proteins in a complex pathway. Cluster biosynthesis primarily occurs in the mitochondria, but key Fe-S proteins also exist in the cytosol. One such protein, glutaredoxin 3 (Grx3), is involved in iron regulation, sensing and mediating [2Fe-2S] cluster delivery to cytosolic protein targets, but the cluster donor for cytosolic Grx3 has not been elucidated. Herein, we delineate the kinetic transfer of [2Fe-2S] clusters into Grx3 from potential cytosolic carrier/scaffold proteins, IscU and Nfu, to evaluate a possible model for Grx3 reconstitution in vivo.

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The role of mitochondria and the CIA machinery in the maturation of cytosolic and nuclear iron–sulfur proteins

Cited by 161 publications

References 132 publications

Cytosolic iron chaperones: Proteins delivering iron cofactors in the cytosol of mammalian cells

Cytosolic iron chaperones: Proteins delivering iron cofactors in the cytosol of mammalian cells

Iron–sulfur cluster biogenesis and trafficking in mitochondria

Cytosolic iron–sulfur cluster transfer—a proposed kinetic pathway for reconstitution of glutaredoxin 3

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