The mitochondrial Hsp70 chaperone Ssq1 facilitates Fe/S cluster transfer from Isu1 to Grx5 by complex formation

Uzarska, Marta A.; Dutkiewicz, Rafał; Freibert, Sven‐Andreas; Lill, Roland; Mühlenhoff, Ulrich

doi:10.1091/mbc.e12-09-0644

Cited by 117 publications

(135 citation statements)

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“…Grx5 possibly serves as an Fe/S cluster transfer protein by transiently coordinating the Isu1-derived [2Fe-2S] cluster between two protein subunits and two protein-bound glutathione molecules (Bandyopadhyay et al 2008b;Shakamuri et al 2012). Recently, Grx5 was shown to specifically associate with Ssq1 at a site different from the chaperone peptide-binding pocket (Uzarska et al 2013). The simultaneous binding of holo-Isu1 and apo-Grx5 to Ssq1 potentially increases the efficiency of Fe/S cluster transfer.…”

Section: Biogenesis Of Mitochondrial Fe/s Proteins By the Isc Assemblmentioning

confidence: 99%

The Role of Mitochondria in Cellular Iron-Sulfur Protein Biogenesis: Mechanisms, Connected Processes, and Diseases

Stehling

Lill

2013

Cold Spring Harbor Perspectives in Biology

183

151

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Section: Biogenesis Of Mitochondrial Fe/s Proteins By the Isc Assemblmentioning

confidence: 99%

The Role of Mitochondria in Cellular Iron-Sulfur Protein Biogenesis: Mechanisms, Connected Processes, and Diseases

Stehling

Lill

2013

Cold Spring Harbor Perspectives in Biology

183

151

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“…Cluster dislocation from Isu1 and Isu2 is executed by the chaperone system comprising Ssq1, Jac1 and Mge1 and the monothiol glutaredoxin Grx5. Ssq1 acts together with Grx5 by transferring the [2Fe-2S] and [4Fe-4S] clusters to target apoproteins (Uzarska et al, 2013). Lack of Grx5 in yeast cells causes mitochondrial iron accumulation, inability to grow in nonfermentable or minimal medium and hypersensitivity to oxidants (Rodríguez-Manzaneque et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Impaired mitochondrial Fe-S cluster biogenesis activates the DNA damage response through different signaling mediators

Pijuan

Carlos

Herrero

et al. 2015

Journal of Cell Science

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Fe-S cluster biogenesis machinery is required for multiple DNA metabolism processes. In this work, we show that, in Saccharomyces cerevisiae, defects at different stages of the mitochondrial Fe-S cluster assembly machinery (ISC) result in increased spontaneous mutation rate and hyper-recombination, accompanied by an increment in Rad52-associated DNA repair foci and a higher phosphorylated state of γH2A histone, altogether supporting the presence of constitutive DNA lesions. Furthermore, ISC assembly machinery deficiency elicits a DNA damage response that upregulates ribonucleotide reductase activity by promoting the reduction of Sml1 levels and the cytosolic redistribution of Rnr2 and Rnr4 enzyme subunits. Depending on the impaired stage of the ISC machinery, different signaling pathway mediators contribute to such a response, converging on Dun1. Thus, cells lacking the glutaredoxin Grx5, which are compromised at the core ISC system, show Mec1-and Rad53-independent Dun1 activation, whereas both Mec1 and Chk1 are required when the non-core ISC member Iba57 is absent. Grx5-null cells exhibit a strong dependence on the error-free postreplication repair and the homologous recombination pathways, demonstrating that a DNA damage response needs to be activated upon ISC impairment to preserve cell viability.

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“…In S. cerevisiae, the inability to immunoprecipitate Grx5 with a radiolabeled 55 Fe/S cluster suggests this moiety to be bound in a labile fashion, a property that would be beneficial for trafficking the cluster to further downstream targets. Cluster binding was, however, detectable by 55 Fe radiolabeling, when Schizosaccharomyces pombe or human Grx5 homologues were expressed ectopically in yeast indicating that these foreign proteins bind the cluster more stably (70). Surprisingly, deletion of S. cerevisiae GRX5 is not lethal, suggesting that the protein's function can be bypassed to some extent, despite its currently accepted central role in Fe/S cluster trafficking in mitochondria (Fig.…”

Section: Chaperone-facilitated [2fe-2s] Cluster Release From Isu1 Andmentioning

confidence: 97%

“…2) (67-69). Grx5 is the only known [2Fe-2S] cluster-binding protein able to directly receive clusters from Isu1 by physically interacting with Ssq1 at a nonsubstrate-binding site (70). Notably, the suggested role of the chaperone system in [2Fe-2S] cluster trafficking has been reconstituted in vitro only in the bacterial ISC system, where the chaperones HscA and HscB stimulated up to 700-fold the [2Fe-2S] cluster transfer from the IscU scaffold to bacterial GrxD (27).…”

Section: Chaperone-facilitated [2fe-2s] Cluster Release From Isu1 Andmentioning

confidence: 99%

“…In turn, that reaction is believed to labilize the [2Fe-2S] cluster on Isu1 providing a facile relay to Grx5. Once the cluster release step is complete, the nucleotide exchange factor Mge1 can recycle Ssq1 by assisting ADP dissociation and allowing the rebinding of ATP (70). These concerted, regulated steps of the chaperone cycle could prevent unwanted [2Fe-2S] cluster release to the solvent, small molecules, or adventitious metal-binding sites.…”

Section: Chaperone-facilitated [2fe-2s] Cluster Release From Isu1 Andmentioning

confidence: 99%

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Iron–sulfur cluster biogenesis and trafficking in mitochondria

Braymer

Lill

2017

Journal of Biological Chemistry

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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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The mitochondrial Hsp70 chaperone Ssq1 facilitates Fe/S cluster transfer from Isu1 to Grx5 by complex formation

Cited by 117 publications

References 84 publications

The Role of Mitochondria in Cellular Iron-Sulfur Protein Biogenesis: Mechanisms, Connected Processes, and Diseases

The Role of Mitochondria in Cellular Iron-Sulfur Protein Biogenesis: Mechanisms, Connected Processes, and Diseases

Impaired mitochondrial Fe-S cluster biogenesis activates the DNA damage response through different signaling mediators

Iron–sulfur cluster biogenesis and trafficking in mitochondria

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