The role of mitochondria in cytosolic-nuclear iron–sulfur protein biogenesis and in cellular iron regulation

Lill, Roland; Srinivasan, Vasundara; Mühlenhoff, Ulrich

doi:10.1016/j.mib.2014.09.015

Cited by 115 publications

(105 citation statements)

References 74 publications

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“…Disruption of these systems can result in either iron shortage or overload, with mitochondrial defects often playing a major role in the iron homeostasis disturbances (49). For example, defects in the mitochondrial ISC biosynthesis pathways can increase iron uptake, resulting in excessive amounts of iron in the cytoplasm (51). In this study, we found that deletion of the yeast mitochondrial monothiol glutaredoxin gene GRX5 involved in ISC biogenesis (22)(23)(24)(25)(26)(27) made ribosomes highly susceptible to ROS-induced damage.…”

Section: Discussionmentioning

confidence: 71%

Iron-dependent cleavage of ribosomal RNA during oxidative stress in the yeast Saccharomyces cerevisiae

Zinskie

Ghosh

Trainor

et al. 2018

Journal of Biological Chemistry

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Stress-induced strand breaks in rRNA have been observed in many organisms, but the mechanisms by which they originate are not well understood. Here, we show that a chemical rather than enzymatic mechanism initiates rRNA cleavages during oxidative stress in yeast (Saccharomyces cerevisiae). We used cells lacking the mitochondrial glutaredoxin Grx5 to demonstrate that oxidant-induced cleavage formation in 25S rRNA correlates with intracellular iron levels. Sequestering free iron by a chemical or genetic means decreased the extent of rRNA degradation and relieved the hypersensitivity of grx5 cells to the oxidants. Importantly, subjecting purified ribosomes to an in vitro iron/ascorbate reaction precisely recapitulated the 25S rRNA cleavage pattern observed in cells, indicating that redox activity of the ribosome-bound iron is responsible for the strand breaks in the rRNA. In summary, our findings provide evidence that oxidative stress-associated rRNA cleavages can occur through rRNA strand scission by redox-active, ribosomebound iron that potentially promotes Fenton reaction-induced hydroxyl radical production, implicating intracellular iron as a key determinant of the effects of oxidative stress on ribosomes. We propose that iron binding to specific ribosome elements primes rRNA for cleavages that may play a role in redox-sensitive tuning of the ribosome function in stressed cells.

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Section: Discussionmentioning

confidence: 71%

Iron-dependent cleavage of ribosomal RNA during oxidative stress in the yeast Saccharomyces cerevisiae

Zinskie

Ghosh

Trainor

et al. 2018

Journal of Biological Chemistry

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“…HSC20 is an essential Fe-S biogenesis factor and it has also been found in the cytosol of mammalian cells (50,53). These findings differed from studies of the yeast model system, Saccharomyces cerevisiae, in which it was asserted that de novo Fe-S cluster biogenesis occurred exclusively in the mitochondrial matrix, whereas the cytoplasmic Fe-S assembly machinery depended on the export of a sulfur-containing compound (X-S), perhaps through the ABC transporter Atm1, for incorporation into cytosolic and nuclear Fe-S proteins (62). Studies in Arabidopsis thaliana led to the identification of a physiological substrate of the ABC transporter ATM3, which is the functional ortholog of yeast Atm1 and mammalian ABCB7.…”

Section: How Iron-sulfur Clusters Are Synthesized and Trafficked In Mmentioning

confidence: 71%

Biogenesis and functions of mammalian iron-sulfur proteins in the regulation of iron homeostasis and pivotal metabolic pathways

Rouault

Maio

2017

Journal of Biological Chemistry

129

109

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Fe-S cofactors are composed of iron and inorganic sulfur in various stoichiometries. A complex assembly pathway conducts their initial synthesis and subsequent binding to recipient proteins. In this minireview, we discuss how discovery of the role of the mammalian cytosolic aconitase, known as iron regulatory protein 1 (IRP1), led to the characterization of the function of its Fe-S cluster in sensing and regulating cellular iron homeostasis. Moreover, we present an overview of recent studies that have provided insights into the mechanism of Fe-S cluster transfer to recipient Fe-S proteins. Discovery of a regulatory role for an iron-sulfur cluster in iron regulatory protein 1Interest in understanding how mammalian cells regulated iron uptake and distribution in the 1980s led to the discovery of a post-transcriptional regulatory mechanism, which was found to be crucial for cellular and systemic iron homeostasis in vertebrates. It was known that the expression of a major iron storage protein, ferritin (Ft), 2 was primarily regulated at the translational rather than transcriptional level (1, 2). However, it was not possible to dissect how ferritin levels were controlled under different conditions of iron availability until the genes encoding H and L ferritin were cloned in 1984 (2). At that time, gel-shift assays were commonly used to demonstrate direct binding of specific transcription factors to DNA sequences. A similar approach revealed that one or more cytosolic proteins were bound to the 5Ј-untranslated (5Ј-UTR) region of ferritin transcripts in mammalian cells (3-5). Moreover, it appeared that the binding factors reflected the iron status of the cell, as ferritin translation and gel-shift binding activity were reduced in cells that were iron-deficient, while conversely increasing in cells that were iron-loaded. The region of the ferritin transcripts responsible for mediating translational regulation was identified and subsequently named the IRE, for iron-responsive element. The IRE was defined through mutagenesis and sequence homology as a short stem-loop structure located near the 5Ј-end of the ferritin transcript. Intensive efforts to identify cytosolic factors that bound to the IRE resulted in cloning of two major cytosolic regulatory proteins, iron regulatory proteins 1 and 2 (IRP1 and IRP2) (5). It was immediately apparent, upon inspection of its primary amino acid sequence, that IRP1 was remarkably similar to mitochondrial aconitase, which was a well-characterized Fe-S protein. A cubane [Fe 4 -S 4 ] cluster in the IRP1 active-site cleft was known to be critical for the reversible aconitase-mediated conversion of citrate to isocitrate (6), which is essential for cholesterol and fatty acid metabolism, as citrate is the substrate of ATP-citrate lyase, which generates acetyl-coenzyme A utilized for cholesterol and lipid biosynthesis. Additionally, citrate has important regulatory roles in glycolysis and fatty acid synthesis and oxidation (7). Isocitrate is also metabolized by the cytosolic NADP-dependent iso...

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“…Moreover, mitochondria harbor the mitochondrial ISC (iron-sulfur cluster assembly) and ISC export systems that are essential for the maturation of all cellular proteins with iron-sulfur (Fe/S) co-factors, whether located in mitochondria, the cytosol or the nucleus (Lill et al, 2014b;Pain and Dancis, 2014;Rouault, 2012). The maturation of extra-mitochondrial proteins requires the export of a small solute that is produced by the mitochondrial ISC system and exported via the mitochondrial ABC transporter Atm1 into the cytosol where it is used by the cytosolic Fe/S protein assembly (CIA) system for the formation of cytosolic and nuclear Fe/S proteins (Lill et al, 2014a;Netz et al, 2014;Paul and Lill, 2015;Sharma et al, 2010). Several cytosolic and nuclear Fe/S proteins play essential roles in protein translation (e.g., the ABC protein Rli1) (Hopfner, 2012), DNA synthesis and repair (e.g., DNA polymerases and helicases) (Fuss et al, 2015;White, 2009), and other aspects of genome stability (Gari et al, 2012;Lill et al, 2014b;Stehling et al, 2012;Wu and Brosh, 2012).…”

Section: Page 4 Of 44mentioning

confidence: 99%

“…1). Cells with defective mitochondrial ISC systems induce iron uptake systems at their plasma membrane Lill et al, 2014a). This de-regulation is widespread in (non-green) eukaryotes, despite fundamental different strategies for the regulation of iron homeostasis (Beilschmidt and Puccio, 2014;Kaplan and Kaplan, 2009;Lane et al, 2015;Outten, 2014).…”

Section: Page 4 Of 44mentioning

confidence: 99%

Compartmentalization of iron between mitochondria and the cytosol and its regulation

Mühlenhoff

Hoffmann

Richter

et al. 2015

European Journal of Cell Biology

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The role of mitochondria in cytosolic-nuclear iron–sulfur protein biogenesis and in cellular iron regulation

Cited by 115 publications

References 74 publications

Iron-dependent cleavage of ribosomal RNA during oxidative stress in the yeast Saccharomyces cerevisiae

Iron-dependent cleavage of ribosomal RNA during oxidative stress in the yeast Saccharomyces cerevisiae

Biogenesis and functions of mammalian iron-sulfur proteins in the regulation of iron homeostasis and pivotal metabolic pathways

Compartmentalization of iron between mitochondria and the cytosol and its regulation

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