Compartmentalization of iron between mitochondria and the cytosol and its regulation

Mühlenhoff, Ulrich; Hoffmann, Bastian; Richter, Nadine; Rietzschel, Nicole; Spantgar, Farah; Stehling, Oliver; Uzarska, Marta A.; Lill, Roland

doi:10.1016/j.ejcb.2015.05.003

Cited by 81 publications

(66 citation statements)

References 234 publications

(341 reference statements)

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“…Iron is an essential nutrient that acts as a cofactor for many enzymes and transport proteins and participates in a wide variety of physiological processes including respiration, DNA metabolism, lipid biosynthesis, oxygen transport and others (48,49). Eukaryotes have developed complex systems for iron uptake, utilization and storage (48)(49)(50).…”

Section: Discussionmentioning

confidence: 99%

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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: 99%

“…Eukaryotes have developed complex systems for iron uptake, utilization and storage (48)(49)(50). 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).…”

Section: Discussionmentioning

confidence: 99%

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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“…Mitochondria contain respiratory complexes which comprise many ironcontaining cofactors. Not surprisingly, mitochondrial iron homeostasis is a tightly regulated process which affects overall cellular iron homeostasis (5). The importance of the metazoan mitoferrins was first demonstrated by analysis of the anemic zebrafish mutant frascati, leading to the discovery that Mfrn1 and -2 play essential roles in providing iron for heme and Fe-S cluster biosyntheses in animal mitochondria (6).…”

mentioning

confidence: 99%

In vitro reconstitution, functional dissection, and mutational analysis of metal ion transport by mitoferrin-1

Christenson

Gallegos

Banerjee

2018

Journal of Biological Chemistry

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Mitoferrin-1 is a promiscuous transition metal transporterThe reactivity of iron is exploited across all kingdoms of life. The physiological roles that iron takes on are many-iron readily participates in redox reactions where it can donate or accept electrons, depending on its oxidation state. Iron plays essential roles in gas transport and sensing and can also act as a non-redox active metal ion cofactor in enzymes. Additionally, iron-containing cofactors can impart stability to folded proteins (1). Iron naturally occurs in the 2+ and the 3+ oxidation states but owing to the insolubility of Fe(III), the bioavailable form of iron is almost exclusively the 2+ form. The main route of cellular iron uptake is via the transferrin receptor pathway whereby transferrin-bound iron is targeted to endosomes and subsequently released from transferrin during endosomal acidification. Fe(II) is transported out of endosomes by divalent metal ion transporter (DMT1) and becomes available for incorporation into iron-containing proteins and cofactors (2).In eukaryotes, mitochondria are the hotspots for iron utilization-these organelles house heme assembly and the majority of Fe-S cluster biosynthesis apparatus (3,4). Mitochondria contain respiratory complexes which comprise many ironcontaining cofactors. Not surprisingly, http://www.jbc.org/cgi

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“…Transport into the mitochondrial inner compartment is mediated by mitoferrin-1, which is found abundantly in erythroid cells, and mitoferrin-2, which is expressed ubiquitously. 9 Several lines of evidence suggest that there is a tight link between mitochondrial and cytosolic iron levels and that mitochondrial demand may regulate cytosolic iron metabolism, at least in part. 10 Excess iron in the cytosol is diverted towards the cytosolic iron storage protein ferritin.…”

Section: Normal Iron Metabolismmentioning

confidence: 99%

Iron and inflammation – the gut reaction

Verma

Cherayil

2017

Metallomics

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Anemia is a frequent complication of many inflammatory disorders, including inflammatory bowel disease. Although the pathogenesis of this problem is multifactorial, a key component is the abnormal elevation of the hormone hepcidin, the central regulator of systemic iron homeostasis. Investigations over the last decade have resulted in important insights into the role of hepcidin in iron metabolism and the mechanisms that lead to hepcidin dysregulation in the context of inflammation. These insights provide the foundation for novel strategies to prevent and treat the anemia associated with inflammatory diseases.

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Compartmentalization of iron between mitochondria and the cytosol and its regulation

Cited by 81 publications

References 234 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

In vitro reconstitution, functional dissection, and mutational analysis of metal ion transport by mitoferrin-1

Iron and inflammation – the gut reaction

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