Mechanisms of cellular iron sensing, regulation of erythropoiesis and mitochondrial iron utilization

Cellular iron homeostasis and mitochondrial iron homeostasis are interdependent. Mitochondria must import iron to form iron–sulfur clusters and heme, and to incorporate these cofactors along with iron ions into mitochondrial proteins that support essential functions, including cellular respiration. In turn, mitochondria supply the cell with heme and enable the biogenesis of cytosolic and nuclear proteins containing iron–sulfur clusters. Impairment in cellular or mitochondrial iron homeostasis is deleterious and can result in numerous human diseases. Due to its reactivity, iron is stored and trafficked through the body, intracellularly, and within mitochondria via carefully orchestrated processes. Here, we focus on describing the processes of and components involved in mitochondrial iron trafficking and storage, as well as mitochondrial iron–sulfur cluster biogenesis and heme biosynthesis. Recent findings and the most pressing topics for future research are highlighted.

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Rim2, a pyrimidine nucleotide exchanger, is needed for iron utilization in mitochondria

Biochemical Journal ◽

10.1042/bj20111036 ◽

2011 ◽

Vol 440 (1) ◽

pp. 137-146 ◽

Cited By ~ 31

Author(s):

Heeyong Yoon ◽

Yan Zhang ◽

Jayashree Pain ◽

Elise R. Lyver ◽

Emmanuel Lesuisse ◽

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Keyword(s):

Iron Transport ◽

Wild Type ◽

Mitochondrial Carrier ◽

Pyrimidine Nucleotide ◽

Mitochondrial Transporter ◽

Mitochondrial Iron ◽

Mitochondrial Carrier Protein ◽

Synthetically Lethal ◽

Yeast Mutants ◽

Iron Utilization

Mitochondria transport and utilize iron for the synthesis of haem and Fe–S clusters. Although many proteins are known to be involved in these processes, additional proteins are likely to participate. To test this hypothesis, in the present study we used a genetic screen looking for yeast mutants that are synthetically lethal with the mitochondrial iron carriers Mrs3 and Mrs4. Several genes were identified, including an isolate mutated for Yfh1, the yeast frataxin homologue. All such triple mutants were complemented by increased expression of Rim2, another mitochondrial carrier protein. Rim2 overexpression was able to enhance haem and Fe–S cluster synthesis in wild-type or Δmrs3/Δmrs4 backgrounds. Conversely Rim2 depletion impaired haem and Fe–S cluster synthesis in wild-type or Δmrs3/Δmrs4 backgrounds, indicating a unique requirement for this mitochondrial transporter for these processes. Rim2 was previously shown to mediate pyrimidine exchange in and out of vesicles. In the present study we found that isolated mitochondria lacking Rim2 exhibited concordant iron defects and pyrimidine transport defects, although the connection between these two functions is not explained. When organellar membranes were ruptured to bypass iron transport, haem synthesis from added iron and porphyrin was still markedly deficient in Rim2-depleted mitochondrial lysate. The results indicate that Rim2 is a pyrimidine exchanger with an additional unique function in promoting mitochondrial iron utilization.

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Evaluation of Fe(III) reduction by mitochondria induced with a respiratory substrate NADH or succinate, using a Fe(II)-specific chelator bathophenanthroline disulfonate in Saccharomyces cerevisiae

Biologia ◽

10.2478/s11756-009-0150-3 ◽

2009 ◽

Vol 64 (5) ◽

Cited By ~ 1

Author(s):

Daisuke Tsugama ◽

Shenkui Liu ◽

Tetsuo Takano

Keyword(s):

Saccharomyces Cerevisiae ◽

Respiratory Chain ◽

Iron Metabolism ◽

Inhibitory Effect ◽

Low Concentration ◽

Isolated Mitochondria ◽

Cellular Iron ◽

Respiratory Chain Activity ◽

Bathophenanthroline Disulfonate ◽

Iron Utilization

AbstractMitochondria are the centers of the cellular iron metabolism. Iron utilization by mitochondria is deeply related to their respiratory chain activity. We isolated mitochondria from Saccharomyces cerevisiae and examined Fe(III) reduction induced by a respiratory substrate (NADH or succinate), using a Fe(II)-specific chelator (bathophenanthroline disulfonate). In the presence of either 50 μM NADH or 5 mM succinate, the amount of reduced Fe(III) was linearly correlated with the amount of mitochondria. As the concentration of the substrate increased, the rate of the mitochondrial Fe(III) reduction reached a plateau. In the presence of 1 mM ADP or 1 mM ATP, the extramitochondrial Fe(III) reduction was repressed when succinate was used as the substrate, but not when NADH was used. ADP had an inhibitory effect even under low concentration of succinate, suggesting that ADP and ATP acted in a manner of both competitive and uncompetitive inhibition.

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