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Overexpression of Drosophila mitoferrin in l(2)mbn cells results in dysregulation of Fer1HCH expression
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Comparative Physiology. (Maria Lind Karlberg)
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Comparative Physiology. (Maria Lind Karlberg)
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Comparative Physiology. (Maria Lind Karlberg)
2009 (English)In: Biochemical Journal, ISSN 0264-6021, E-ISSN 1470-8728, Vol. 421, no Part 3, 463-471 p.Article in journal (Refereed) Published
Abstract [en]

Mrs3p and Mrs4p (Mrs3/4p) are yeast mitochondrial iron carrier proteins that play important roles in ISC (iron-sulphur cluster) and haem biosynthesis. At low iron conditions, mitochondrial and cytoplasmic ISC protein maturation is correlated with MRS3/4 expression. Zebrafish mitoferrin1 (mfrn1), one of two MRS3/4 orthologues, is essential for erythropoiesis, but little is known about the ubiquitously expressed paralogue mfrn2. In the present study we identified a single mitoferrin gene (dmfrn) in the genome of Drosophila melanogaster, which is probably an orthologue of mfrn2. Overexpression of dmfrn in the Drosophila l(2)mbn cell line (mbn-dmfrn) resulted in decreased binding between IRP-1A (iron regulatory protein 1A) and stem-loop RNA structures referred to as IREs (iron responsive elements). mbn-dmfrn cell lines also had increased cytoplasmic aconitase activity and slightly decreased iron content. In contrast, iron loading results in decreased IRP-1A-IRE binding, but increased cellular iron content, in experimental mbn-dmfrn and control cell lines. Iron loading also increases cytoplasmic aconitase activity in all cell lines, but with slightly higher activity observed in mbn-dmfrn cells. From this we concluded that dmfrn overexpression stimulates cytoplasmic ISC protein maturation, as has been reported for MRS3/4 overexpression. Compared with control cell lines, mbn-dmfrn cells had higher Fer1HCH (ferritin 1 heavy chain homologue) transcript and protein levels. RNA interference of the putative Drosophila orthologue of human ABCB7, a mitochondrial transporter involved in cytoplasmic ISC protein maturation, restored Fer1HCH transcript levels of iron-treated mbn-dmfrn cells to those of control cells grown in normal medium. These results suggest that dmfrn overexpression in l(2)mbn cells causes an 'overestimation' of the cellular iron content, and that regulation of Fer1HCH transcript abundance probably depends on cytoplasmic ISC protein maturation.

Place, publisher, year, edition, pages
2009. Vol. 421, no Part 3, 463-471 p.
Keyword [en]
Drosophila, iron homoeostasis, iron transport, mitochondrial iron metabolism
National Category
Biological Sciences
Research subject
Biology with specialization in Comparative Physiology
Identifiers
URN: urn:nbn:se:uu:diva-114111DOI: 10.1042/BJ20082231ISI: 000268615900014PubMedID: 19453295OAI: oai:DiVA.org:uu-114111DiVA: diva2:292959
Available from: 2010-02-10 Created: 2010-02-10 Last updated: 2017-12-12Bibliographically approved
In thesis
1. Mitochondrial Iron Metabolism: Study of mitoferrin in Drosophila melanogaster
Open this publication in new window or tab >>Mitochondrial Iron Metabolism: Study of mitoferrin in Drosophila melanogaster
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Iron has a dualistic character. On the one hand it is essential for the life of most organisms, on the other hand it is involved in the generation of reactive oxygen species that are implicated in diseases and aging. During evolution efficient mechanisms for uptake, handling and storage of iron in a safe way have developed to keep the balance between iron availability and minimizing the hazards. In eukaryotes, mitochondria are the central organelle for “metabolizing” iron and consequently play an important role in cellular iron homeostasis.

Mitoferrins are mitochondrial carrier proteins, which are involved in iron transport into mitochondria. In vertebrates two mitoferrins exist, one (mitoferrin1) of which is essential for heme synthesis during erythropoiesis, while the function of the other (mitoferrin2) is not well defined. In the fruit fly we found only one mitoferrin gene (dmfrn), which codes most likely for a functional homologueof vertebrate mitoferrin2.

In Drosophila cell culture, dmfrn overexpression resulted in an overestimation of cell sensed iron levels. The signal responsible for this, is most likely a yet unidentified compound of ISC synthesis. In the cell culture system we also showed that iron chelation blocks the progression of the cell cycle in a reversible and therefore most likely controlled way.

Study of different dmfrn mutants indicates a role of dmfrn during spermatogenesis and development to adulthood. As dmfrn deletion mutants are not lethal, it is likely that other lower affinity iron transporters exist. A similar conclusion has been drawn by others from the study of yeast mitoferrin homologuemutants. Rim2p/Mrs12p has recently been implicated in mitochondrial iron transport, and might be an alternative metal carrier. We identified a putative homologuein the fruit fly and found a possible link between mutants in this gene and iron.

Our results emphasize the importance of the mitochondrial iron metabolism in cellular iron homeostasis. We also show for the first time, a direct connection between the mitochondrial iron metabolism and spermatogenesis. Mutants characterized and developed by us will help to study these processes in further detail and reveal the underlying mechanisms.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2010. 55 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 713
Keyword
iron, Drosophila, mitochondria, mitoferrin, ferritin, spermatogenesis, cell cycle, DFO, MRS12
National Category
Biochemistry and Molecular Biology
Research subject
Biology with specialization in Comparative Physiology
Identifiers
urn:nbn:se:uu:diva-114201 (URN)978-91-554-7722-6 (ISBN)
Public defence
2010-03-25, Lindahlsalen, Evolutionary Biology Centre, Norbyvägen 18A, Uppsala, 10:00 (English)
Opponent
Supervisors
Available from: 2010-03-03 Created: 2010-02-11 Last updated: 2010-03-03Bibliographically approved

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