Mitochondrial Iron Overload: Causes and Consequences

Overview

Journal Curr Opin Genet Dev

Publisher Elsevier

Specialties Biology
Genetics

Date 2016 Mar 31

PMID 27026139

Citations 41

Authors

Tracey A Rouault

Affiliations

Soon will be listed here.

Abstract

Pathological overload of iron in the mitochondrial matrix has been observed in numerous diseases, including sideroblastic anemias, which have many causes, and in genetic diseases that affect iron-sulfur cluster biogenesis, heme synthesis, and mitochondrial protein translation and its products. Although high expression of the mitochondrial iron importer, mitoferrin, appears to be an underlying common feature, it is unclear what drives high mitoferrin expression and what other proteins are involved in trapping excess toxic iron in the mitochondrial matrix. Numerous examples of human diseases and model systems suggest that mitochondrial iron homeostasis is coordinated through transcriptional remodeling. A cytosolic/nuclear molecule may affect a transcriptional factor to coordinate the events that lead to iron accumulation, but no candidates for this role have yet been identified.

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References

Kispal G, Csere P, Guiard B, Lill R . The ABC transporter Atm1p is required for mitochondrial iron homeostasis. FEBS Lett. 1998; 418(3):346-50. DOI: 10.1016/s0014-5793(97)01414-2. View

Crooks D, Ghosh M, Haller R, Tong W, Rouault T . Posttranslational stability of the heme biosynthetic enzyme ferrochelatase is dependent on iron availability and intact iron-sulfur cluster assembly machinery. Blood. 2009; 115(4):860-9. PMC: 2815515. DOI: 10.1182/blood-2009-09-243105. View

Brown A, Amunts A, Bai X, Sugimoto Y, Edwards P, Murshudov G . Structure of the large ribosomal subunit from human mitochondria. Science. 2014; 346(6210):718-722. PMC: 4246062. DOI: 10.1126/science.1258026. View

Shi Y, Ghosh M, Kovtunovych G, Crooks D, Rouault T . Both human ferredoxins 1 and 2 and ferredoxin reductase are important for iron-sulfur cluster biogenesis. Biochim Biophys Acta. 2011; 1823(2):484-92. PMC: 3546607. DOI: 10.1016/j.bbamcr.2011.11.002. View

Lane D, Merlot A, Huang M, Bae D, Jansson P, Sahni S . Cellular iron uptake, trafficking and metabolism: Key molecules and mechanisms and their roles in disease. Biochim Biophys Acta. 2015; 1853(5):1130-44. DOI: 10.1016/j.bbamcr.2015.01.021. View

Vinothkumar K, Zhu J, Hirst J . Architecture of mammalian respiratory complex I. Nature. 2014; 515(7525):80-84. PMC: 4224586. DOI: 10.1038/nature13686. View

Korolnek T, Hamza I . Like iron in the blood of the people: the requirement for heme trafficking in iron metabolism. Front Pharmacol. 2014; 5:126. PMC: 4045156. DOI: 10.3389/fphar.2014.00126. View

Malcovati L, Cazzola M . Refractory anemia with ring sideroblasts. Best Pract Res Clin Haematol. 2014; 26(4):377-85. DOI: 10.1016/j.beha.2013.09.005. View

Ghosh M, Zhang D, Rouault T . Iron misregulation and neurodegenerative disease in mouse models that lack iron regulatory proteins. Neurobiol Dis. 2015; 81:66-75. PMC: 4567523. DOI: 10.1016/j.nbd.2015.02.026. View

10.

Rouault T, Tong W . Iron-sulfur cluster biogenesis and human disease. Trends Genet. 2008; 24(8):398-407. PMC: 2574672. DOI: 10.1016/j.tig.2008.05.008. View

11.

Pandey A, Golla R, Yoon H, Dancis A, Pain D . Persulfide formation on mitochondrial cysteine desulfurase: enzyme activation by a eukaryote-specific interacting protein and Fe-S cluster synthesis. Biochem J. 2012; 448(2):171-87. DOI: 10.1042/BJ20120951. View

12.

Invernizzi R, Travaglino E, Della Porta M, Galli A, Malcovati L, Rosti V . Effects of mitochondrial ferritin overexpression in normal and sideroblastic erythroid progenitors. Br J Haematol. 2013; 161(5):726-737. DOI: 10.1111/bjh.12316. View

13.

Sheftel A, Stehling O, Pierik A, Elsasser H, Muhlenhoff U, Webert H . Humans possess two mitochondrial ferredoxins, Fdx1 and Fdx2, with distinct roles in steroidogenesis, heme, and Fe/S cluster biosynthesis. Proc Natl Acad Sci U S A. 2010; 107(26):11775-80. PMC: 2900682. DOI: 10.1073/pnas.1004250107. View

14.

Srinivasan V, Pierik A, Lill R . Crystal structures of nucleotide-free and glutathione-bound mitochondrial ABC transporter Atm1. Science. 2014; 343(6175):1137-40. DOI: 10.1126/science.1246729. View

15.

Crooks D, Natarajan T, Jeong S, Chen C, Park S, Huang H . Elevated FGF21 secretion, PGC-1α and ketogenic enzyme expression are hallmarks of iron-sulfur cluster depletion in human skeletal muscle. Hum Mol Genet. 2013; 23(1):24-39. PMC: 3857942. DOI: 10.1093/hmg/ddt393. View

16.

Lill R, Srinivasan V, Muhlenhoff U . The role of mitochondria in cytosolic-nuclear iron–sulfur protein biogenesis and in cellular iron regulation. Curr Opin Microbiol. 2014; 22:111-9. DOI: 10.1016/j.mib.2014.09.015. View

17.

Marinoni E, de Oliveira J, Nicolet Y, Raulfs E, Amara P, Dean D . (IscS-IscU)2 complex structures provide insights into Fe2S2 biogenesis and transfer. Angew Chem Int Ed Engl. 2012; 51(22):5439-42. DOI: 10.1002/anie.201201708. View

18.

Navarro J, Botella J, Metzendorf C, Lind M, Schneuwly S . Mitoferrin modulates iron toxicity in a Drosophila model of Friedreich's ataxia. Free Radic Biol Med. 2015; 85:71-82. DOI: 10.1016/j.freeradbiomed.2015.03.014. View

19.

Wofford J, Lindahl P . Mitochondrial Iron-Sulfur Cluster Activity and Cytosolic Iron Regulate Iron Traffic in Saccharomyces cerevisiae. J Biol Chem. 2015; 290(45):26968-26977. PMC: 4646409. DOI: 10.1074/jbc.M115.676668. View

20.

Puccio H, Simon D, Cossee M, Tiziano F, Melki J, Hindelang C . Mouse models for Friedreich ataxia exhibit cardiomyopathy, sensory nerve defect and Fe-S enzyme deficiency followed by intramitochondrial iron deposits. Nat Genet. 2001; 27(2):181-6. DOI: 10.1038/84818. View