Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Function and biogenesis of iron–sulphur proteins


Iron–sulphur (Fe–S) clusters have long been recognized as essential and versatile cofactors of proteins involved in catalysis, electron transport and sensing of ambient conditions. Despite the relative simplicity of Fe–S clusters in terms of structure and composition, their synthesis and assembly into apoproteins is a highly complex and coordinated process in living cells. Different biogenesis machineries in both bacteria and eukaryotes have been discovered that assist Fe–S-protein maturation according to uniform biosynthetic principles. The importance of Fe–S proteins for life is documented by an increasing number of diseases linked to these components and their biogenesis.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: A model for Fe–S-protein biogenesis in bacteria: the ISC and SUF machineries.
Figure 2: A model for Fe–S-protein assembly in mitochondria.
Figure 3: The roles of mitochondria and the CIA machinery in Fe–S-protein biogenesis in the cytosol and nucleus of eukaryotes.


  1. 1

    Beinert, H., Holm, R. H. & Münck, E. Iron-sulfur clusters: nature's modular, multipurpose structures. Science 277, 653–659 (1997).

    CAS  PubMed  Google Scholar 

  2. 2

    Meyer, J. Iron-sulfur protein folds, iron-sulfur chemistry, and evolution. J. Biol. Inorg. Chem. 13, 157–170 (2008).

    CAS  PubMed  Google Scholar 

  3. 3

    Malkin, R. & Rabinowitz, J. C. The reconstitution of clostridial ferredoxin. Biochem. Biophys. Res. Commun. 23, 822–827 (1966).

    CAS  PubMed  Google Scholar 

  4. 4

    Johnson, D. C., Dean, D. R., Smith, A. D. & Johnson, M. K. Structure, function and formation of biological iron-sulfur clusters. Annu. Rev. Biochem. 74, 247–281 (2005).

    CAS  Google Scholar 

  5. 5

    Balk, J. & Lobreaux, S. Biogenesis of iron-sulfur proteins in plants. Trends Plant Sci. 10, 324–331 (2005).

    CAS  Google Scholar 

  6. 6

    Lill, R. & Mühlenhoff, U. Iron-sulfur protein biogenesis in eukaryotes: components and mechanisms. Annu. Rev. Cell Dev. Biol. 22, 457–486 (2006).

    CAS  Google Scholar 

  7. 7

    Vickery, L. E. & Cupp-Vickery, J. R. Molecular chaperones HscA/Ssq1 and HscB/Jac1 and their roles in iron-sulfur protein maturation. Crit. Rev. Biochem. Mol. Biol. 42, 95–111 (2007).

    CAS  PubMed  Google Scholar 

  8. 8

    Lill, R. & Mühlenhoff, U. Maturation of iron-sulfur proteins in eukaryotes: mechanisms, connected processes, and diseases. Annu. Rev. Biochem. 77, 669–700 (2008).

    CAS  PubMed  Google Scholar 

  9. 9

    Ayala-Castro, C., Saini, A. & Outten, F. W. Fe-S cluster assembly pathways in bacteria. Microbiol. Mol. Biol. Rev. 72, 110–125 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. 10

    Rouault, T. A. & Tong, W. H. Iron-sulfur cluster biogenesis and human disease. Trends Genet. 24, 398–407 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. 11

    Xu, X. M. & Moller, S. G. Iron-sulfur cluster biogenesis systems and their crosstalk. ChemBioChem 9, 2355–2362 (2008).

    CAS  PubMed  Google Scholar 

  12. 12

    Fontecave, M. & Ollagnier-de-Choudens, S. Iron-sulfur cluster biosynthesis in bacteria: mechanisms of cluster assembly and transfer. Arch. Biochem. Biophys. 474, 226–237 (2008).

    CAS  PubMed  Google Scholar 

  13. 13

    Bandyopadhyay, S., Chandramouli, K. & Johnson, M. K. Iron-sulfur cluster biosynthesis. Biochem. Soc. Trans. 36, 1112–1119 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. 14

    Booker, S. J., Cicchillo, R. M. & Grove, T. L. Self-sacrifice in radical S-adenosylmethionine proteins. Curr. Opin. Chem. Biol. 11, 543–552 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. 15

    Rudolf, J., Makrantoni, V., Ingledew, W. J., Stark, M. J. & White, M. F. The DNA repair helicases XPD and FancJ have essential iron-sulfur domains. Mol. Cell 23, 801–808 (2006).

    CAS  PubMed  Google Scholar 

  16. 16

    Kispal, G. et al. Biogenesis of cytosolic ribosomes requires the essential iron-sulphur protein Rli1p and mitochondria. EMBO J. 24, 589–598 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. 17

    Karcher, A., Schele, A. & Hopfner, K. P. X-ray structure of the complete ABC enzyme ABCE1 from Pyrococcus abyssi . J. Biol. Chem. 283, 7962–7971 (2008).

    CAS  PubMed  Google Scholar 

  18. 18

    Imlay, J. A. Cellular defenses against superoxide and hydrogen peroxide. Annu. Rev. Biochem. 77, 755–776 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 19

    Walden, W. E. et al. Structure of dual function iron regulatory protein 1 complexed with ferritin IRE-RNA. Science 314, 1903–1908 (2006).

    ADS  CAS  PubMed  Google Scholar 

  20. 20

    Rouault, T. A. The role of iron regulatory proteins in mammalian iron homeostasis and disease. Nature Chem. Biol. 2, 406–414 (2006).

    CAS  Google Scholar 

  21. 21

    Wallander, M. L., Leibold, E. A. & Eisenstein, R. S. Molecular control of vertebrate iron homeostasis by iron regulatory proteins. Biochim. Biophys. Acta 1763, 668–689 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. 22

    Volz, K. The functional duality of iron regulatory protein 1. Curr. Opin. Struct. Biol. 18, 106–111 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. 23

    Kispal, G., Csere, P., Prohl, C. & Lill, R. The mitochondrial proteins Atm1p and Nfs1p are required for biogenesis of cytosolic Fe/S proteins. EMBO J. 18, 3981–3989 (1999). This paper and reference 28 functionally characterize the first components of the mitochondrial ISC assembly machinery and show the role of mitochondria for both cytosolic Fe–S-protein biogenesis and iron homeostasis.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. 24

    Rubio, L. M. & Ludden, P. W. Biosynthesis of the iron-molybdenum cofactor of nitrogenase. Annu. Rev. Microbiol. 62, 93–111 (2008).

    CAS  PubMed  Google Scholar 

  25. 25

    Hu, Y., Fay, A. W., Lee, C. C., Yoshizawa, J. & Ribbe, M. W. Assembly of nitrogenase MoFe protein. Biochemistry 47, 3973–3981 (2008).

    CAS  PubMed  Google Scholar 

  26. 26

    Leach, M. R. & Zamble, D. B. Metallocenter assembly of the hydrogenase enzymes. Curr. Opin. Chem. Biol. 11, 159–165 (2007).

    CAS  PubMed  Google Scholar 

  27. 27

    Zheng, L., Cash, V. L., Flint, D. H. & Dean, D. R. Assembly of iron-sulfur clusters. Identification of an iscSUA-hscBA-fdx gene cluster from Azotobacter vinelandii . J. Biol. Chem. 273, 13264–13272 (1998). This paper describes the isc operon encoding components of the bacterial ISC assembly machinery.

    CAS  PubMed  Google Scholar 

  28. 28

    Schilke, B., Voisine, C., Beinert, H. & Craig, E. Evidence for a conserved system for iron metabolism in the mitochondria of Saccharomyces cerevisiae . Proc. Natl Acad. Sci. USA 96, 10206–10211 (1999).

    ADS  CAS  PubMed  Google Scholar 

  29. 29

    Yuvaniyama, P., Agar, J. N., Cash, V. L., Johnson, M. K. & Dean, D. R. NifS-directed assembly of a transient [2Fe-2S] cluster within the NifU protein. Proc. Natl Acad. Sci. USA 97, 599–604 (2000). This paper introduces the concept of de novo Fe–S-cluster assembly on a scaffold protein.

    ADS  CAS  PubMed  Google Scholar 

  30. 30

    Mühlenhoff, U., Gerber, J., Richhardt, N. & Lill, R. Components involved in assembly and dislocation of iron-sulfur clusters on the scaffold protein Isu1p. EMBO J. 22, 4815–4825 (2003). This paper defines various stages of mitochondrial Fe–S-protein assembly and verifies the scaffold concept in vivo.

    PubMed  PubMed Central  Google Scholar 

  31. 31

    Raulfs, E. C., O'Carroll, I. P., Dos Santos, P. C., Unciuleac, M. C. & Dean, D. R. In vivo iron-sulfur cluster formation. Proc. Natl Acad. Sci. USA 105, 8591–8596 (2008).

    ADS  CAS  PubMed  Google Scholar 

  32. 32

    Unciuleac, M. C. et al. In vitro activation of apo-aconitase using a [4Fe-4S] cluster-loaded form of the IscU [Fe-S] cluster scaffolding protein. Biochemistry 46, 6812–6821 (2007).

    CAS  PubMed  Google Scholar 

  33. 33

    Chandramouli, K. et al. Formation and properties of [4Fe-4S] clusters on the IscU scaffold protein. Biochemistry 46, 6804–6811 (2007).

    CAS  PubMed  Google Scholar 

  34. 34

    Zheng, L., White, R. H., Cash, V. L., Jack, R. F. & Dean, D. R. Cysteine desulfurase activity indicates a role for NifS in metallocluster biosynthesis. Proc. Natl Acad. Sci. USA 90, 2754–2758 (1993). This paper identifies and characterizes the founding member of cysteine desulphurases.

    ADS  CAS  PubMed  Google Scholar 

  35. 35

    Kaiser, J. T. et al. Crystal structure of a NifS-like protein from Thermotoga maritima: implications for iron-sulfur cluster assembly. J. Mol. Biol. 297, 451–464 (2000).

    CAS  PubMed  Google Scholar 

  36. 36

    Cupp-Vickery, J. R., Urbina, H. & Vickery, L. E. Crystal structure of IscS, a cysteine desulfurase from Escherichia coli . J. Mol. Biol. 330, 1049–1059 (2003).

    CAS  PubMed  Google Scholar 

  37. 37

    Wiedemann, N. et al. Essential role of Isd11 in iron-sulfur cluster synthesis on Isu scaffold proteins. EMBO J. 25, 184–195 (2006).

    CAS  Google Scholar 

  38. 38

    Adam, A. C., Bornhövd, C., Prokisch, H., Neupert, W. & Hell, K. The Nfs1 interacting protein Isd11 has an essential role in Fe/S cluster biogenesis in mitochondria. EMBO J. 25, 174–183 (2006).

    CAS  PubMed  Google Scholar 

  39. 39

    Gerber, J., Mühlenhoff, U. & Lill, R. An interaction between frataxin and Isu1/Nfs1 that is crucial for Fe/S cluster synthesis on Isu1. EMBO Rep. 4, 906–911 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. 40

    Layer, G., Ollagnier-de Choudens, S., Sanakis, Y. & Fontecave, M. Iron-sulfur cluster biosynthesis: characterization of Escherichia coli CyaY as an iron donor for the assembly of [2Fe-2S] clusters in the scaffold IscU. J. Biol. Chem. 281, 16256–16263 (2006).

    CAS  PubMed  Google Scholar 

  41. 41

    Bencze, K. Z. et al. The structure and function of frataxin. Crit. Rev. Biochem. Mol. Biol. 41, 269–291 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. 42

    Wang, T. & Craig, E. A. Binding of yeast frataxin to the scaffold for Fe-S cluster biogenesis, Isu. J. Biol. Chem. 283, 12674–12679 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. 43

    Adinolfi, S. et al. Bacterial frataxin CyaY is the gatekeeper of iron-sulfur cluster formation catalyzed by IscS. Nature Struct. Mol. Biol. 16, 390–396 (2009).

    CAS  Google Scholar 

  44. 44

    Schilke, B. et al. Evolution of mitochondrial chaperones utilized in Fe-S cluster biogenesis. Curr. Biol. 16, 1660–1665 (2006).

    CAS  PubMed  Google Scholar 

  45. 45

    Cupp-Vickery, J. R., Silberg, J. J., Ta, D. T. & Vickery, L. E. Crystal structure of IscA, an iron-sulfur cluster assembly protein from Escherichia coli . J. Mol. Biol. 338, 127–137 (2004).

    CAS  PubMed  Google Scholar 

  46. 46

    Dutkiewicz, R. et al. Sequence-specific interaction between mitochondrial Fe-S scaffold protein Isu and Hsp70 Ssq1 is essential for their in vivo function. J. Biol. Chem. 279, 29167–29174 (2004).

    CAS  PubMed  Google Scholar 

  47. 47

    Chandramouli, K. & Johnson, M. K. HscA and HscB stimulate [2Fe-2S] cluster transfer from IscU to apoferredoxin in an ATP-dependent reaction. Biochemistry 45, 11087–11095 (2006). This paper and reference 49 define the role of heat-shock proteins in Fe–S-cluster transfer from scaffold to target proteins in vitro.

    CAS  PubMed  PubMed Central  Google Scholar 

  48. 48

    Andrew, A. J., Dutkiewicz, R., Knieszner, H., Craig, E. A. & Marszalek, J. Characterization of the interaction between the J-protein Jac1 and the scaffold for Fe-S cluster biogenesis, Isu1. J. Biol. Chem. 281, 14580–14587 (2006).

    CAS  PubMed  Google Scholar 

  49. 49

    Bonomi, F., Iametti, S., Morleo, A., Ta, D. & Vickery, L. E. Studies on the mechanism of catalysis of iron-sulfur cluster transfer from IscU[2Fe2S] by HscA/HscB chaperones. Biochemistry 47, 12795–12801 (2008).

    CAS  PubMed  Google Scholar 

  50. 50

    Bandyopadhyay, S. et al. Chloroplast monothiol glutaredoxins as scaffold proteins for the assembly and delivery of [2Fe-2S] clusters. EMBO J. 27, 1122–1133 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. 51

    Gelling, C., Dawes, I. W., Richhardt, N., Lill, R. & Mühlenhoff, U. Mitochondrial Iba57p is required for Fe/S cluster formation on aconitase and activation of radical SAM enzymes. Mol. Cell. Biol. 28, 1851–1861 (2008).

    CAS  PubMed  Google Scholar 

  52. 52

    Tan, G., Lu, J., Bitoun, J. P., Huang, H. & Ding, H. IscA/SufA paralogs are required for the [4Fe-4S] cluster assembly in enzymes of multiple physiological pathways in Escherichia coli under aerobic growth conditions. Biochem J. 420, 463–472 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. 53

    Loiseau, L. et al. ErpA, an iron sulfur (Fe S) protein of the A-type essential for respiratory metabolism in Escherichia coli . Proc. Natl Acad. Sci. USA 104, 13626–13631 (2007).

    ADS  CAS  PubMed  Google Scholar 

  54. 54

    Gupta, V. et al. Native Escherichia coli SufA, coexpressed with SufBCDSE, purifies as a [2Fe-2S] protein and acts as an Fe-S transporter to Fe-S target enzymes. J. Am. Chem. Soc. 131, 6149–6153 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. 55

    Bych, K. et al. The iron-sulphur protein Ind1 is required for effective complex I assembly. EMBO J. 27, 1736–1746 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. 56

    Takahashi, Y. & Tokumoto, U. A third bacterial system for the assembly of iron-sulfur clusters with homologs in archaea and plastids. J. Biol. Chem. 277, 28380–28383 (2002).

    CAS  PubMed  Google Scholar 

  57. 57

    Tokumoto, U., Kitamura, S., Fukuyama, K. & Takahashi, Y. Interchangeability and distinct properties of bacterial Fe-S cluster assembly systems: functional replacement of the isc and suf operons in Escherichia coli with the nifSU-like operon from Helicobacter pylori . J. Biochem. 136, 199–209 (2004).

    CAS  PubMed  Google Scholar 

  58. 58

    Outten, F. W., Wood, M. J., Munoz, F. M. & Storz, G. The SufE protein and the SufBCD complex enhance SufS cysteine desulfurase activity as part of a sulfur transfer pathway for Fe-S cluster assembly in E. coli . J. Biol. Chem. 278, 45713–45719 (2003). This paper and reference 59 describe the first functional analyses and interactions of the Suf proteins.

    CAS  PubMed  Google Scholar 

  59. 59

    Loiseau, L., Ollagnier-de-Choudens, S., Nachin, L., Fontecave, M. & Barras, F. Biogenesis of Fe-S cluster by the bacterial Suf system: SufS and SufE form a new type of cysteine desulfurase. J. Biol. Chem. 278, 38352–38359 (2003).

    CAS  PubMed  Google Scholar 

  60. 60

    Kessler, D. Enzymatic activation of sulfur for incorporation into biomolecules in prokaryotes. FEMS Microbiol. Rev. 30, 825–840 (2006).

    CAS  PubMed  Google Scholar 

  61. 61

    Layer, G. et al. SufE transfers sulfur from SufS to SufB for iron-sulfur cluster assembly. J. Biol. Chem. 282, 13342–13350 (2007).

    CAS  PubMed  Google Scholar 

  62. 62

    Sendra, M., Ollagnier de Choudens, S., Lascoux, D., Sanakis, Y. & Fontecave, M. The SUF iron-sulfur cluster biosynthetic machinery: sulfur transfer from the SUFS-SUFE complex to SUFA. FEBS Lett. 581, 1362–1368 (2007).

    CAS  PubMed  Google Scholar 

  63. 63

    Liu, G. et al. High-quality homology models derived from NMR and X-ray structures of E. coli proteins YgdK and Suf E suggest that all members of the YgdK/Suf E protein family are enhancers of cysteine desulfurases. Protein Sci. 14, 1597–1608 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. 64

    Nachin, L., Loiseau, L., Expert, D. & Barras, F. SufC: an unorthodox cytoplasmic ABC/ATPase required for [Fe-S] biogenesis under oxidative stress. EMBO J. 22, 427–437 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. 65

    Liu, J. et al. Structural characterization of an iron-sulfur cluster assembly protein IscU in a zinc-bound form. Proteins 59, 875–881 (2005).

    CAS  PubMed  Google Scholar 

  66. 66

    Riboldi, G. P., Verli, H. & Frazzon, J. Structural studies of the Enterococcus faecalis SufU [Fe-S] cluster protein. BMC Biochem. 10, 3 (2009).

    PubMed  PubMed Central  Google Scholar 

  67. 67

    Ye, H., Pilon, M. & Pilon-Smits, E. A. CpNifS-dependent iron-sulfur cluster biogenesis in chloroplasts. New Phytol. 171, 285–292 (2006).

    CAS  PubMed  Google Scholar 

  68. 68

    Yabe, T. et al. The Arabidopsis chloroplastic NifU-like protein CnfU, which can act as an iron-sulfur cluster scaffold protein, is required for biogenesis of ferredoxin and photosystem I. Plant Cell 16, 993–1007 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. 69

    Gerber, J., Neumann, K., Prohl, C., Mühlenhoff, U. & Lill, R. The yeast scaffold proteins Isu1p and Isu2p are required inside mitochondria for maturation of cytosolic Fe/S proteins. Mol. Cell. Biol. 24, 4848–4857 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. 70

    Rouault, T. A. & Tong, W. H. Iron-sulphur cluster biogenesis and mitochondrial iron homeostasis. Nature Rev. Mol. Cell Biol. 6, 345–351 (2005).

    CAS  Google Scholar 

  71. 71

    Tong, W. H. & Rouault, T. A. Functions of mitochondrial ISCU and cytosolic ISCU in mammalian iron-sulfur cluster biogenesis and iron homeostasis. Cell Metab. 3, 199–210 (2006). This paper and references 72 97 demonstrate the general conservation of Fe–S-protein biogenesis in vertebrates.

    CAS  PubMed  Google Scholar 

  72. 72

    Biederbick, A. et al. Role of human mitochondrial Nfs1 in cytosolic iron-sulfur protein biogenesis and iron regulation. Mol. Cell. Biol. 26, 5675–5687 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. 73

    Pondarre, C. et al. The mitochondrial ATP-binding cassette transporter Abcb7 is essential in mice and participates in cytosolic iron-sulphur cluster biogenesis. Hum. Mol. Genet. 15, 953–964 (2006).

    CAS  PubMed  Google Scholar 

  74. 74

    Cavadini, P. et al. RNA silencing of the mitochondrial ABCB7 transporter in HeLa cells causes an iron-deficient phenotype with mitochondrial iron overload. Blood 109, 3552–3559 (2007).

    CAS  PubMed  Google Scholar 

  75. 75

    Mesecke, N. et al. A disulfide relay system in the intermembrane space of mitochondria that mediates protein import. Cell 121, 1059–1070 (2005).

    CAS  PubMed  Google Scholar 

  76. 76

    Netz, D. J., Pierik, A. J., Stümpfig, M., Mühlenhoff, U. & Lill, R. The Cfd1-Nbp35 complex acts as a scaffold for iron-sulfur protein assembly in the yeast cytosol. Nature Chem. Biol. 3, 278–286 (2007). This paper defines various stages of cytosolic Fe–S-protein assembly and identifies Cfd1–Nbp35 as a cytosolic scaffold.

    CAS  Google Scholar 

  77. 77

    Roy, A., Solodovnikova, N., Nicholson, T., Antholine, W. & Walden, W. E. A novel eukaryotic factor for cytosolic Fe-S cluster assembly. EMBO J. 22, 4826–4835 (2003). This paper identifies Cfd1 as the first extra-mitochondrial Fe–S-protein biogenesis component.

    CAS  PubMed  PubMed Central  Google Scholar 

  78. 78

    Hausmann, A. et al. The eukaryotic P-loop NTPase Nbp35: an essential component of the cytosolic and nuclear iron-sulfur protein assembly machinery. Proc. Natl Acad. Sci. USA 102, 3266–3271 (2005).

    ADS  CAS  PubMed  Google Scholar 

  79. 79

    Srinivasan, V. et al. Structure of the yeast WD40 domain protein Cia1, a component acting late in iron-sulfur protein biogenesis. Structure 15, 1246–1257 (2007).

    CAS  PubMed  Google Scholar 

  80. 80

    Zhang, Y. et al. Dre2, a conserved eukaryotic Fe/S cluster protein, functions in cytosolic Fe/S protein biogenesis. Mol. Cell. Biol. 28, 5569–5582 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. 81

    Song, D. & Lee, F. S. A role for IOP1 in mammalian cytosolic iron-sulfur protein biogenesis. J. Biol. Chem. 283, 9231–9238 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. 82

    Stehling, O. et al. Human Nbp35 is essential for both cytosolic iron-sulfur protein assembly and iron homeostasis. Mol. Cell. Biol. 28, 5517–5528 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. 83

    Lill, R. & Mühlenhoff, U. Iron-sulfur protein biogenesis in eukaryotes. Trends Biochem. Sci. 30, 133–141 (2005).

    CAS  PubMed  Google Scholar 

  84. 84

    Klinge, S., Hirst, J., Maman, J. D., Krude, T. & Pellegrini, L. An iron-sulfur domain of the eukaryotic primase is essential for RNA primer synthesis. Nature Struct. Mol. Biol. 14, 875–877 (2007).

    CAS  Google Scholar 

  85. 85

    van der Giezen, M. & Tovar, J. Degenerate mitochondria. EMBO Rep. 6, 525–530 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. 86

    Embley, T. M. & Martin, W. Eukaryotic evolution, changes and challenges. Nature 440, 623–630 (2006).

    ADS  CAS  Google Scholar 

  87. 87

    Tovar, J. et al. Mitochondrial remnant organelles of Giardia function in iron-sulphur protein maturation. Nature 426, 172–176 (2003).

    ADS  CAS  Google Scholar 

  88. 88

    Goldberg, A. V. et al. Localization and functionality of microsporidian iron–sulphur cluster assembly proteins. Nature 452, 624–628 (2008).

    ADS  CAS  Google Scholar 

  89. 89

    Wingert, R. A. et al. Deficiency of glutaredoxin 5 reveals Fe–S clusters are required for vertebrate haem synthesis. Nature 436, 1035–1039 (2005).

    ADS  CAS  PubMed  Google Scholar 

  90. 90

    Shaw, G. C. et al. Mitoferrin is essential for erythroid iron assimilation. Nature 440, 96–100 (2006).

    ADS  CAS  PubMed  Google Scholar 

  91. 91

    Mochel, F. et al. Splice mutation in the iron-sulfur cluster scaffold protein ISCU causes myopathy with exercise intolerance. Am. J. Hum. Genet. 82, 652–660 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. 92

    Olsson, A., Lind, L., Thornell, L. E. & Holmberg, M. Myopathy with lactic acidosis is linked to chromosome 12q23.3–24.11 and caused by an intron mutation in the ISCU gene resulting in a splicing defect. Hum. Mol. Genet. 17, 1666–1667 (2008).

    CAS  PubMed  Google Scholar 

  93. 93

    Mueller, E. G. Trafficking in persulfides: delivering sulfur in biosynthetic pathways. Nature Chem. Biol. 2, 185–194 (2006).

    CAS  Google Scholar 

  94. 94

    Nakai, Y., Nakai, M., Lill, R., Suzuki, T. & Hayashi, H. Thio modification of yeast cytosolic tRNA is an iron-sulfur protein-dependent pathway. Mol. Cell. Biol. 27, 2841–2847 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. 95

    Kaplan, J., McVey Ward, D., Crisp, R. J. & Philpott, C. C. Iron-dependent metabolic remodeling in S. cerevisiae . Biochim. Biophys. Acta 1763, 646–651 (2006).

    CAS  PubMed  Google Scholar 

  96. 96

    Rutherford, J. C. et al. Activation of the iron-regulon by the yeast Aft1/Aft2 transcription factors depends on mitochondrial, but not cytosolic iron-sulfur protein biogenesis. J. Biol. Chem. 280, 10135–10140 (2005).

    CAS  PubMed  Google Scholar 

  97. 97

    Stehling, O., Elsässer, H. P., Brückel, B., Mühlenhoff, U. & Lill, R. Iron-sulfur protein maturation in human cells: evidence for a function of frataxin. Hum. Mol. Genet. 13, 3007–3015 (2004).

    CAS  PubMed  Google Scholar 

  98. 98

    Campuzano, V. et al. Friedreich's ataxia: autosomal recessive disease caused by an intronic GAA triplet repeat expansion. Science 271, 1423–1427 (1996).

    ADS  CAS  PubMed  Google Scholar 

  99. 99

    Bekri, S. et al. Human ABC7 transporter: gene structure and mutation causing X-linked sideroblastic anemia with ataxia (XLSA/A) with disruption of cytosolic iron-sulfur protein maturation. Blood 96, 3256–3264 (2000).

    CAS  PubMed  Google Scholar 

  100. 100

    Amutha, B. et al. GTP is required for iron-sulfur cluster biogenesis in mitochondria. J. Biol. Chem. 283, 1362–1371 (2008).

    CAS  PubMed  Google Scholar 

Download references


I wish to thank all present and past members of my group for their excellent and dedicated work. Generous financial support from the Deutsche Forschungsgemeinschaft (SFB 593 and TR1, Gottfried-Wilhelm Leibniz programme and GRK 1216), the Max-Planck Gesellschaft, the von Behring-Röntgen-Stiftung, the German-Israeli Foundation for Scientific Research and Development, the Alexander von Humboldt-Stiftung, Rhön Klinikum AG and Fonds der Chemischen Industrie is gratefully acknowledged. I apologize to all colleagues whose original work could not be discussed or cited owing to length limitations.

Author information



Ethics declarations

Competing interests

The author declares no competing financial interests.

Additional information

Reprints and permissions information is available at

Correspondence should be addressed to the author (

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Lill, R. Function and biogenesis of iron–sulphur proteins. Nature 460, 831–838 (2009).

Download citation

Further reading


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing