Mitochondrial iron-sulfur cluster biogenesis (Homo sapiens)

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2, 5, 9, 17, 20...291-3, 8, 10...2, 6, 7, 22, 25...14, 192 IronFXN mitochondrial matrixNFS1pyridoxal phosphate FXNISD11NFS1ISCU NFS1pyridoxal phosphate FXNNFS1ISD11ISCU2Fe-2S Cluster mitochondrial intermembrane spaceFDXRFAD FDXRFADH2 2 IronFXNNFS1ISD11ISCU cytosolNFS1pyridoxal phosphate FAD L-CysFDXRFADFXNPXLP NFS1-1 FDXR PXLP FDXRFADH2FXN2Fe-2S cluster FDX1/1L H+PXLP FADH2 NADPHFDX1/1L Fe2+ ISCU-1 NADP+ISCU-1 LYRM4 L-AlaFXNISD11NFS1ISCULYRM4 FXNLYRM4 FXNNFS1ISD11ISCU2Fe-2S ClusterFe2+2 IronFXNNFS1ISD11ISCUMitoferrin1/2NFS1-1 ISCU-1 NFS1-1 FDXR Fe2+2, 4, 8, 322, 4, 8, 22, 322, 4, 6, 8, 22...


Description

Iron-sulfur (Fe-S) proteins are localized in the cytosol, nucleus, and mitochondria of mammalian cells (reviewed in Stemmler et al. 2010, Rouault 2012, Bandyopadhyay et al. 2008, Lill 2009, Lill et al. 2012). Fe-S protein biogenesis in the mitochondrial matrix involves the iron-sulfur cluster (ISC) assembly machinery. Ferrous iron is transported across the inner mitochondrial membrane into the mitochondrial matrix by Mitoferrin-1 and Mitoferrin-2. (Mitoferrin-1 is enriched in erythroid cells while Mitoferrin-2 is ubiquitous.) Frataxin binds ferrous iron in the mitochondrial matrix. The cysteine desulfurase NFS1 in a subcomplex with ISD11 provides the sulfur by converting cyteine into alanine and forming a persulfide which is used for cluster formation on ISCU, the scaffold protein. Interaction between NFS1 and ISD11 is necessary for desulfurase activity. Frataxin binds to a complex containing NFS1, ISD11, and ISCU and is proposed to function as an iron donor to ISCU or as an allosteric switch that activates sulfur transfer and Fe-S cluster assembly (Tsai and Barondeau 2010). Cluster formation also involves the electron transfer chain ferredoxin reductase and ferredoxin. ISCU initially forms clusters containing 2 iron atoms and 2 sulfur atoms ([2Fe-2S] clusters). They are released by the function of HSP70-HSC20 chaperones and the monothiol glutaredoxin GLRX5 and used for assembly of [2Fe-2S] proteins. Assembly of larger clusters such as [4Fe-4S] clusters may involve the function of ISCA1, ISCA2, and IBA57. The clusters are transferred to apo-enzymes such as the respiratory complexes, aconitase, and lipoate synthase through dedicated targeting factors such as IND1, NFU1, and BOLA3. Original Pathway at Reactome: http://www.reactome.org/PathwayBrowser/#DB=gk_current&FOCUS_SPECIES_ID=48887&FOCUS_PATHWAY_ID=1362409

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Bibliography

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History

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CompareRevisionActionTimeUserComment
114883view16:39, 25 January 2021ReactomeTeamReactome version 75
113329view11:40, 2 November 2020ReactomeTeamReactome version 74
112541view15:50, 9 October 2020ReactomeTeamReactome version 73
101454view11:32, 1 November 2018ReactomeTeamreactome version 66
100992view21:11, 31 October 2018ReactomeTeamreactome version 65
100528view19:45, 31 October 2018ReactomeTeamreactome version 64
100075view16:28, 31 October 2018ReactomeTeamreactome version 63
99626view15:01, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
93991view13:50, 16 August 2017ReactomeTeamreactome version 61
93599view11:28, 9 August 2017ReactomeTeamreactome version 61
87954view13:07, 25 July 2016RyanmillerOntology Term : 'classic metabolic pathway' added !
86706view09:24, 11 July 2016ReactomeTeamreactome version 56
83054view09:47, 18 November 2015ReactomeTeamVersion54
81756view09:56, 26 August 2015ReactomeTeamVersion53
76911view08:18, 17 July 2014ReactomeTeamFixed remaining interactions
76616view11:59, 16 July 2014ReactomeTeamFixed remaining interactions
75947view10:00, 11 June 2014ReactomeTeamRe-fixing comment source
75650view10:54, 10 June 2014ReactomeTeamReactome 48 Update
75005view13:52, 8 May 2014AnweshaFixing comment source for displaying WikiPathways description
74649view08:42, 30 April 2014ReactomeTeamNew pathway

External references

DataNodes

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NameTypeDatabase referenceComment
2 Iron

FXN NFS1 ISD11

ISCU		ComplexREACT_152530 (Reactome)
2Fe-2S cluster MetaboliteCHEBI:33739 (ChEBI)
FAD MetaboliteCHEBI:16238 (ChEBI)
FADH2 MetaboliteCHEBI:17877 (ChEBI)
FDX1/1L ComplexREACT_150657 (Reactome)
FDX1/1L ComplexREACT_151081 (Reactome)
FDXR FADH2ComplexREACT_150903 (Reactome)
FDXR FADComplexREACT_151835 (Reactome)
FDXR ProteinP22570 (Uniprot-TrEMBL)
FXN

ISD11 NFS1

ISCU		ComplexREACT_150577 (Reactome)
FXN

NFS1 ISD11 ISCU

2Fe-2S Cluster		ComplexREACT_151067 (Reactome)
FXNProteinQ16595 (Uniprot-TrEMBL)
Fe2+ MetaboliteCHEBI:18248 (ChEBI)
Fe2+MetaboliteCHEBI:18248 (ChEBI)
H+MetaboliteCHEBI:15378 (ChEBI)
ISCU-1 ProteinQ9H1K1-1 (Uniprot-TrEMBL)
L-AlaMetaboliteCHEBI:16977 (ChEBI)
L-CysMetaboliteCHEBI:17561 (ChEBI)
LYRM4 ProteinQ9HD34 (Uniprot-TrEMBL)
Mitoferrin1/2ProteinREACT_152226 (Reactome)
NADP+MetaboliteCHEBI:18009 (ChEBI)
NADPHMetaboliteCHEBI:16474 (ChEBI)
NFS1-1 ProteinQ9Y697-1 (Uniprot-TrEMBL) By analogy with yeast Hfs1, human NFS1 probably has an N-terminal transit peptide that is removed by mitochondrial processing peptidase. The cleavage site is unknown.
PXLP MetaboliteCHEBI:18405 (ChEBI)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
2 Iron

FXN NFS1 ISD11

ISCU		REACT_150385 (Reactome)
FDX1/1L ArrowREACT_150196 (Reactome)
FDX1/1L ArrowREACT_150385 (Reactome)
FDX1/1L REACT_150196 (Reactome)
FDX1/1L REACT_150385 (Reactome)
FDXR FADArrowREACT_150196 (Reactome)
FDXR FADH2ArrowREACT_150376 (Reactome)
FDXR FADH2REACT_150196 (Reactome)
FDXR FADREACT_150376 (Reactome)
FXN

ISD11 NFS1

ISCU		REACT_150163 (Reactome)
FXN

NFS1 ISD11 ISCU

2Fe-2S Cluster		ArrowREACT_150385 (Reactome)
Fe2+REACT_150163 (Reactome)
H+ArrowREACT_150196 (Reactome)
H+REACT_150376 (Reactome)
L-AlaArrowREACT_150385 (Reactome)
L-CysREACT_150385 (Reactome)
Mitoferrin1/2REACT_150305 (Reactome)
NADP+ArrowREACT_150376 (Reactome)
NADPHREACT_150376 (Reactome)
REACT_150163 (Reactome) Frataxin (FXN) specifically binds 2 atoms of ferrous iron per monomer (reviewed in Stemmler et al. 2010). Iron bound to Frataxin may (Yoon and Cowan 2003, Gerber et al. 2003) or may not (Schmucker et al. 2011) enhance the interaction of Frataxin with NFS1, ICSU, and ISD11. Frataxin was shown to stimulate the cysteine desulfurase activity of NFS1 and was proposed to be a regulator of sulfur production (Tsai et al. 2010). The formation of sulfide by NFS1 is most efficiently observed when NFS1 is in complex with ISD11, ISCU, and FXN in the presence of cysteine and iron. This means that only the complete system of NFS1, ISD11, ISCU, FXN, cysteine, and iron is fully active as a desulfurase. FXN therefore seems to be a regulator of the cysteine desulfurase permitting sulfide production only when all components needed for Fe-S cluster synthesis are present and the ISCU-bound Fe-S cluster can be formed.
REACT_150196 (Reactome) Two electrons are transferred from reduced ferredoxin reductase (FDXR, adrenodoxin reductase) to two ferredoxin-1 or ferredoxin-1L (FDX1, FDX1L) molecules, each of which binds one electron. Two protons are released during the reaction.
REACT_150305 (Reactome) As inferred from biochemical studies in yeast and phenotypic studies in mouse, Mitoferrin-1 (SLC25A37) and Mitoferrin-2 (SLC25A28) transport ferrous iron across the inner mitochondrial membrane. Mitoferrin-1 is essential for maintaining mitochondrial iron uptake in developing erythroid cells; mitoferrin-2 is ubiquitously expressed. Defects in Mitoferrin-1 and Mitoferrin-2 cause a reduction in mitochondrial iron acquisition and biogenesis of iron-sulfur clusters and heme.
REACT_150376 (Reactome) Two electrons and one proton are transferred from NADPH to the FAD moiety of ferredoxin reductase. A proton from the medium is also taken up by ferredoxin reductase.
REACT_150385 (Reactome) Iron-sulfur clusters are assembled on the scaffold, ISCU. Based on homology with bacterial IscU:IscS complexes (reviewed in Johnson et al. 2005), one molecule of ISCU is bound to each subunit of a NFS1 dimer (Marinoni et al. 2012). A single complex may thus be capable of assembling two 2Fe-2S clusters. Sulfide is provided by desulfuration of cysteine by NFS1:ISD11 (Biederbick et al. 2006, Shi et al. 2009, Tsai and Barondeau 2010). It has been proposed that ferrous iron is delivered by FXN (Gerber et al. 2003, Yoon and Cowan 2003, Schmucker et al. 2011) bound to ISCU (inferred from yeast, Wang and Craig 2008), although more recent studies suggested that FXN functions as an allosteric effector to stimulate sulfide transfer (Tsai et al. 2010). Holo-ISCU (ISCU bound to a newly synthesized 2Fe-2S cluster) transiently interacts with a dedicated HSP70 chaperone system including Mortalin (GRP75) and HSP20 and GLRX5 (GRX5). Electrons supplied by FDXL1 (FDX2) are required and may reduce the sulfur from S0 to S2-. NFU1 binds an Fe-S cluster (Tong et al. 2003, inferred from bacteria Yuvaniyama et al. 2000) and, from biochemical studies of bacterial NFU1 homologues, is proposed to be an intermediate Fe-S cluster carrier (Bandyopadhy et al. 2008). Mutations in human NFU1 affect only a subset of Fe-S proteins (Navarro-Sastre et al. 2011).
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