Mitochondrial iron-sulfur cluster biogenesis (Homo sapiens)

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2, 8, 11, 13, 19...91, 18, 20, 27, 35...4, 13, 14, 16, 22...3, 5-7, 10...34, 37cytosolmitochondrial intermembrane spacemitochondrial matrixPXLP FXN(81-210) ISCU-1 SLC25A28 FXN(81-210) L-CysISCA2 ISCA2 FDX1L NADPHFe2+FDX1 NFS1-1 FDX1,FDX1L (red.)H+NADP+FDX1 Fe2+HSCBSLC25A37 2Fe-2S cluster 4Fe-4S cluster ISCU-1 ISCA1:ISCA2Mitoferrin1,2GLRX5:2Fe-2SFDXR Fe2+ FADH2 GLRX5 NFS1-1 L-AlaPXLP FAD ISCA1 LYRM4 ISCA1 FDXR:FADISCU-1 (2Fe-2S)(1+) GLRX5FDX1L ISCA1:ISCA2:4Fe-4SFXN:NFS1:ISD11:ISCU:2Fe-2S Cluster(2Fe-2S)2+ FXN:ISD11:NFS1:ISCU2Iron:FXN:NFS1:ISD11:ISCUPXLP NFS1-1 2Fe-2S cluster FDX1,FDX1L (ox.)FDXR LYRM4 FXN(81-210) FDXR:FADH2LYRM4 4, 24, 26, 404, 16, 24, 26, 40184, 16, 22, 24, 26...18


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 (SLC25A37) and Mitoferrin-2 (SLC25A28). (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. View original pathway at:Reactome.

Comments

Reactome-Converter 
Pathway is converted from Reactome ID: 1362409
Reactome-version 
Reactome version: 66
Reactome Author 
Reactome Author: Lill, R

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Bibliography

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History

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CompareRevisionActionTimeUserComment
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
(2Fe-2S)(1+) MetaboliteCHEBI:33738 (ChEBI)
(2Fe-2S)2+ MetaboliteCHEBI:33737 (ChEBI)
2 Iron:FXN:NFS1:ISD11:ISCUComplexR-HSA-1362401 (Reactome)
2Fe-2S cluster MetaboliteCHEBI:33739 (ChEBI)
4Fe-4S cluster MetaboliteCHEBI:49883 (ChEBI)
FAD MetaboliteCHEBI:16238 (ChEBI)
FADH2 MetaboliteCHEBI:17877 (ChEBI)
FDX1 ProteinP10109 (Uniprot-TrEMBL)
FDX1,FDX1L (ox.)ComplexR-HSA-2408370 (Reactome)
FDX1,FDX1L (red.)ComplexR-HSA-2408372 (Reactome)
FDX1L ProteinQ6P4F2 (Uniprot-TrEMBL)
FDXR ProteinP22570 (Uniprot-TrEMBL)
FDXR:FADH2ComplexR-HSA-2395502 (Reactome)
FDXR:FADComplexR-HSA-2395508 (Reactome)
FXN(81-210) ProteinQ16595 (Uniprot-TrEMBL)
FXN:ISD11:NFS1:ISCUComplexR-HSA-1362404 (Reactome)
FXN:NFS1:ISD11:ISCU:2Fe-2S ClusterComplexR-HSA-1362398 (Reactome)
Fe2+ MetaboliteCHEBI:18248 (ChEBI)
Fe2+MetaboliteCHEBI:18248 (ChEBI)
GLRX5 ProteinQ86SX6 (Uniprot-TrEMBL)
GLRX5:2Fe-2SComplexR-HSA-8878793 (Reactome)
GLRX5ProteinQ86SX6 (Uniprot-TrEMBL)
H+MetaboliteCHEBI:15378 (ChEBI)
HSCBProteinQ8IWL3 (Uniprot-TrEMBL)
ISCA1 ProteinQ9BUE6 (Uniprot-TrEMBL)
ISCA1:ISCA2:4Fe-4SComplexR-HSA-8878796 (Reactome)
ISCA1:ISCA2ComplexR-HSA-8878840 (Reactome)
ISCA2 ProteinQ86U28 (Uniprot-TrEMBL)
ISCU-1 ProteinQ9H1K1-1 (Uniprot-TrEMBL)
L-AlaMetaboliteCHEBI:57972 (ChEBI)
L-CysMetaboliteCHEBI:35235 (ChEBI)
LYRM4 ProteinQ9HD34 (Uniprot-TrEMBL)
Mitoferrin1,2ComplexR-HSA-1362399 (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)
SLC25A28 ProteinQ96A46 (Uniprot-TrEMBL)
SLC25A37 ProteinQ9NYZ2 (Uniprot-TrEMBL)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
2 Iron:FXN:NFS1:ISD11:ISCUArrowR-HSA-1362416 (Reactome)
2 Iron:FXN:NFS1:ISD11:ISCUR-HSA-1362408 (Reactome)
2 Iron:FXN:NFS1:ISD11:ISCUmim-catalysisR-HSA-1362408 (Reactome)
FDX1,FDX1L (ox.)ArrowR-HSA-1362408 (Reactome)
FDX1,FDX1L (ox.)R-HSA-2395512 (Reactome)
FDX1,FDX1L (red.)ArrowR-HSA-1362408 (Reactome)
FDX1,FDX1L (red.)ArrowR-HSA-2395512 (Reactome)
FDX1,FDX1L (red.)R-HSA-1362408 (Reactome)
FDX1,FDX1L (red.)mim-catalysisR-HSA-1362408 (Reactome)
FDXR:FADArrowR-HSA-2395512 (Reactome)
FDXR:FADH2ArrowR-HSA-2395517 (Reactome)
FDXR:FADH2R-HSA-2395512 (Reactome)
FDXR:FADR-HSA-2395517 (Reactome)
FXN:ISD11:NFS1:ISCUR-HSA-1362416 (Reactome)
FXN:NFS1:ISD11:ISCU:2Fe-2S ClusterArrowR-HSA-1362408 (Reactome)
Fe2+ArrowR-HSA-1362417 (Reactome)
Fe2+R-HSA-1362416 (Reactome)
Fe2+R-HSA-1362417 (Reactome)
GLRX5:2Fe-2SR-HSA-8878815 (Reactome)
GLRX5ArrowR-HSA-8878815 (Reactome)
H+ArrowR-HSA-2395512 (Reactome)
H+R-HSA-2395517 (Reactome)
HSCBArrowR-HSA-8878815 (Reactome)
ISCA1:ISCA2:4Fe-4SArrowR-HSA-8878815 (Reactome)
ISCA1:ISCA2R-HSA-8878815 (Reactome)
L-AlaArrowR-HSA-1362408 (Reactome)
L-CysR-HSA-1362408 (Reactome)
Mitoferrin1,2mim-catalysisR-HSA-1362417 (Reactome)
NADP+ArrowR-HSA-2395517 (Reactome)
NADPHR-HSA-2395517 (Reactome)
R-HSA-1362408 (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).
R-HSA-1362416 (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.
R-HSA-1362417 (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.
R-HSA-2395512 (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.
R-HSA-2395517 (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.
R-HSA-8878815 (Reactome) Iron-sulfur clusters containing 4Fe-4S are assembled from 2Fe-2S clusters on ISCA1:ISCA2 heterodimers (Banci et al. 2014, Brancaccio et al. 2014, inferred from Saccharomyces cerevisiae in Mühlenhoff et al. 2011). GLRX5:2Fe-2S can donate 2Fe-2S clusters to ISCA1:ISCA2 in vitro (Banci et al. 2014, Brancaccio et al. 2014). It is unclear if other proteins also donate 2Fe-2S clusters. Two conserved C-terminal cysteines of ISCA1:ISCA2 heterodimers extract [2Fe-2S] clusters from GLRX5, forming a ISCA1:ISCA2:GLRX5 intermediate containing two 2Fe-2S clusters (Brancaccio et al. 2017). The physiological electron donor required to convert the two 2Fe-2S clusters bound to the intermediate into a 4Fe-4S cluster is not yet characterized. ISCA1, ISCA2, and IBA57 are required for formation of holoenzymes such as aconitase that contain 4Fe-4S clusters (Sheftel et al. 2012). HSCB (HSC20), the homolog of yeast JAC1, interacts with HSPA9 and appears to facilitate the reaction (Uhrigshardt et al. 2010).
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