Reactome | Mitochondrial iron-sulfur cluster biogenesis

Mitochondrial iron-sulfur cluster biogenesis

Stable Identifier

R-HSA-1362409

DOI

10.3180/REACT_150353.1

Type

Pathway

Species

Homo sapiens

Compartment

mitochondrial inner membrane, mitochondrial matrix, mitochondrial intermembrane space

ReviewStatus

5/5

Locations in the PathwayBrowser

Expand all

General

SBML | | PDF

SVG | | PPTX | SBGN

Mitochondrial iron-sulfur cluster biogenesis

Click the image above or here to open this pathway in the Pathway Browser

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.

Literature References

PubMed ID	Title	Journal	Year
19021507	Iron-sulfur cluster biosynthesis Bandyopadhyay, S, Chandramouli, K, Johnson, MK	Biochem Soc Trans	2008
20060739	Iron-sulfur proteins in health and disease Sheftel, A, Stehling, O, Lill, R	Trends Endocrinol. Metab.	2010
20522547	Frataxin and mitochondrial FeS cluster biogenesis Stemmler, TL, Lesuisse, E, Pain, D, Dancis, A	J Biol Chem	2010
19675643	Function and biogenesis of iron-sulphur proteins Lill, R	Nature	2009
22609301	The role of mitochondria in cellular iron-sulfur protein biogenesis and iron metabolism Lill, R, Hoffmann, B, Molik, S, Pierik, AJ, Rietzschel, N, Stehling, O, Uzarska, MA, Webert, H, Wilbrecht, C, Mühlenhoff, U	Biochim. Biophys. Acta	2012
20873749	Human frataxin is an allosteric switch that activates the Fe-S cluster biosynthetic complex Tsai, CL, Barondeau, DP	Biochemistry	2010
22382365	Biogenesis of iron-sulfur clusters in mammalian cells: new insights and relevance to human disease Rouault, TA	Dis Model Mech	2012
23906713	The role of mitochondria in cellular iron-sulfur protein biogenesis: mechanisms, connected processes, and diseases Stehling, O, Lill, R	Cold Spring Harb Perspect Biol	2013