Iron-Sulfur Cluster Biogenesis Project

Iron-Sulfur Cluster Biogenesis Project

Overview

Iron-sulfur (Fe-S) clusters are ancient and essential cofactors required for numerous cellular processes including electron transfer, enzyme catalysis, and gene regulation. The mitochondrial ISC assembly machinery is the primary system in eukaryotes, with cytosolic Fe-S assembly dependent on mitochondrial function.

Model Species

Primary: Homo sapiens (human)
- Already reviewed HSCB in this project
- Multiple rare diseases (Friedreich's ataxia, etc.)

Core Pathway Architecture

1. Mitochondrial ISC Assembly

Core machinery for de novo cluster synthesis:
- NFS1 - Cysteine desulfurase (sulfur donor)
- ISCU - Scaffold protein
- FXN - Frataxin (iron donor/regulator)
- LYRM4 (ISD11) - NFS1 stabilizer
- FDXR/FDX2 - Ferredoxin reductase/ferredoxin

2. Cluster Transfer (Chaperone System)

Transfer from scaffold to recipients:
- HSPA9 - Mitochondrial Hsp70
- HSCB - J-domain co-chaperone (already reviewed!)
- GLRX5 - Glutaredoxin 5

3. [4Fe-4S] Cluster Assembly

Late-acting ISC machinery:
- ISCA1/ISCA2 - A-type carriers
- IBA57 - [4Fe-4S] assembly factor
- NFU1 - Alternative scaffold
- BOLA3 - [4Fe-4S] maturation

4. Mitochondrial Export

5. Cytosolic Iron-Sulfur Assembly (CIA)

Cytosolic/nuclear Fe-S protein maturation:
- CIAO1 - CIA targeting complex
- CIAO2A/2B - CIA factors
- CIAO3 (NARFL) - CIA component
- MMS19 - Late-acting factor

Candidate Genes (~20)

Gene UniProt Function
NFS1 Q9Y697 Cysteine desulfurase
ISCU Q9H1K1 Scaffold
FXN Q16595 Frataxin
LYRM4 Q9HD34 NFS1 partner
HSPA9 P38646 Hsp70 chaperone
HSCB Q8IWL3 Co-chaperone (reviewed)
GLRX5 Q86SX6 Glutaredoxin
ISCA1 Q9BUE6 [4Fe-4S] assembly
ISCA2 Q86U28 [4Fe-4S] assembly
IBA57 Q5T440 [4Fe-4S] factor
NFU1 Q9UMS0 Alternative scaffold
BOLA3 Q53S33 [4Fe-4S] factor
ABCB7 O75027 Mitochondrial export
CIAO1 O76071 CIA complex
MMS19 Q96T76 CIA factor

Disease Relevance

Project Status