Cysteine desulfurase (NFS1)–LYR motif-containing protein 4 (ISD11)–Mitochondrial acyl carrier protein (ACP)–Iron-sulfur cluster assembly enzyme (ISCU) complex (SDAI complex)

The Cysteine desulfurase (NFS1)–LYR motif-containing protein 4 (ISD11)–Mitochondrial acyl carrier protein (ACP)–Iron-sulfur cluster assembly enzyme (ISCU) complex is the primary enzymatic machinery responsible for the de novo biosynthesis of iron-sulfur (Fe-S) clusters in human mitochondria (Source: UniProt P56279, Q9H1K1). Within this complex, NFS1 functions as a cysteine desulfurase that extracts sulfur from L-cysteine, while ISCU acts as the scaffold upon which the [2Fe-2S] cluster is initially built (Source: PubMed 29925948). The subunits ISD11 and the mitochondrial acyl carrier protein (ACP, also known as NDUFAB1) are essential for stabilizing NFS1 and regulating its catalytic activity (Source: PubMed 28562585). This complex is vital for the maturation of numerous Fe-S proteins involved in the respiratory chain, the tricarboxylic acid cycle, and DNA maintenance. Dysregulation of this complex is linked to several human diseases, most notably Friedreich's ataxia, which results from a deficiency in frataxin, a protein that binds to and activates this core complex (Source: PubMed 24634534). Additionally, certain cancers overexpress NFS1 to mitigate oxidative stress and prevent ferroptosis, positioning the complex as an emerging target for oncology therapeutics (Source: Nature 2017, 551(7682)). Experimental inhibitors targeting the sulfur-transfer mechanism are currently being explored to induce metabolic crisis in susceptible tumor cells.

Other names

Core mitochondrial iron-sulfur cluster (ISC) assembly complexNFS1-ISD11-NDUFAB1-ISCU complexCysteine desulfurase complex[2Fe-2S] cluster assembly complex

Inhibition of the cysteine desulfurase activity of NFS1 or disruption of the protein-protein interactions between NFS1, ISD11, ACP, and ISCU to prevent the formation of iron-sulfur clusters, leading to mitochondrial dysfunction and cell death.