Fungal mitochondrial iron-sulfur cluster assembly machinery (ISC machinery)

The fungal mitochondrial iron-sulfur (Fe-S) cluster assembly (ISC) machinery is a multi-protein system essential for the synthesis of Fe-S clusters, which serve as critical inorganic cofactors for proteins involved in electron transport, DNA repair, and metabolic catalysis (Lill & Freibert, 2020, Annual Review of Biochemistry). The core components of this machinery include the cysteine desulfurase Nfs1, the scaffold protein Isu1/2, and the frataxin homolog Yfh1, which work coordinately to assemble [2Fe-2S] and [4Fe-4S] clusters (Braymer & Lill, 2017, Journal of Biological Chemistry). In fungi such as Saccharomyces cerevisiae and pathogenic Candida species, this system is indispensable for viability, as it provides the necessary clusters for both mitochondrial and cytosolic Fe-S proteins (Outten & Albetel, 2013, Molecular Microbiology). Due to its central role in fungal metabolism and the distinct structural features of certain fungal ISC components compared to their human orthologs, the machinery is a high-priority target for novel antifungal drug development (Verma et al., 2022, Frontiers in Cellular and Infection Microbiology). Inhibition of the ISC pathway leads to a cascade of cellular failures, including the loss of respiratory function, mitochondrial iron accumulation, and increased sensitivity to oxidative stress (Lill & Freibert, 2020, Annual Review of Biochemistry). While no clinical drugs currently target this system exclusively, experimental inhibitors and metal-based compounds like gallium are being explored for their ability to disrupt fungal iron utilization and Fe-S cluster biogenesis (Verma et al., 2022, Frontiers in Cellular and Infection Microbiology). Associated Fe-S proteins, such as aconitase and respiratory complexes, lose their function upon disruption of this biogenesis pathway, further contributing to fungal cell death.

Other names

Mitochondrial iron-sulfur cluster biogenesis systemISC biogenesis pathwayNfs1-Isu1-Yfh1 complexFungal ISC system

Disruption of the synthesis of iron-sulfur clusters by inhibiting core enzymes or scaffold proteins, leading to the inactivation of essential Fe-S dependent enzymes and metabolic collapse.