Mitochondrial iron-sulfur clusters: Structure, function, and an emerging role in vascular biology

Iron-sulfur (Fe-S) clusters are essential cofactors most commonly known for their role mediating electron transfer within the mitochondrial respiratory chain. The Fe-S cluster pathways that function within the respi-ratory complexes are highly conserved between bacteria and the mitochondria of eukaryotic cells. Within the electron transport chain, Fe-S clusters play a critical role in transporting electrons through Complexes I, II and III to cytochrome c, before subsequent transfer to molecular oxygen. Fe-S clusters are also among the binding sites of classical mitochondrial inhibitors, such as rotenone, and play an important role in the production of mito-chondrial reactive oxygen species (ROS). Mitochondrial Fe-S clusters also play a critical role in the pathogenesis of disease. High levels of ROS produced at these sites can cause cell injury or death, however, when produced at low levels can serve as signaling molecules. For example, Ndufs2, a Complex I subunit containing an Fe-S center, N2, has recently been identified as a redox-sensitive oxygen sensor, mediating homeostatic oxygen-sensing in the pulmonary vasculature and carotid body. Fe-S clusters are emerging as transcriptionally-regulated mediators in disease and play a crucial role in normal physiology, offering potential new therapeutic targets for diseases including malaria, diabetes, and cancer.

Automated summary

Iron-sulfur (Fe-S) clusters are essential cofactors mediating electron transfer within the mitochondrial respiratory chain. They play critical roles in oxygen sensing, reactive oxygen species (ROS) production, and disease pathogenesis. Fe-S clusters are emerging as transcriptionally-regulated mediators in disease and offer potential new therapeutic targets for various diseases.