Both human ferredoxins 1 and 2 and ferredoxin reductase are important for iron-sulfur cluster biogenesis

► We show that RNAi of human FDX1 compromises iron-sulfur cluster biogenesis. ► We also show that RNAi of human FDX2 compromises iron-sulfur cluster biogenesis. ► The two homologous human ferredoxins function in iron-sulfur cluster biogenesis. ► RNAi of the human FDX reductase (FDXR) compromises iron-sulfur cluster biogenesis. ► FDX-FDXR dysfunction disturbs mitochondrial and cytosolic iron homeostasis.