Iron‑sulfur (FeS) clusters are cofactors of numerous proteins involved in essential cellular functions including respiration, protein translation, DNA synthesis and repair, ribosome maturation, anti-viral responses, and isopropylmalate isomerase activity. Novel FeS proteins are still being discovered due to the widespread use of cryogenic electron microscopy (cryo-EM) and elegant genetic screens targeted at protein discovery. A complex sequence of biochemical reactions mediated by a conserved machinery controls biosynthesis of FeS clusters. In eukaryotes, a remarkable epistasis has been observed: the mitochondrial machinery, termed ISC (Iron-Sulfur Cluster), lies upstream of the cytoplasmic machinery, termed CIA (Cytoplasmic Iron‑sulfur protein Assembly). The basis for this arrangement is the production of a hitherto uncharacterized intermediate, termed X-S or (Fe-S)int, produced in mitochondria by the ISC machinery, exported by the mitochondrial ABC transporter Atm1 (ABCB7 in humans), and then utilized by the CIA machinery for the cytoplasmic/nuclear FeS cluster assembly. Genetic and biochemical findings supporting this sequence of events are herein presented. New structural views of the Atm1 transport phases are reviewed. The key compartmental roles of glutathione in cellular FeS cluster biogenesis are highlighted. Finally, data are presented showing that every one of the ten core components of the mitochondrial ISC machinery and Atm1, when mutated or depleted, displays similar phenotypes: mitochondrial and cytoplasmic FeS clusters are both rendered deficient, consistent with the epistasis noted above.
Keywords: (Fe-S)(int); Atm1; Cytoplasm; FeS cluster trafficking; FeS proteins; Glutaredoxin; Glutathione; Mitochondria; X-S.
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