Defects in Mitochondrial Iron-Sulfur Cluster Assembly Induce Cysteine S-Polythiolation on Iron-Sulfur Apoproteins

Mitochondria play a central role in the maturation of proteins with iron-sulfur (Fe/S) clusters. During their biogenesis, the apoforms of Fe/S proteins expose unprotected Fe/S cluster-coordinating cysteine side chains, rendering them vulnerable to oxidative modifications that interfere with subsequent Fe/S cluster insertion. Whether and how cells protect these delicate cysteine residues are unknown.

In this study, we show that sulfhydryl groups of Fe/S cluster-coordinating cysteine residues of mitochondrial Fe/S apoproteins acquire cyclic S-polythiol modifications. These adducts are the result of persulfide addition, followed by a subsequent oxidation step. These modifications not only accumulate upon defects in the early stages of the mitochondrial Fe/S cluster assembly system but are also found in wild-type cells under normal growth conditions. They are, however, not found on Fe/S apoproteins in the cytosol.

Our work describes a novel in vivo chemical modification of cysteine side chains in mitochondrial Fe/S apoproteins. These cyclic S-polythiolation adducts are resistant to oxidation, yet can be removed by reductive cleavage, suggesting that they serve as a reversible protection device for cysteine ligands sensitive to oxidative modification. Antioxid. Redox Signal. 25, 28-40.