Controlled Protonation of [2Fe-2S] Leading to MitoNEET Analogues and Concurrent Cluster Modification.

MitoNEET, a key regulatory protein in mitochondrial energy metabolism, exhibits a uniquely ligated [2Fe-2S] cluster with one histidine and three cysteines. This unique cluster has been postulated to sense the redox environment and release Fe-S cofactors under acidic pH. Reported herein is a synthetic system that shows how [2Fe-2S] clusters react with protons and rearrange their coordination geometry. The low-temperature stable, site-differentiated clusters [Fe2S2(SPh)3(CF3COO)]2- and [Fe2S2(SPh)3(py)]- have been prepared via controlled protonation below -35 °C and characterized by NMR, UV-vis, and X-ray absorption spectroscopy. Both complexes exhibit anodically shifted redox potentials compared to [Fe2S2(SPh)4]2- and convert to [Fe4S4(SPh)4]2- upon warming to room temperature. The current study provides insight into how mitoNEET releases its [2Fe-2S] in response to highly tuned acidic conditions, the chemistry of which may have further implications in Fe-S biogenesis.