MitoNEET is a uniquely folded 2Fe-2S outer mitochondrial membrane protein stabilized by pioglitazone

Mark L. Paddock, Sandra E. Wiley, Herbert L. Axelrod, Aina E. Cohen, Melinda Roy, Edward C. Abresch, Dominique Capraro, Anne N. Murphy, Rachel Nechushtai, Jack E. Dixon, Patricia A. Jennings*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

227 Scopus citations


Iron-sulfur (Fe-S) proteins are key players in vital processes involving energy homeostasis and metabolism from the simplest to most complex organisms. We report a 1.5 Å x-ray crystal structure of the first identified outer mitochondrial membrane Fe-S protein, mitoNEET. Two protomers intertwine to form a unique dimeric structure that constitutes a new fold to not only the ∼650 reported Fe-S protein structures but also to all known proteins. We name this motif the NEET fold. The protomers form a two-domain structure: a β-cap domain and a cluster-binding domain that coordinates two acid-labile 2Fe-2S clusters. Binding of pioglitazone, an insulin-sensitizing thiazolidinedione used in the treatment of type 2 diabetes, stabilizes the protein against 2Fe-2S cluster release. The biophysical properties of mitoNEET suggest that it may participate in a redox-sensitive signaling and/or in Fe-S cluster transfer.

Original languageAmerican English
Pages (from-to)14342-14347
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number36
StatePublished - 4 Sep 2007


  • Diabetes
  • FeS cluster
  • Iron homeostasis
  • Oxidative stress
  • Thiazolidinedione


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