MitoNEET: An Iron‐Containing Outer Mitochondrial Membrane Protein that Regulates Oxidative Capacity

The thiazolidinedione pioglitazone is an effective insulin sensitizing agent used in the treatment of type 2 diabetes. Potential non‐genomic drug effects led others to discover that pioglitazone binds to a protein named mitoNEET (1). Bioinformatic analysis revealed that mitoNEET is one of a small family of proteins containing putative CDGSH‐type zinc finger domains, along with MitoNEET Related 1 (Miner1) and MitoNEET Related 2 (Miner2). The mitoNEET gene is present only in vertebrates and is widely expressed in rodent tissues with the exception of pancreatic islets. Metal analysis of recombinant protein indicated that mitoNEET lacked zinc, but instead bound greater than 1 mole Fe/mole of protein. The conserved sequence C‐X‐C‐X 2 ‐(S/T)‐X 3 ‐P‐X‐C‐D‐G‐(S/A/T)‐H is a defining feature of these unique proteins and is likely involved in iron binding. Localization studies demonstrated that mitoNEET is an integral outer mitochondrial membrane protein. An amino‐terminal anchor sequence tethers the protein to the outer membrane with the CDGSH‐domain oriented toward the cytoplasm. Cardiac mitochondria isolated from mitoNEET null mice demonstrated reduced oxidative capacity, suggesting mitoNEET is an important iron‐containing protein involved in the control of maximal mitochondrial respiratory rates (2).