MitoNEET is a Regulator of the Cellular Thiol State in Health and Disease - PROJECT SUMMARY
MitoNEET is a druggable target, with recognized roles in type-2 diabetes, cancer, and Parkinson’s Disease. The redox-
active [2Fe-2S] cluster of mitoNEET, localized in the cytosol at the outer mitochondrial membrane, has enzymatic capacity
to convert thiol-containing molecules known to regulate the cellular redox balance, such as cysteine and glutathione. The
electronic properties and stability of the [2Fe-2S] cluster of mitoNEET are sensitive to pH, mutagenesis, ligand binding,
and covalent modification. Cluster instability and release from mitoNEET cause an increase of free iron in the cytosol. The
iron increase is a known harmful event that at the least causes oxidative stress and at most kills the cell through the initiation
of ferroptosis. Metabolic activity towards thiols combined with the instability of the cluster makes mitoNEET well-
positioned to act as both a sensor for free thiol content in cells and a putative perpetrator of ferroptosis. We hypothesize that
mitoNEET has a unique role in contributing to redox homeostasis through the metabolism of sulfur-containing intermediates
and signaling into the ferroptosis pathway. It contributes to the cell's ability to maintain physiological glutathione
concentrations and the cytosolic free iron pool.
