CDGSH iron-sulfur domain-containing protein (NEET protein) (NEET)

Mitochondrial NEET proteins, also known as CDGSH iron-sulfur domain-containing (CISD) proteins, are a unique class of [2Fe-2S] cluster-binding proteins located primarily in the mitochondria and endoplasmic reticulum. The family consists of three members in humans: CISD1 (mitoNEET), CISD2 (NAF-1), and CISD3 (Miner2), which play critical roles in regulating mitochondrial iron homeostasis, reactive oxygen species (ROS) levels, and bioenergetics (PMID: 17360355, 21825116). These proteins act as redox-sensitive switches that can transfer their iron-sulfur clusters to acceptor proteins, thereby modulating cellular pathways such as apoptosis, autophagy, and ferroptosis. Dysregulation of NEET proteins is implicated in a wide range of pathologies, including type 2 diabetes, neurodegenerative disorders like Parkinson's disease, and various cancers where they support tumor cell proliferation (PMID: 33184277, PMC8021574). NEET proteins were first identified as the mitochondrial targets of the thiazolidinedione class of anti-diabetic drugs, such as pioglitazone, which stabilize the [2Fe-2S] cluster and mitigate mitochondrial dysfunction (PMID: 17360355). Recent therapeutic strategies focus on developing small molecules that either stabilize or destabilize these clusters to treat metabolic diseases or induce ferroptosis in cancer cells. For instance, molecules like Mito-C and M1 have been designed to modulate mitochondrial morphology and iron levels, offering potential treatments for viral infections and metabolic syndrome (PMID: 33184277). Given their central role in maintaining organelle crosstalk and cellular health, NEET proteins represent a promising frontier for disease-modifying therapies in aging and chronic metabolic conditions.

Other names

Mitochondrial NEET proteinsCISD proteinsCDGSH iron-sulfur domain-containing protein 1 (CISD1)CDGSH iron-sulfur domain-containing protein 2 (CISD2)CDGSH iron-sulfur domain-containing protein 3 (CISD3)MitoNEETNutrient-deprivation autophagy factor 1 (NAF-1)Miner1Miner2ERISMiNT

Drugs targeting NEET proteins typically act by stabilizing or destabilizing the [2Fe-2S] cluster within the CDGSH domain, thereby modulating the rate of cluster transfer to acceptor proteins and regulating mitochondrial iron and ROS levels.