CDGSH iron-sulfur domain-containing protein 3, mitochondrial (CISD3)

CDGSH iron-sulfur domain-containing protein 3 (CISD3) is a monomeric, soluble mitochondrial matrix protein and a member of the NEET (CDGSH iron-sulfur domain) family. It contains two [2Fe-2S] clusters, which it donates to mitochondrial respiratory complex I and possibly complex II, supporting electron transport and redox balance within mitochondria. Unlike its membrane-bound homodimeric counterparts (mitoNEET/CISD1 and NAF-1/CISD2), CISD3 supports iron homeostasis and the regulation of ROS, influences mitochondrial fission/fusion pathways, and is essential for muscle and overall cellular health. CISD3 is implicated in cancer, diabetes, and neurodegenerative disease through its role in ferroptosis and apoptosis regulation. Its expression serves as a biomarker in several cancers and may be explored as a therapeutic target to induce selective cell death in tumor cells.

Other names

CISD3MiNT (Mitochondrial inner NEET protein)Miner2MitoNEET-related protein 2MitoNEET related 2Mitochondrial inner NEET protein

Iron chelators promote loss of the iron-sulfur cluster and destabilize CISD3, affecting its role in iron homeostasis and mitochondrial function. Modulation (inhibition or overexpression) of CISD3 impacts mitochondrial iron levels, ROS generation, and ferroptosis—thus, drugs that inhibit CISD3 could promote ferroptotic cell death in cancer therapy.