Ciao3, also known as NARFL or IOP1, is a crucial component of the cytosolic iron-sulfur cluster assembly (CIA) pathway. Iron-sulfur clusters are essential for the function of many proteins involved in key cellular processes, such as DNA metabolism, energy metabolism, and response to oxidative stress [1-3, 6-10]. The CIA pathway delivers these clusters to nuclear and cytosolic proteins, and Ciao3 operates at a cross-road of this machinery [1].

Knockout of Iop1 (encoding Ciao3) in Mus musculus leads to embryonic lethality before embryonic day 10.5. Acute, inducible global knockout in adult mice results in lethality and significantly diminished activity of cytosolic aconitase, an iron-sulfur protein, in liver extracts. Inducible knockout in mouse embryonic fibroblasts causes decreased activity of cytosolic aconitase and loss of cell viability, indicating a defective cytosolic iron-sulfur cluster assembly [3]. In lung cancer cells, knockdown of NARFL (Ciao3) leads to mitochondrial dysfunction via the HIF-1α-DNMT1 axis, increasing drug resistance and cell migration, and NSCLC patients with NARFL deficiency have a poor survival rate [2].

In conclusion, Ciao3 is essential for cytosolic iron-sulfur cluster assembly, which is vital for normal embryonic development, maintenance of cytosolic iron-sulfur protein activity, and energy metabolism in cells. Its deficiency is associated with severe consequences, including embryonic lethality and mitochondrial dysfunction-related diseases such as poor prognosis in non-small cell lung cancer. Studies using gene knockout mouse models have significantly enhanced our understanding of Ciao3's role in these biological processes and disease conditions.

References:

1. Maione, Vincenzo, Grifagni, Deborah, Torricella, Francesco, Cantini, Francesca, Banci, Lucia. 2020. CIAO3 protein forms a stable ternary complex with two key players of the human cytosolic iron-sulfur cluster assembly machinery. In Journal of biological inorganic chemistry : JBIC : a publication of the Society of Biological Inorganic Chemistry, 25, 501-508. doi:10.1007/s00775-020-01778-z. https://pubmed.ncbi.nlm.nih.gov/32222833/

2. Liu, Hongzhou, Wu, Xueqin, Yang, Tianrong, Xu, Ying, Peng, Jie. 2023. NARFL deficiency caused mitochondrial dysfunction in lung cancer cells by HIF-1α-DNMT1 axis. In Scientific reports, 13, 17176. doi:10.1038/s41598-023-44418-7. https://pubmed.ncbi.nlm.nih.gov/37821486/

3. Song, Daisheng, Lee, Frank S. 2011. Mouse knock-out of IOP1 protein reveals its essential role in mammalian cytosolic iron-sulfur protein biogenesis. In The Journal of biological chemistry, 286, 15797-805. doi:10.1074/jbc.M110.201731. https://pubmed.ncbi.nlm.nih.gov/21367862/