Sfxn5, a member of the sideroflexin family, encodes a protein that functions as a metabolite transporter located in the mitochondrial membrane. It is involved in the citrate-cholesterol-PI(4,5)P2 pathway, which is crucial for actin polymerization during neutrophil spreading. This process is essential for neutrophil adhesion, migration, and recruitment to inflammatory tissues, highlighting its overall biological importance. Genetic models, such as mice and zebrafish, are valuable for studying Sfxn5 [1].

In a study using small interfering RNA transfection in mice and morpholino injection in zebrafish to achieve Sfxn5 deficiency, neutrophil recruitment was significantly decreased. Sfxn5-deficient neutrophils showed impaired spreading and associated cellular phenotypes like cell adhesion, chemotaxis, and ROS production. Actin polymerization, critical for neutrophil spreading, was also partially inhibited. Mechanistically, Sfxn5 deficiency led to decreased levels of cytosolic citrate, acetyl-CoA, cholesterol, and PI(4,5)P2. Exogenous supplementation with citrate or cholesterol could partially reverse these effects [1].

In conclusion, Sfxn5 is essential for maintaining cytosolic citrate levels, ensuring sufficient cholesterol synthesis to promote actin polymerization in a PI(4,5)P2-dependent manner during neutrophil spreading. The study using Sfxn5-deficient mice and zebrafish models reveals its significance in neutrophil-related inflammatory recruitment processes, providing insights into the underlying mechanisms of neutrophil-mediated immune responses.

References:

1. Zhang, Huan, Meng, Ling, Liu, Yang, Fan, Sijia, Ren, Chunguang. . Sfxn5 Regulation of Actin Polymerization for Neutrophil Spreading Depends on a Citrate-Cholesterol-PI(4,5)P2 Pathway. In Journal of immunology (Baltimore, Md. : 1950), 211, 462-473. doi:10.4049/jimmunol.2200863. https://pubmed.ncbi.nlm.nih.gov/37326485/