Sfxn2, a member of the SFXN protein family, is a mitochondrial outer membrane protein crucial for mitochondrial iron metabolism [1,2]. Mitochondrial iron is essential for heme biosynthesis and iron-sulfur cluster assembly, and Sfxn2 is involved in these key pathways, which are vital for cellular energy production and overall homeostasis [2]. Genetic models, such as knockout models, can be valuable in further elucidating its function.

In SFXN2-knockout (KO) cells, there is an increased mitochondrial iron content, accompanied by decreases in the heme content and heme-dependent enzyme activities, while the activities of iron-sulfur cluster-dependent enzymes remain unchanged [2]. Abnormal iron metabolism in these KO cells impairs mitochondrial respiration and accelerates iron-mediated cell death [2]. In multiple myeloma (MM), SFXN2 is significantly elevated and correlated with poor outcomes. SFXN2 overexpression promotes MM cell proliferation and suppresses starvation-induced autophagy/mitophagy, while SFXN2 knockdown aggravates mitochondria damage and autophagic processes in MM cell lines. Inhibition of SFXN2 shows anti-myeloma activity in vivo using a myeloma xenograft model [1].

In conclusion, Sfxn2 plays a critical role in regulating mitochondrial bioenergetics, mitophagy, cellular iron metabolism, and redox homeostasis [1]. The study of Sfxn2 KO models has provided insights into its role in diseases like multiple myeloma, highlighting its potential as a therapeutic target in such disease areas [1].