Abstract
Sideroflexin4 (SFXN4) is a member of a family of nuclear-encoded mitochondrial proteins. Rare germline mutations in SFXN4 lead to phenotypic characteristics of mitochondrial disease including impaired mitochondrial respiration and hematopoetic abnormalities. We sought to explore the function of this protein. We show that knockout of SFXN4 has profound effects on Fe-S cluster formation. This in turn diminishes mitochondrial respiratory chain complexes and mitochondrial respiration and causes a shift to glycolytic metabolism. SFXN4 knockdown reduces the stability and activity of cellular Fe-S proteins, affects iron metabolism by influencing the cytosolic aconitase–IRP1 switch, redistributes iron from the cytosol to mitochondria, and impacts heme synthesis by reducing levels of ferrochelatase and inhibiting translation of ALAS2. We conclude that SFXN4 is essential for normal functioning of mitochondria, is necessary for Fe-S cluster biogenesis and iron homeostasis, and plays a critical role in mitochondrial respiration and synthesis of heme.
Highlights
Sideroflexin[4] (SFXN4) is a member of a family of nuclear-encoded mitochondrial proteins
Since mutational loss of sideroflexin 4 (SFXN4) leads to hematopoetic abnormalities, we explored the mechanisms of action of SFXN4 in erythropoietic cells
To confirm that the decrease in respiratory activity did not result from a decrease in the number of mitochondria, we assessed the effect of SFXN4 knockout on mitochondrial DNA copy number
Summary
Sideroflexin[4] (SFXN4) is a member of a family of nuclear-encoded mitochondrial proteins. We conclude that SFXN4 is essential for normal functioning of mitochondria, is necessary for Fe-S cluster biogenesis and iron homeostasis, and plays a critical role in mitochondrial respiration and synthesis of heme. The protein was localized on the mitochondrial inner membrane, and a knockdown experiment in zebrafish demonstrated reduced hemoglobin content and impaired respiration, consistent with a diagnosis of mitochondrial disorder. Apart from this seminal finding, very little is known about the function of SFXN4. ALA is transported to the cytosol and undergoes a series of enzymatic modifications prior to the final step in heme synthesis, which occurs in mitochondria and is mediated by ferrochelatase (FECH), an Fe-S cluster-containing protein that inserts iron into protoporphyrin IX to form heme[9]. The requirement of FECH for an Fe-S cofactor links heme synthesis and Fe-S biogenesis
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call