Regulation of mitochondrial iron homeostasis by sideroflexin 2

Abstract

Mitochondrial iron is indispensable for heme biosynthesis and iron–sulfur cluster assembly. Several mitochondrial transmembrane proteins have been implicated to function in the biosynthesis of heme and iron–sulfur clusters by transporting reaction intermediates. However, several mitochondrial proteins related to iron metabolism remain uncharacterized. Here, we show that human sideroflexin 2 (SFXN2), a member of the SFXN protein family, is involved in mitochondrial iron metabolism. SFXN2 is an evolutionarily conserved protein that localized to mitochondria via its transmembrane domain. SFXN2 -knockout (KO) cells had an increased mitochondrial iron content, which was associated with decreases in the heme content and heme-dependent enzyme activities. By contrast, the activities of iron–sulfur cluster-dependent enzymes were unchanged in SFXN2 -KO cells. Moreover, abnormal iron metabolism impaired mitochondrial respiration in SFXN2 -KO cells and accelerated iron-mediated death of these cells. Our findings demonstrate that SFXN2 functions in mitochondrial iron metabolism by regulating heme biosynthesis. Electronic supplementary material The online version of this article (10.1007/s12576-018-0652-2) contains supplementary material, which is available to authorized users.

Sideroflexin 4 affects Fe-S cluster biogenesis, iron metabolism, mitochondrial respiration and heme biosynthetic enzymes

“…Two recent publications shed light on the function of other sideroflexins: SFXN1 was found to be a serine transporter; however, SFXN4 did not compensate for the defects found in sideroflexin 1 mutants 35 . Sideroflexin 2, an outer mitochondrial membrane protein, has 20% sequence homology with SFXN4 and affects the iron content of mitochondria and heme synthesis, but has no effect on iron sulfur cluster formation 36 . Activity of respiratory complex one was also unchanged in a SFXN2 knockout 36 .…”

“…Sideroflexin 2, an outer mitochondrial membrane protein, has 20% sequence homology with SFXN4 and affects the iron content of mitochondria and heme synthesis, but has no effect on iron sulfur cluster formation 36 . Activity of respiratory complex one was also unchanged in a SFXN2 knockout 36 . The function of SFXN4 therefore appears distinct from that of other SFXN family members studied to date.…”

The fungal mitochondrial membrane protein, BbOhmm, antagonistically controls hypoxia tolerance

“…Iron is an essential element involved in diverse biological processes, including oxygen transport, metabolism, respiration and cell cycle development (Zhang, 2014;Muckenthaler et al, 2017;Lv and Shang, 2018). A large portion of cellular iron is bound to heme that is used in a variety of proteins especially respiratory complexes, and cellular and mitochondrial iron concentrations are tightly regulated, including by various import/ export mechanisms (Napier et al, 2005;Kafina and Paw, 2017;Mon et al, 2019). Mitochondrial iron transporters, for example, DMT1 (MMT1), MRS3/4 and ABCB10 transport iron into mitochondria, whereas ABCB7 (Atm1) and ABCB8 (FXN), are mitochondrial iron efflux proteins (Mühlenhoff et al, 2003;Shaw et al, 2006;Chen et al, 2009;Zhao and Enns, 2012).…”

“…The increased in heme concentration can help account for the increased complex III and IV activities seen in ΔBbOhmm cells under LO conditions, since the two complexes contain heme (Alam et al, 2016). Mitochondrial iron is also indispensable for iron-sulfur (Fe-S) cluster assembly (Mon et al, 2019). Although no obvious change in mitochondrial iron levels was examined in either ΔBbOhmm or BbOhmm OE cells as compared to WT cells under AO condition, we cannot exclude the possibility that Fe-S cluster synthesis was altered in these cells.…”

Identification of Prognostic Organic Cation and Anion Transporters in Different Cancer Entities by In Silico Analysis

“…So far, no function has been described for UNC13B in cancer. SFXN2 , or sideroflexin 2 , is an evolutionary conserved protein that is expressed in outer mitochondrial membrane and is involved in iron homeostasis [ 29 ]. Similar to UNC13B , studies showing any functional correlation of SFXN2 with cancer progression, developments, etc.…”