Regulation of mitochondrial iron homeostasis by sideroflexin 2

J Physiol Sci. 2019 Mar;69(2):359-373. doi: 10.1007/s12576-018-0652-2. Epub 2018 Dec 20.


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.

Keywords: Heme; Iron; Mitochondria; OXPHOS; Respiration.

MeSH terms

  • Amino Acid Sequence
  • Biological Transport
  • Cation Transport Proteins / metabolism*
  • Cell Line
  • Cell Line, Tumor
  • HEK293 Cells
  • HeLa Cells
  • Heme / metabolism
  • Homeostasis
  • Humans
  • Iron / metabolism*
  • Mitochondria / metabolism*
  • Mitochondrial Proteins / metabolism
  • Sequence Alignment


  • Cation Transport Proteins
  • Mitochondrial Proteins
  • SFXN2 protein, human
  • Heme
  • Iron