Regulation of mitochondrial iron homeostasis by sideroflexin 2

• Published in: The journal of physiological sciences Vol. 69; no. 2; pp. 359 - 373
• Main Authors: Mon, Ei Ei, Wei, Fan-Yan, Ahmad, Raja Norazireen Raja, Yamamoto, Takahiro, Moroishi, Toshiro, Tomizawa, Kazuhito
• Format: Journal Article
• Language: English
• Published: Japan Springer 01.03.2019; BioMed Central; Springer Japan
• Subjects: Biosynthesis; Electron transport; Enzymatic activity; Enzymes; Heme; Hemoglobin synthesis; Homeostasis; Intermediates; Iron; Membrane proteins; Metabolism; Mitochondria; Original Paper; Physiological aspects; Protein turnover; Sulfur; Sulfur compounds; OXPHOS; Mitochondria; Iron; Respiration; Heme
• ISSN: 1880-6546; 1880-6562
• DOI: 10.1007/s12576-018-0652-2

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.