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

Regulation of mitochondrial iron homeostasis by sideroflexin 2.

Author information

1
Department of Molecular Physiology, Faculty of Life Sciences, Kumamoto University, Honjo 1-1-1, Chuo-Ku, Kumamoto, 860-8556, Japan.
2
Department of Molecular Physiology, Faculty of Life Sciences, Kumamoto University, Honjo 1-1-1, Chuo-Ku, Kumamoto, 860-8556, Japan. fywei@kumamoto-u.ac.jp.
3
Precursory Research for Embryonic Science and Technology (PRESTO), Japan Science and Technology Agency (JST), Kawaguchi, 332-0012, Japan. fywei@kumamoto-u.ac.jp.
4
Department of Molecular Enzymology, Faculty of Life Sciences, Kumamoto University, Kumamoto, 860-8556, Japan.
5
Center for Metabolic Regulation of Healthy Aging, Faculty of Life Sciences, Kumamoto University, Kumamoto, 860-8556, Japan.
6
Precursory Research for Embryonic Science and Technology (PRESTO), Japan Science and Technology Agency (JST), Kawaguchi, 332-0012, Japan.
7
Department of Molecular Physiology, Faculty of Life Sciences, Kumamoto University, Honjo 1-1-1, Chuo-Ku, Kumamoto, 860-8556, Japan. tomikt@kumamoto-u.ac.jp.
8
Center for Metabolic Regulation of Healthy Aging, Faculty of Life Sciences, Kumamoto University, Kumamoto, 860-8556, Japan. tomikt@kumamoto-u.ac.jp.
9
Neutron Therapy Research Center, Okayama University, Okayama, 700-8558, Japan. tomikt@kumamoto-u.ac.jp.

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.

KEYWORDS:

Heme; Iron; Mitochondria; OXPHOS; Respiration

PMID:
30570704
DOI:
10.1007/s12576-018-0652-2

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