Structure of the human monomeric NEET protein MiNT and its role in regulating iron and reactive oxygen species in cancer cells

Proc Natl Acad Sci U S A. 2018 Jan 9;115(2):272-277. doi: 10.1073/pnas.1715842115.

Colin H Lipper ¹, Ola Karmi ², Yang Sung Sohn ², Merav Darash-Yahana ², Heiko Lammert ³ ⁴ ⁵ ⁶, Luhua Song ⁷, Amy Liu ⁷, Ron Mittler ⁷, Rachel Nechushtai ², José N Onuchic ⁸ ⁴ ⁵ ⁶, Patricia A Jennings ⁹

Affiliations

1 Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92093.
2 The Alexander Silberman Institute of Life Science, Hebrew University of Jerusalem, Edmond J. Safra Campus at Givat Ram, Jerusalem 91904, Israel.
3 Center for Theoretical Biological Physics, Rice University, Houston, TX 77005.
4 Department of Physics and Astronomy, Rice University, Houston, TX 77005.
5 Department of Chemistry, Rice University, Houston, TX 77005.
6 Department of Biosciences, Rice University, Houston, TX 77005.
7 Department of Biological Sciences, University of North Texas, Denton, TX 76203.
8 Center for Theoretical Biological Physics, Rice University, Houston, TX 77005; jonuchic@rice.edu pajennings@ucsd.edu.
9 Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92093; jonuchic@rice.edu pajennings@ucsd.edu.

PMID: 29259115 DOI: 10.1073/pnas.1715842115

Abstract

The NEET family is a relatively new class of three related [2Fe-2S] proteins (CISD1-3), important in human health and disease. While there has been growing interest in the homodimeric gene products of CISD1 (mitoNEET) and CISD2 (NAF-1), the importance of the inner mitochondrial CISD3 protein has only recently been recognized in Cancer. The CISD3 gene encodes for a monomeric protein that contains two [2Fe-2S] CDGSH motifs, which we term mitochondrial inner NEET protein (MiNT). It folds with a pseudosymmetrical fold that provides a hydrophobic motif on one side and a relatively hydrophilic surface on the diametrically opposed surface. Interestingly, as shown by molecular dynamics simulation, the protein displays distinct asymmetrical backbone motions, unlike its homodimeric counterparts that face the cytosolic side of the outer mitochondrial membrane/endoplasmic reticulum (ER). However, like its counterparts, our biological studies indicate that knockdown of MiNT leads to increased accumulation of mitochondrial labile iron, as well as increased mitochondrial reactive oxygen production. Taken together, our study suggests that the MiNT protein functions in the same pathway as its homodimeric counterparts (mitoNEET and NAF-1), and could be a key player in this pathway within the mitochondria. As such, it represents a target for Anticancer or antidiabetic drug development.

Keywords

NEET proteins; cancer; iron homeostasis; iron-sulfur proteins; mitochondria.

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