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

Colin H. Lipper, Ola Karmi, Yang Sung Sohn, Merav Darash-Yahana, Heiko Lammert, Luhua Song, Amy Liu, Ron Mittler, Rachel Nechushtai, José N. Onuchic*, Patricia A. Jennings

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

53 Scopus citations

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.

Original languageAmerican English
Pages (from-to)272-277
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume115
Issue number2
DOIs
StatePublished - 9 Jan 2017

Bibliographical note

Funding Information:
ACKNOWLEDGMENTS. Work at the laboratory of P.A.J. is supported by NIH Grant GM101467. Work at the Center for Theoretical Biological Physics is sponsored by the National Science Foundation (NSF; Grants PHY-1427654 and CHE-1614101). R.N. and R.M. acknowledge the support of NSF-Binational Science Foundation (BSF) Grant NSF-MCB-1613462 (to R.M.) and BSF Grant 2015831 (to R.N.). Work at the laboratory of R.N. is also supported by funding from the Israel Science Foundation (Grant ISF-865/13). The funders had no role in the design, data collection, analysis, decision to publish, or preparation of the manuscript.

Funding Information:
Work at the laboratory of P.A.J. is supported by NIH Grant GM101467. Work at the Center for Theoretical Biological Physics is sponsored by the National Science Foundation (NSF; Grants PHY-1427654 and CHE-1614101). R.N. and R.M. acknowledge the support of NSF-Binational Science Foundation (BSF) Grant NSF-MCB-1613462 (to R.M.) and BSF Grant 2015831 (to R.N.). Work at the laboratory of R.N. is also supported by funding from the Israel Science Foundation (Grant ISF-865/13). The funders had no role in the design, data collection, analysis, decision to publish, or preparation of the manuscript.

Keywords

  • Cancer
  • Iron homeostasis
  • Iron-sulfur proteins
  • Mitochondria
  • NEET proteins

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