A VDAC1-mediated NEET protein chain transfers [2Fe-2S] clusters between the mitochondria and the cytosol and impacts mitochondrial dynamics

Ola Karmi, Henri Baptiste Marjault, Fang Bai, Susmita Roy, Yang Sung Sohn, Merav Darash Yahana, Faruck Morcos, Konstantinos Ioannidis, Yaakov Nahmias, Patricia A. Jennings, Ron Mittler, José N. Onuchic*, Rachel Nechushtai*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

Abstract

Mitochondrial inner NEET (MiNT) and the outer mitochondrial membrane (OMM) mitoNEET (mNT) proteins belong to the NEET protein family. This family plays a key role in mitochondrial labile iron and reactive oxygen species (ROS) homeostasis. NEET proteins contain labile [2Fe-2S] clusters which can be transferred to apo-acceptor proteins. In eukaryotes, the biogenesis of [2Fe-2S] clusters occurs within the mitochondria by the iron-sulfur cluster (ISC) system; the clusters are then transferred to [2Fe-2S] proteins within the mitochondria or exported to cytosolic proteins and the cytosolic iron-sulfur cluster assembly (CIA) system. The last step of export of the [2Fe-2S] is not yet fully characterized. Here we show that MiNT interacts with voltage-dependent anion channel 1 (VDAC1), a major OMM protein that connects the intermembrane space with the cytosol and participates in regulating the levels of different ions including mitochondrial labile iron (mLI). We further show that VDAC1 is mediating the interaction between MiNT and mNT, in which MiNT transfers its [2Fe-2S] clusters from inside the mitochondria to mNT that is facing the cytosol. This MiNT-VDAC1-mNT interaction is shown both experimentally and by computational calculations. Additionally, we show that modifying MiNT expression in breast cancer cells affects the dynamics of mitochondrial structure and morphology, mitochondrial function, and breast cancer tumor growth. Our findings reveal a pathway for the transfer of [2Fe-2S] clusters, which are assembled inside the mitochondria, to the cytosol.

Original languageAmerican English
Article numbere2121491119
JournalProceedings of the National Academy of Sciences of the United States of America
Volume119
Issue number7
DOIs
StatePublished - 15 Feb 2022

Bibliographical note

Publisher Copyright:
© 2022 National Academy of Sciences. All rights reserved.

Keywords

  • CISD3
  • MitoNEET
  • Mitochondrial inner NEET protein (MiNT)
  • VDAC1
  • [2Fe-2S] cluster

Fingerprint

Dive into the research topics of 'A VDAC1-mediated NEET protein chain transfers [2Fe-2S] clusters between the mitochondria and the cytosol and impacts mitochondrial dynamics'. Together they form a unique fingerprint.

Cite this