Redox-dependent gating of VDAC by mitoNEET

Colin H. Lipper, Jason T. Stofleth, Fang Bai, Yang Sung Sohn, Susmita Roy, Ron Mittler, Rachel Nechushtai, José N. Onuchic*, Patricia A. Jennings

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

88 Scopus citations

Abstract

MitoNEET is an outer mitochondrial membrane protein essential for sensing and regulation of iron and reactive oxygen species (ROS) homeostasis. It is a key player in multiple human maladies including diabetes, cancer, neurodegeneration, and Parkinson’s diseases. In healthy cells, mitoNEET receives its clusters from the mitochondrion and transfers them to acceptor proteins in a process that could be altered by drugs or during illness. Here, we report that mitoNEET regulates the outer-mitochondrial membrane (OMM) protein voltage-dependent anion channel 1 (VDAC1). VDAC1 is a crucial player in the cross talk between the mitochondria and the cytosol. VDAC proteins function to regulate metabolites, ions, ROS, and fatty acid transport, as well as function as a “governator” sentry for the transport of metabolites and ions between the cytosol and the mitochondria. We find that the redox-sensitive [2Fe-2S] cluster protein mitoNEET gates VDAC1 when mitoNEET is oxidized. Addition of the VDAC inhibitor 4,4′-diisothiocyanatostilbene-2,2′-disulfonate (DIDS) prevents both mitoNEET binding in vitro and mitoNEET-dependent mitochondrial iron accumulation in situ. We find that the DIDS inhibitor does not alter the redox state of MitoNEET. Taken together, our data indicate that mitoNEET regulates VDAC in a redox-dependent manner in cells, closing the pore and likely disrupting VDAC’s flow of metabolites.

Original languageAmerican English
Pages (from-to)19924-19929
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume116
Issue number40
DOIs
StatePublished - 1 Oct 2019

Bibliographical note

Publisher Copyright:
© 2019 National Academy of Sciences. All rights reserved.

Keywords

  • CISD1
  • Direct coupling
  • Ferroptosis
  • MitoNEET
  • VDAC1

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