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Redox-dependent gating of VDAC by mitoNEET.

Proc. Natl. Acad. Sci. U.S.A.2019 Oct 01;116(40):19924-19929. Epub 2019 Sep 16
Colin H Lipper 1 , Jason T Stofleth 1 , Fang Bai 2 , Yang-Sung Sohn 3 , Susmita Roy 2 , Ron Mittler 4 , Rachel Nechushtai 5 , José N Onuchic 2 , Patricia A Jennings 6
Colin H Lipper 1 , Jason T Stofleth 1 , Fang Bai 2 , Yang-Sung Sohn 3 , Susmita Roy 2 , Ron Mittler 4 , Rachel Nechushtai 5 , José N Onuchic 2 , Patricia A Jennings 6
+ et al

[No authors listed]

Author information
  • 1 Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, CA 92093-0375.
  • 2 Department of Biosciences, Rice University, Houston, TX 77005.
  • 3 Department of Chemistry, Rice University, Houston, TX 77005.
  • 4 Christopher S. Bond Life Sciences Center, University of Missouri, Columbia, MO 65201.
  • 5 The Alexander Silberman Institute of Life Science, The Hebrew University of Jerusalem, Jerusalem 91904, Israel.
  • 6 Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, CA 92093-0375; jonuchic@rice.edu pajennings@ucsd.edu.

摘要


MitoNEET is an outer mitochondrial membrane protein essential for sensing and regulation of iron and reactive oxygen species 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, 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.

KEYWORDS: CISD1, VDAC1, direct coupling, ferroptosis, mitoNEET