Redox-dependent gating of VDAC by mitoNEET

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.

Voltage-Dependent Anion Channels Influence Cytotoxicity of ME-344, a Therapeutic Isoflavone

“…Since HO-1 initiates catabolism of heme and increases cellular iron levels ( Suttner and Dennery, 1999 ), ME-344 binding to both HO-1 and VDACs may imply that it shares some properties with erastin. Interactions between VDAC and mitoNEET, an integral outer mitochondrial iron sulfur cluster protein that can regulate VDAC transport in cancer cells, can be disrupted by agents (e.g., pioglitazone) that target VDAC and is redox-dependent ( Paddock et al, 2007 ; Lipper et al, 2019 ). ME-344 appears to have promiscuous affinity for a number of mitochondrial proteins, inducing apoptosis by disrupting mitochondrial homeostasis and promoting ROS production, loss of ΔΨ m , Bax translocation, and cytochrome c release.…”

Nrf2 and Ferroptosis: A New Research Direction for Neurodegenerative Diseases

“…Voltage-dependent anion channel 1 (VDAC1) is a crucial player in the cross-talk between the mitochondria and the cytosol, and it is regulated by mitoNEET; mitoNEET gates VDAC1 when mitoNEET is oxidized. Further study found that pharmacological inhibition of VDAC1 prevents mitoNEET-dependent mitochondrial iron accumulation in situ (Lipper et al, 2019).…”

Cardiac-specific loss of mitoNEET expression is linked with age-related heart failure

“…Recently, it has been shown that mitoNEET plays a critical role in cytosolic Fe-S cluster repair of iron-regulatory protein-1 14 . MitoNEET can also regulates free iron level within mitochondria by regulating the channel function of voltage-dependent anion channel 1 15 . The systemic inducible knockdown of mitoNEET was found to cause mitochondrial iron overload in adipocytes and liver, and increased iron-mediated mitochondrial lipid peroxidation 16 .…”