New protein could offer a fresh target for cancer treatment

An international study in the Proceedings of the National Academy of Sciences shows a fascinating new drug target – a cell protein dubbed mitoNEET that determines how materials are transported from the mitochondria to the rest of the cell.

The mitochondria are tiny bean-shaped parts of almost every cell that are responsible for supplying power for all cellular functions – the powerhouses of the cell. They draw out the energy in food molecules and convert it to usable chemical energy. The mitochondria are bounded by inner and outer membrane layers that isolate them from the rest of the cell. These membranes are perforated by multiple pores, formed by specially designed proteins called porins that act like channels.

Among these, the most abundant type is the voltage-dependent anion channel (VDAC) found on the outer mitochondrial membrane (OMM). The VDAC controls mitochondrial respiration, and also carries a whole array of ions and molecules between the mitochondria and the rest of the cell. It is important in degenerative neurologic disorders like Alzheimer’s disease and in regulating apoptosis within the cell. The activity of VDAC can be modulated by mitoNEET’s redox state (that is, whether it is oxidized or reduced).

The regulatory protein mitoNEET is part of the NEET protein family that carries clustered iron-sulfur molecules between various cell destinations. These clusters are evidently involved in regulating redox processes within the cells, that is, chemical reactions that involve the transfer of electrons between various molecules. Such processes are vital in controlling cell functioning via a host of metabolic processes. They have also been found to play a role in a variety of diseases like diabetes, cancer, Parkinson’s disease and cystic fibrosis.

Mitochondrial dysfunction occurs to various extents in each of these conditions, and is mediated by the mitoNEET protein. The mitoNEET protein is attached to the outer mitochondrial surface, in direct connection with the VDAC protein. The affinity of these two proteins is typically low in the normal state when mitoNEET is reduced. However, when mitoNEET is oxidized, as in cancer or cell damage, it binds rapidly and at high rates. This causes VDAC dysfunction in many forms of disease, including cancer.

The VDAC-mitoNEET interaction is important in regulating the opening and closing of the channel. When cells are exposed to oxidative conditions, as in inflammation, infection or cancer, oxidized mitoNEET binds to the VDAC causing these channels to close. This inhibits the transport of important metabolic products like ATP, ADP, pyruvate and fatty acids across the OMM. This, in turn, shuts down mitochondrial fatty acid metabolism, leading to the build-up of fat inside the cell. Alcohol also reduces mitochondrial function by inducing the closure of VDAC, and this reduces ATP production in the mitochondria as well as causing fatty acids to build up.

This could explain why fatty liver disease occurs in conditions related to insulin resistance and chronic drinking, because these conditions also cause oxidative stress. In fact, when the gene responsible for mitoNEET synthesis is absent in one breed of laboratory mice, these mice do not develop fatty liver even when fed with alcohol. Iron influx into the mitochondria also occurs when oxidized mitoNEET binds to the VDAC, causing an iron overload under oxidative stress conditions.

The role of mitoNEET in redox-dependent regulation of cell metabolism is indicated by the presence of the iron-sulfur cluster that is active in oxidation-reduction reactions, its connection with the glutathione antioxidant system, and its known activity in preventing cardiac cell apoptosis via oxidative stress. Thus the redox state of the iron-sulfur clusters switches the mitoNEET on and off, producing very marked changes in the way it interacts with other proteins like VDAC and eventually affecting the functioning of the cell.

Since reactive oxygen species (ROS) like superoxide are primarily provided within the cell by mitochondria, the mitoNEET quickly senses changes in the redox status of the cell and other cytosol processes due to its location on the outer side of the OMM.

"This indicates that the mechanism of interaction is redox-dependent and that targeting of the highly important VDAC complex in diseased states can be fine-tuned.”

Researcher Jose Onuchic

The VDAC-mitoNEET interaction is thus dependent on the iron-redox connection. This discovery provides a central control point that is essential for multiple cell reactions involved in both normal and disease-related cell function. For instance, using a chemical that can alter the redox state near the VDAC-mitoNEET binding site can alter the affinity of the interaction.

The scientists feel confident that it should be possible to discover one or more chemicals to modulate this interaction within cancer cells. This should allow the drug to target multiple cancers.

"Identifying a master point of regulation for these processes that is mediated by the mitoNEET-VDAC interaction is a major step forward in our understanding of these processes.”

Researcher Ron Mittler

Journal reference:

Colin H. Lipper, Jason T. Stofleth, Fang Bai, Yang-Sung Sohn, Susmita Roy, Ron Mittler, Rachel Nechushtai, José N. Onuchic, and Patricia A. Jennings. Redox-dependent gating of VDAC by mitoNEET. PNAS. September 16, 2019. https://doi.org/10.1073/pnas.1908271116.