VDAC3 As a Potential Marker of Mitochondrial Status Is Involved in Cancer and Pathology

Abstract

VDAC3 is the least known isoform of the mammalian voltage-dependent anion selective channels of the outer mitochondrial membrane. It has been recently shown that cysteine residues of VDAC3 are found over-oxidized. The VDAC3 cysteine over-oxidation was associated with the oxidizing environment and the abundance of reactive oxygen species (ROS) in the intermembrane space. In this work, we have examined the role of VDAC3 in general pathogenic mechanisms at the basis of mitochondrial dysfunction and involving the mitochondrial quality control. Many of the diseases reported here, including cancer and viral infections, are often associated with significant changes in the intracellular redox state. In this sense, VDAC3 bearing oxidative modifications could become marker of the oxidative load in the mitochondria and part of the ROS signaling pathway.

Keywords: VDAC3; aging; cancer; cysteine over-oxidation; mitochondria quality control; mitochondrial dysfunction; mitophagy.

Figure 1

Multi-alignment of human mammalian voltage-dependent anion selective channel (VDAC) isoforms. The multi-alignment, obtained by the Clustal-X software, reports as a pink box the N-terminal sequence of VDAC1, in mauve the sequences forming the 19 β-strands, and in pale green the sequences corresponding to cytosol-exposed loops. The non-colored sequences correspond to the intermembrane-exposed turns (intermembrane space, IMS). The strands localization refers to the structure reported in Ref. (19), while the assignment of IMS or cytosolic loops follows the paper by Tomasello et al. (26). Cysteine residues of VDAC2 and VDAC3 are in red and outlined in yellow, and the red arrows show those cysteine residues protruding in the intermembrane space.

Figure 2

Proposed model of mitochondrial reactive oxygen species (ROS) and VDAC3 cysteine residues interaction. Little amounts of ROS oxidize some VDAC3 cysteines that protrude toward the mitochondrial intermembrane space up to sulfinic and sulfonic oxidation states. In addition to a conformational change in the protein, such irreversible modifications recruit the PINK/Parkin system that in turn ubiquitinates VDAC3. This step, followed by the proteasome degradation of the ubiquitinated protein, is preliminary to the mitochondrial quality control (upper panel). The progressive accumulation of ROS, due to mitochondrial stress, increases the amount of oxidized cysteines in VDAC3. This phenomenon stimulates the incorporation of single damaged proteins, or membrane patches containing damaged proteins, into mitochondria-derived vesicles, subsequently targeted to lysosomes (middle panel). When the ROS level reaches a maximum threshold, almost all VDAC3 proteins of the outer mitochondrial membrane become heavily modified by irreversible oxidations. Conformational changes derived from these modifications signal the redox state of the mitochondria to the rest of the cell. Damaged, reactive oxygen species-producing mitochondria are therefore removed through mitophagy (lower panel).

Figure 3

Involvement of VDAC3 in cancer. The anti-tumor agent erastin induces rapid, oxidative, non-apoptotic death in human tumor cells that have mutations in the oncogenes HRAS, KRAS, or BRAF. On the outer mitochondrial membrane, erastin binds VDAC2 and VDAC3 but is not able to interact with VDAC1. After erastin treatment, VDAC2 and VDAC3 expression is strongly reduced, while VDAC1 is still present at later time points (left panel). Dimeric αβ-tubulin is able to inhibit VDAC1 and VDAC2 conductance more than VDAC3 ones. This interaction suppresses mitochondrial respiration and contributes to the establishment of the Warburg metabolism in tumor cells. Erastin prevents and reverses tubulin-induced voltage-dependent anion selective channel blockage and promotes mitochondrial metabolism (right panel).