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.

A lower affinity to cytosolic proteins reveals VDAC3 isoform-specific role in mitochondrial biology

“…VDAC is the primary transport channel in the MOM, controlling mitochondria permeability and function. The vast majority of studies involving VDAC in a wide variety of mitochondria-associated pathologies focuses exclusively on VDAC1 or VDAC2, while VDAC3 channels remain poorly characterized (Shoshan-Barmatz and Ben-Hail, 2012; Reina et al, 2016b; Camara et al, 2017; Maurya and Mahalakshmi, 2017; Shoshan-Barmatz et al, 2017). The main reason for this discrepancy stems from the difficulty in obtaining stable and homogeneous VDAC3 samples for insertions in PLM, and thus the lack of quantitative in vitro characterization.…”

“…In particular, Okazaki et al (2015) required reducing agents to observe proper VDAC3 gating. Similarly, the oxidation state of cysteines was found to be important for the insertion and activity of VDAC3 samples (Reina et al, 2016b). It must be pointed out that in these previous works, any reducing agent was avoided during purification and reconstitution steps, with the purpose of not altering the naturally occurring oxidation state of cysteines (Reina et al, 2016a; Saletti et al, 2017).…”

Novel Channels of the Outer Membrane of Mitochondria: Recent Discoveries Change Our View

“…Another exciting possibility regarding regulation of the newly identified channels is that, similarly to VDACs, their activity depends on the oxidation state of the protein itself . Recent studies highlighted the role of cysteine oxidation in determining the pore size of the VDAC3 porin isoform, proposing that effective metabolite flux across these huge pores might be linked to the redox state in the intermembrane space of mitochondria.…”

Cysteine residues in mitochondrial intermembrane space proteins: more than just import

“…For example, induction of ROS production by incubation of mitochondria, isolated from rat hearts, with the complex III inhibitor antimycin A, which results in O 2 ° − release to the IMS, led to oxidation of cysteines in IMS proteins such as TIMM50, VDAC3, OPA1 and AK2 (Bleier et al ., ). Oxidative modifications on VDAC3 but also VDAC2 were also reported by other studies (De Pinto et al ., ; Reina et al ., ). A different study characterizing IMS proteins as H 2 O 2 targets in yeast mitochondria identified IMS proteins such as Pet191 and cytochrome b 2 (Topf et al ., ).…”