VDAC2

VDAC2 encodes a mitochondrial outer-membrane voltage-dependent anion channel and supports isoform-specific regulation of mitochondrial structure, metabolite exchange, and cell-death signaling^[1]. Mechanistically, VDAC2 binds BAK and restrains BAK activation, thereby limiting mitochondrial apoptosis in viable cells^[2]. In tBID-triggered apoptosis, however, VDAC2 recruits BAK to mitochondria, and defined VDAC2 motifs are required for BAK import and tBID-induced mitochondrial apoptosis^[3][4]. VDAC2 also enables efficient BAX-mediated apoptosis and limits tumor development, distinguishing BAX regulation from BAK regulation at the mitochondrial outer membrane^[5]. In ferroptosis models, Nedd4 ubiquitylates VDAC2/3 to suppress erastin-induced ferroptosis in melanoma, while VDAC2 and VDAC3 together facilitate erastin-induced ferroptotic cell death^[6]. In tumor-immunity models, VDAC2 loss sensitizes tumor cells to IFNγ-induced mitochondrial DNA release, cGAS-STING activation, tumor destruction, and inflammatory remodeling^[7]. Compared with related isoforms, VDAC2 shows a distinct apoptosis role: it is required for efficient BAX-mediated apoptosis but inhibits BAK-mediated apoptosis^[5]. For experimental applications, WEHI-9625 binds VDAC2 and stabilizes the BAK-VDAC2 interaction to block mouse BAK-driven apoptosis^[8].