The VDAC2-BAK axis regulates peroxisomal membrane permeability

• Published in: The Journal of cell biology Vol. 216; no. 3; pp. 709 - 722
• Main Authors: Hosoi, Ken-Ichiro, Miyata, Non, Mukai, Satoru, Furuki, Satomi, Okumoto, Kanji, Cheng, Emily H, Fujiki, Yukio
• Format: Journal Article
• Language: English
• Published: United States Rockefeller University Press 06.03.2017; The Rockefeller University Press
• Subjects: Animals; bcl-2 Homologous Antagonist-Killer Protein - metabolism; bcl-2-Associated X Protein - metabolism; Biosynthesis; Cell Line; Cell Membrane Permeability - physiology; Cellular biology; CHO Cells; Cricetinae; Cricetulus; Cytosol - metabolism; Cytosol - physiology; Genetic disorders; Membrane Proteins - metabolism; Membranes; Mitochondria; Mitochondria - metabolism; Mitochondria - physiology; Permeability; Peroxisomal Disorders - metabolism; Peroxisomes - metabolism; Protein expression; Voltage-Dependent Anion Channel 2 - metabolism
• ISSN: 0021-9525; 1540-8140
• DOI: 10.1083/jcb.201605002

Peroxisomal biogenesis disorders (PBDs) are fatal genetic diseases consisting of 14 complementation groups (CGs). We previously isolated a peroxisome-deficient Chinese hamster ovary cell mutant, ZP114, which belongs to none of these CGs. Using a functional screening strategy, VDAC2 was identified as rescuing the peroxisomal deficiency of ZP114 where VDAC2 expression was not detected. Interestingly, knockdown of or overexpression of the BAK inhibitors BCL-X and MCL-1 restored peroxisomal biogenesis in ZP114 cells. Although VDAC2 is not localized to the peroxisome, loss of VDAC2 shifts the localization of BAK from mitochondria to peroxisomes, resulting in peroxisomal deficiency. Introduction of peroxisome-targeted BAK harboring the Pex26p transmembrane region into wild-type cells resulted in the release of peroxisomal matrix proteins to cytosol. Moreover, overexpression of BAK activators PUMA and BIM permeabilized peroxisomes in a BAK-dependent manner. Collectively, these findings suggest that BAK plays a role in peroxisomal permeability, similar to mitochondrial outer membrane permeabilization.