The VDAC2-BAK axis regulates peroxisomal membrane permeability.
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 ofBAKor overexpression of the BAK inhibitors BCL-XLand 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.
Department of Biology, Faculty of Sciences, Kyushu University, Nishi-ku, Fukuoka 819-0395, Japan.|Graduate School of Systems Life Sciences, Kyushu University, Nishi-ku, Fukuoka 819-0395, Japan.
Ken-Ichiro
KI
Hosoi
Department of Biology, Faculty of Sciences, Kyushu University, Nishi-ku, Fukuoka 819-0395, Japan.
Non
0000-0002-5945-909X
N
Miyata
Department of Biology, Faculty of Sciences, Kyushu University, Nishi-ku, Fukuoka 819-0395, Japan.
Satoru
S
Mukai
Department of Biology, Faculty of Sciences, Kyushu University, Nishi-ku, Fukuoka 819-0395, Japan.|Graduate School of Systems Life Sciences, Kyushu University, Nishi-ku, Fukuoka 819-0395, Japan.
Satomi
S
Furuki
Department of Biology, Faculty of Sciences, Kyushu University, Nishi-ku, Fukuoka 819-0395, Japan.|Graduate School of Systems Life Sciences, Kyushu University, Nishi-ku, Fukuoka 819-0395, Japan.
Kanji
K
Okumoto
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065.|Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065.
Emily H
EH
Cheng
Medical Institute of Bioregulation, Kyushu University, Higashi-ku, Fukuoka 812-8582, Japan yfujiki@kyudai.jp.
Yukio
0000-0002-8138-6376
Y
Fujiki
D000818:Animals; D016466:CHO Cells; D002460:Cell Line; D002463:Cell Membrane Permeability / Q000502:physiology*; D006224:Cricetinae; D003412:Cricetulus; D003600:Cytosol / Q000378:metabolism / Q000502:physiology; D008565:Membrane Proteins / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism / Q000502:physiology; D018901:Peroxisomal Disorders / Q000378:metabolism; D020675:Peroxisomes / Q000378:metabolism*; D050996:Voltage-Dependent Anion Channel 2 / Q000378:metabolism*; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000378:metabolism*; D051028:bcl-2-Associated X Protein / Q000378:metabolism
D008565:Membrane Proteins; D050996:Voltage-Dependent Anion Channel 2; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein