The porin VDAC2 is the mitochondrial platform for Bax retrotranslocation.
The pro-apoptotic Bcl-2 protein Bax can permeabilize the outer mitochondrial membrane and therefore commit human cells to apoptosis. Bax is regulated by constant translocation to the mitochondria and retrotranslocation back into the cytosol. Bax retrotranslocation depends on pro-survival Bcl-2 proteins and stabilizes inactive Bax. Here we show that Bax retrotranslocation shuttles membrane-associated and membrane-integral Bax from isolated mitochondria. We further discover the mitochondrial porin voltage-dependent anion channel 2 (VDAC2) as essential component and platform for Bax retrotranslocation. VDAC2 ensures mitochondria-specific membrane association of Bax and in the absence of VDAC2 Bax localizes towards other cell compartments. Bax retrotranslocation is also regulated by nucleotides and calcium ions, suggesting a potential role of the transport of these ions through VDAC2 in Bax retrotranslocation. Together, our results reveal the unanticipated bifunctional role of VDAC2 to target Bax specifically to the mitochondria and ensure Bax inhibition by retrotranslocation into the cytosol.
Institute for Biochemistry and Molecular Biology, ZBMZ, Faculty of Medicine, University of Freiburg, 79104 Freiburg, Germany.|Faculty of Biology, University of Freiburg, 79104 Freiburg, Germany.
Joachim
J
Lauterwasser
Institute for Biochemistry and Molecular Biology, ZBMZ, Faculty of Medicine, University of Freiburg, 79104 Freiburg, Germany.|Spemann Graduate School of Biology and Medicine, SGBM, 79104 Freiburg, Germany.
Franziska
F
Todt
Institute for Biochemistry and Molecular Biology, ZBMZ, Faculty of Medicine, University of Freiburg, 79104 Freiburg, Germany.|Faculty of Biology, University of Freiburg, 79104 Freiburg, Germany.
Ralf M
RM
Zerbes
Department of Biochemistry and Molecular Biology, Monash University, Clayton, Melbourne, Australia.
Thanh Ngoc
TN
Nguyen
Department of Pediatric Medicine, Genetics, Texas Children's Hospital, Houston, TX 77030, USA.
William
W
Craigen
Department of Biochemistry and Molecular Biology, Monash University, Clayton, Melbourne, Australia.
Michael
M
Lazarou
Institute for Biochemistry and Molecular Biology, ZBMZ, Faculty of Medicine, University of Freiburg, 79104 Freiburg, Germany.|Medical Biochemistry and Molecular Biology, Saarland University, D-66421 Homburg, Germany.|BIOSS, Centre for Biological Signaling Studies, University of Freiburg, 79104 Freiburg, Germany.
Martin
M
van der Laan
Institute for Biochemistry and Molecular Biology, ZBMZ, Faculty of Medicine, University of Freiburg, 79104 Freiburg, Germany.|BIOSS, Centre for Biological Signaling Studies, University of Freiburg, 79104 Freiburg, Germany.
Frank
F
Edlich
D017209:Apoptosis; D002413:Cations, Divalent / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D055786:Gene Knockout Techniques; D045325:HCT116 Cells; D006801:Humans; D008928:Mitochondria / Q000378:metabolism*; D051336:Mitochondrial Membranes / Q000378:metabolism; D008954:Models, Biological; D009711:Nucleotides / Q000378:metabolism; D021381:Protein Transport; D050996:Voltage-Dependent Anion Channel 2 / Q000378:metabolism*; D051028:bcl-2-Associated X Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
C494826:BAX protein, human; D002413:Cations, Divalent; D009711:Nucleotides; C494765:VDAC2 protein, human; D050996:Voltage-Dependent Anion Channel 2; D051028:bcl-2-Associated X Protein