The porin VDAC2 is the mitochondrial platform for Bax retrotranslocation

• Published in: Scientific reports Vol. 6; no. 1; p. 32994
• Main Authors: Lauterwasser, Joachim, Todt, Franziska, Zerbes, Ralf M., Nguyen, Thanh Ngoc, Craigen, William, Lazarou, Michael, van der Laan, Martin, Edlich, Frank
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 13-09-2016; Nature Publishing Group
• Subjects: 631/80/2023/2022; 631/80/82/23; Apoptosis; BAX protein; Bcl protein; Bcl-2 protein; Calcium; Cytosol; Humanities and Social Sciences; Ions; Membranes; Mitochondria; multidisciplinary; Nucleotides; Science; Translocation
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep32994

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.