The VDAC1 N-terminus is essential both for apoptosis and the protective effect of anti-apoptotic proteins

作者：Salah Abu‐Hamad, Nir Arbel, Doron Calo, Laetitia Arzoine, Adrian Israelson, Nurit Keinan, Ronit Ben-Romano, Orr Friedman, Varda Shoshan‐Barmatz · 发表于：Journal of Cell Science · 年份：2009 · DOI：10.1242/jcs.040188 · 被引用次数：233 · 研究领域：Cell death mechanisms and regulation、Mitochondrial Function and Pathology、ATP Synthase and ATPases Research

The release of mitochondrial-intermembrane-space pro-apoptotic proteins, such as cytochrome c, is a key step in initiating apoptosis. Our study addresses two major questions in apoptosis: how are mitochondrial pro-apoptotic proteins released and how is this process regulated? Accumulating evidence indicates that the voltage-dependent anion channel (VDAC) plays a central role in mitochondria-mediated apoptosis. Here, we demonstrate that the N-terminal domain of VDAC1 controls the release of cytochrome c, apoptosis and the regulation of apoptosis by anti-apoptotic proteins such as hexokinase and Bcl2. Cells expressing N-terminal truncated VDAC1 do not release cytochrome c and are resistant to apoptosis, induced by various stimuli. Employing a variety of experimental approaches, we show that hexokinase and Bcl2 confer protection against apoptosis through interaction with the VDAC1 N-terminal region. We also demonstrate that apoptosis induction is associated with VDAC oligomerization. These results show VDAC1 to be a component of the apoptosis machinery and offer new insight into the mechanism of cytochrome c release and how anti-apoptotic proteins regulate apoptosis and promote tumor cell survival.