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First published online May 20, 2009
doi: 10.1242/10.1242/jcs.040188

Journal of Cell Science 122, 1906-1916 (2009)
Published by The Company of Biologists 2009
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Research Article

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

Salah Abu-Hamad*, Nir Arbel*, Doron Calo, Laetitia Arzoine, Adrian Israelson, Nurit Keinan, Ronit Ben-Romano, Orr Friedman and Varda Shoshan-Barmatz{ddagger}

Department of Life Sciences and the National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva, 84105, Israel

{ddagger} Author for correspondence (e-mail: vardasb{at}bgu.ac.il)

Accepted 26 February 2009

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.

Key words: Apoptosis, Bcl2, hexokinase, mitochondria, VDAC1


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