Article
- The EMBO Journal (2005) 24, 1375 - 1386
- doi:10.1038/sj.emboj.7600614
Published online: 17 March 2005
Subject Categories:
Export of mitochondrial AIF in response to proapoptotic stimuli depends on processing at the intermembrane space
Hidenori Otera1, Shigenori Ohsakaya1, Zen-Ichiro Nagaura1, Naotada Ishihara1 and Katsuyoshi Mihara1
- Department of Molecular Biology, Graduate School of Medical Science, Kyushu University, Fukuoka, Japan
Correspondence to:
Katsuyoshi Mihara, Department of Molecular Biology, Graduate School of Medical Science, Kyushu University, Fukuoka 812-8582, Japan. Tel.: +81 92 642 6176; Fax: +81 92 642 6183; E-mail: mihara@cell.med.kyushu-u.ac.jp
Received 22 November 2004; Accepted 10 February 2005
Abstract
Apoptosis-inducing factor (AIF) is a mitochondrial intermembrane flavoprotein that is translocated to the nucleus in response to proapoptotic stimuli, where it induces nuclear apoptosis. Here we show that AIF is synthesized as an 
67-kDa preprotein with an N-terminal extension and imported into mitochondria, where it is processed to the 62-kDa mature form. Topology analysis revealed that mature AIF is a type-I inner membrane protein with the N-terminus exposed to the matrix and the C-terminal portion to the intermembrane space. Upon induction of apoptosis, processing of mature AIF to an 57-kDa form occurred caspase-independently in the intermembrane space, releasing the processed form into the cytoplasm. Bcl-2 or Bcl-XL inhibited both these events. These findings indicate that AIF release from mitochondria occurs by a two-step process: detachment from the inner membrane by apoptosis-induced processing in the intermembrane space and translocation into the cytoplasm. The results also suggest the presence of a unique protease that is regulated by proapoptotic stimuli in caspase-independent cell death.
Keywords:
- AIF,
- apoptosis,
- mitochondria,
- protein export,
- protein import
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