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| Subject Categories: Membranes & Transport | Differentiation & Death |
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| The EMBO Journal
(2005) 24, 1375–1386, doi:10.1038/sj.emboj.7600614 Published online 17 March 2005 |
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| Export of mitochondrial AIF in response to proapoptotic stimuli depends on processing at the intermembrane space |
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| Hidenori Otera, Shigenori Ohsakaya, Zen-Ichiro Nagaura, Naotada Ishihara and Katsuyoshi Mihara |
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Department of Molecular Biology, Graduate School of Medical Science, Kyushu University, Fukuoka, Japan To whom correspondence should be addressed 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; Published online 17 March 2005. |
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| Abstract |
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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. |
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| Keywords: AIF, apoptosis, mitochondria, protein export, protein import |
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Top of page MORE ARTICLES LIKE THISThese links to content published by NPG are automatically generated RESEARCHThe EMBO Journal Article (01 Sep 2003) The EMBO Journal Article (01 Sep 2003) Regulation of mitochondrial morphology through proteolytic cleavage of OPA1 The EMBO Journal Article (12 Jul 2006) |
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