Export of mitochondrial AIF in response to proapoptotic stimuli depends on processing at the intermembrane space

Hidenori Otera, Shigenori Ohsakaya, Zen Ichiro Nagaura, Naotada Ishihara, Katsuyoshi Mihara

Research output: Contribution to journalArticle

256 Citations (Scopus)


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 Bel-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.

Original languageEnglish
Pages (from-to)1375-1386
Number of pages12
JournalEMBO Journal
Issue number7
Publication statusPublished - Apr 6 2005


All Science Journal Classification (ASJC) codes

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

Cite this