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Export of mitochondrial AIF in response to proapoptotic stimuli depends on processing at the intermembrane space
Author(s) -
Otera Hidenori,
Ohsakaya Shigenori,
Nagaura ZenIchiro,
Ishihara Naotada,
Mihara Katsuyoshi
Publication year - 2005
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/sj.emboj.7600614
Subject(s) - intermembrane space , mitochondrial intermembrane space , microbiology and biotechnology , biology , apoptosis inducing factor , cytoplasm , mitochondrion , inner membrane , inner mitochondrial membrane , translocase of the inner membrane , translocase of the outer membrane , apoptosis , programmed cell death , caspase , biochemistry , bacterial outer membrane , atp–adp translocase , mitochondrial membrane transport protein , escherichia coli , gene
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.