Export of Mitochondrial AIF in Response to Proapoptotic Stimuli Depends on Processing at the Intermembrane Space

Overview

Journal EMBO J

Specialties Biotechnology
Molecular Biology

Date 2005 Mar 19

PMID 15775970

Citations 128

Authors

Hidenori Otera

Shigenori Ohsakaya

Zen-ichiro Nagaura

Naotada Ishihara

Katsuyoshi Mihara

Affiliations

Soon will be listed here.

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 approximately 67-kDa preprotein with an N-terminal extension and imported into mitochondria, where it is processed to the approximately 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 approximately 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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