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Apoptosis-inducing factor (AIF): key to the conserved caspase-independent pathways of cell death?
Céline Candé1, Francesco Cecconi, Philippe Dessen
1Centre National de la Recherche Scientifique, UMR 1599, Institut Gustave Roussy, 39 rue Camille-Desmoulins, F-94805 Villejuif, France.
Abstract:
Numerous pro-apoptotic signal transducing molecules act on mitochondria and provoke the permeabilization of the outer mitochondrial membrane, thereby triggering the release of potentially toxic mitochondrial proteins. One of these proteins, apoptosis-inducing factor (AIF), is a phylogenetically old flavoprotein which, in healthy cells, is confined to the mitochondrial intermembrane space. Upon lethal signaling, AIF translocates, via the cytosol, to the nucleus where it binds to DNA and provokes caspase-independent chromatin condensation. The crystal structures of both human and mouse AIF have been determined, and the fine mechanisms accounting for its oxidoreductase activity and its electrostatic interaction with double-stranded DNA have been elucidated. Importantly, the apoptogenic and oxidoreductase functions of AIF can be dissociated. Thus, mutations that abolish the AIF-DNA interaction suppress AIF-induced chromatin condensation, yet have no effect on the NADH oxidase activity. Recent studies suggest AIF to be a major factor determining caspase-independent neuronal death, emphasizing the central role of mitochondria in the control of physiological and pathological cell demise.
Insights
Apoptosis-inducing factor (AIF) triggers cell death by translocating to the nucleus and condensing chromatin. Its functions, including oxidoreductase activity and DNA binding, can be separated, highlighting mitochondria
Area of Science:
- Biochemistry
- Cell Biology
- Molecular Biology
Background:
- Pro-apoptotic molecules signal through mitochondria, causing outer membrane permeabilization and release of toxic proteins.
- Apoptosis-inducing factor (AIF) is a mitochondrial protein involved in programmed cell death.
- AIF translocates to the nucleus upon lethal signaling, inducing caspase-independent chromatin condensation.
Purpose of the Study:
- To elucidate the structural and functional mechanisms of apoptosis-inducing factor (AIF).
- To investigate the dissociation of AIF's apoptogenic and oxidoreductase activities.
- To emphasize the role of mitochondria in physiological and pathological cell death.
Main Methods:
- Determination of crystal structures of human and mouse AIF.
- Elucidation of AIF's oxidoreductase activity mechanisms.
- Analysis of AIF's electrostatic interaction with double-stranded DNA.
Main Results:
- Crystal structures reveal mechanisms of AIF's oxidoreductase activity and DNA binding.
- Mutations disrupting AIF-DNA interaction abolish chromatin condensation but not NADH oxidase activity.
- AIF is a key factor in caspase-independent neuronal death.
Conclusions:
- AIF's apoptogenic and oxidoreductase functions are dissociable.
- Mitochondria play a central role in controlling cell death pathways.
- AIF's nuclear functions are critical for initiating chromatin condensation in apoptosis.