Dissociating the dual roles of apoptosis-inducing factor in maintaining mitochondrial structure and apoptosis

The mitochondrial protein apoptosis‐inducing factor (AIF) translocates to the nucleus and induces apoptosis. Recent studies, however, have indicated the importance of AIF for survival in mitochondria. In the absence of a means to dissociate these two functions, the precise roles of AIF remain unclea...

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Bibliographic Details
Published in:The EMBO journal 2006-09, Vol.25 (17), p.4061-4073
Main Authors: Cheung, Eric CC, Joza, Nicholas, Steenaart, Nancy AE, McClellan, Kelly A, Neuspiel, Margaret, McNamara, Stephen, MacLaurin, Jason G, Rippstein, Peter, Park, David S, Shore, Gordon C, McBride, Heidi M, Penninger, Josef M, Slack, Ruth S
Format: Article
Language:English
Subjects:
Adenosine Triphosphate - metabolism
Animals
Apoptosis
Apoptosis Inducing Factor - genetics
Apoptosis Inducing Factor - physiology
apoptosis-inducing factor (AIF)
Cell Survival
Cells, Cultured
DNA Damage
Membrane Potentials - physiology
Mice
Mice, Knockout
Microscopy, Electron, Transmission
mitochondria
Mitochondria - physiology
Mitochondria - ultrastructure
Mitochondrial Membranes - metabolism
Mitochondrial Membranes - ultrastructure
Molecular biology
neuron
Neurons
Neurons - physiology
Neurons - ultrastructure
Oxygen Consumption
Prosencephalon - embryology
Prosencephalon - metabolism
Protein Transport
Proteins
Rodents
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Summary:The mitochondrial protein apoptosis‐inducing factor (AIF) translocates to the nucleus and induces apoptosis. Recent studies, however, have indicated the importance of AIF for survival in mitochondria. In the absence of a means to dissociate these two functions, the precise roles of AIF remain unclear. Here, we dissociate these dual roles using mitochondrially anchored AIF that cannot be released during apoptosis. Forebrain‐specific AIF null (tel. AifΔ) mice have defective cortical development and reduced neuronal survival due to defects in mitochondrial respiration. Mitochondria in AIF deficient neurons are fragmented with aberrant cristae, indicating a novel role of AIF in controlling mitochondrial structure. While tel. AifΔ Apaf1−/− neurons remain sensitive to DNA damage, mitochondrially anchored AIF expression in these cells significantly enhanced survival. AIF mutants that cannot translocate into nucleus failed to induce cell death. These results indicate that the proapoptotic role of AIF can be uncoupled from its physiological function. Cell death induced by AIF is through its proapoptotic activity once it is translocated to the nucleus, not due to the loss of AIF from the mitochondria.
ISSN:0261-4189
1460-2075
DOI:10.1038/sj.emboj.7601276