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 unclear. Here, we dissociate these dual roles using mitochondrially anchored AIF that cannot be released during apoptosis. Forebrain-specific AIF null (tel. AifDelta) 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. AifDelta 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.
Cheung
Eric C C
EC
Ottawa Health Research Institute, Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada.
Joza
Nicholas
N
Steenaart
Nancy A E
NA
McClellan
Kelly A
KA
Neuspiel
Margaret
M
McNamara
Stephen
S
MacLaurin
Jason G
JG
Rippstein
Peter
P
Park
David S
DS
Shore
Gordon C
GC
McBride
Heidi M
HM
Penninger
Josef M
JM
Slack
Ruth S
RS
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D051033:Apoptosis Inducing Factor / Q000235:genetics / Q000502:physiology*; D002470:Cell Survival; D002478:Cells, Cultured; D004249:DNA Damage; D008564:Membrane Potentials / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D046529:Microscopy, Electron, Transmission; D008928:Mitochondria / Q000502:physiology* / Q000648:ultrastructure; D051336:Mitochondrial Membranes / Q000378:metabolism / Q000648:ultrastructure; D009474:Neurons / Q000502:physiology / Q000648:ultrastructure; D010101:Oxygen Consumption; D016548:Prosencephalon / Q000196:embryology / Q000378:metabolism; D021381:Protein Transport
D051033:Apoptosis Inducing Factor; C494830:AIFM1 protein, mouse; D000255:Adenosine Triphosphate