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

Abstract

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.

Mitochondrial dynamics in the regulation of neuronal cell death

“…While excitotoxic cell death also converges on mitochondria, the upstream signalling events are quite distinct. We and others have shown that this mode of cell death occurs independent of Bax/Bak because deletion of these proteins does not affect the rate of cell death [8][9][10]. During acute brain injury such as stroke, oxygen levels are reduced, which leads to an abrupt decrease in ATP production and rapid depolarization of the plasma membrane which occurs early after the ischemic insult in stroke.…”

“…Apart from the apoptotic role of AIF following its release and translocation to the nucleus [3,[139][140][141][142], AIF also has a physiological Fig. 4 During excitotoxicity, elongated mitochondria along the neurite and at the synapse can buffer Ca 2+ more effectively than fragmented mitochondria.…”

“…Although the maintenance of AIF within the mitochondria delayed MOMP in the null background, the apoptotic role of AIF in the nucleus is, however, still a very important aspect of AIF function during cell death. In neurons that have the endogenous pool of AIF that can be translocated to the nucleus, the presence of mitochondrial anchored AIF does not delay cytochrome C release and inhibit cell death at longer time points, indicating that AIF is still an important factor in neuronal apoptosis following its release and translocation to the nucleus [142]. In conclusion, these results show that apart from Bax/Bak control of the release of apoptotic factors, mitochondrial itself can also control the release of cytochrome c by remodeling the cristae utilizing its own intermembrane space proteins such as Opa1 and AIF.…”

Autophagy is involved in cytotoxic effects of crotoxin in human breast cancer cell line MCF-7 cells

“…Some studies found that caspase-3-mediated events appeared to be dispensable in determining the overall killing of cells, since 50 kb DNA fragments, chromatin condensation, Rb, gelsolin, and poly (ADP-ribose) polymerase (PARP) cleavage also occurred in caspase-3-deficient MCF-7 cells [19][20][21] . When caspase-3 has no contribution to cell death, cells can still die apoptotically by non caspase-3-dependent or caspase-independent mechanisms due to the activation of other effective caspases or the nuclear translocation of AIF [22] .…”

Mitochondria and the central nervous system: searching for a pathophysiological basis of psychiatric disorders

“…5 This is similar to AIF and HtrA2, which could impair mitochondrial function when released into the cytosol. 31,32 In addition, studies have shown that mitochondria can themselves release controlled amounts of cytochrome c, Smac, HtrA2, and AIF, by a still-unclear mechanism. 33,34 Inhibitors of caspase -1 and -3 modify LTP of synaptic transmission in hippocampal synapses, 35,36 indicating functions for apoptotic cascades in synaptic plasticity.…”