AIF deficiency compromises oxidative phosphorylation

Vahsen, Nicola; Candé, Céline; Brière, Jean-Jacques; Bénit, Paule; Joza, Nicholas; Larochette, Nathanaël; Mastroberardino, Pier G.; Péquignot, Marie O.; Casares, Noëlia; Lazar, Vladimir; Féraud, Olivier; Debili, Najet; Wissing, Silke; Engelhardt, Silvia; Madeo, Frank; Piacentini, Mauro; Penninger, Josef; Schägger, Hermann; Rustin, Pierre; Kroemer, Guido

doi:10.1038/sj.emboj.7600461

Cited by 562 publications

(534 citation statements)

References 51 publications

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“…Recent studies have suggested that AIF is a central mediator of relevant experimental models of cell death (Corbiere et al, 2004;Kang et al, 2004;Liu et al, 2004a;Cheung et al, 2005;Ishitsuka et al, 2005;Park et al, 2005). However, AIF is a janus protein with a vital role in cells via its redox activity, and a lethal role by participating to chromatinolysis and chromatin condensation once translocated to the nucleus (Lipton and Bossy-Wetzel, 2002;Vahsen et al, 2004). This double activity of AIF may explain why AIF-siRNA failed to completely block cell death in A3D8-treated HEL cells.…”

Section: Discussionmentioning

confidence: 99%

CD44 ligation induces caspase-independent cell death via a novel calpain/AIF pathway in human erythroleukemia cells

et al. 2006

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Ligation of the cell surface molecule CD44 by anti-CD44 monoclonal antibodies (mAbs) has been shown to induce cell differentiation, cell growth inhibition and in some cases, apoptosis in myeloid leukemic cells. We report, herein, that exposure of human erythroleukemic HEL cells to the anti-CD44 mAb A3D8 resulted in cell growth inhibition followed by caspase-independent apoptosis-like cell death. This process was associated with the disruption of mitochondrial membrane potential (DWm), the mitochondrial release of apoptosis-inducing factor (AIF), but not of cytochrome c, and the nuclear translocation of AIF. All these effects including cell death, loss of mitochondrial DWm and AIF release were blocked by pretreatment with the poly (ADP-ribose) polymerase inhibitor isoquinoline. A significant protection against cell death was also observed by using small interfering RNA for AIF. Moreover, we show that calpain protease was activated before the appearance of apoptosis, and that calpain inhibitors or transfection of calpain-siRNA decrease A3D8-induced cell death, and block AIF release. These data suggest that CD44 ligation triggers a novel caspaseindependent cell death pathway via calpain-dependent AIF release in erythroleukemic HEL cells.

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Section: Discussionmentioning

confidence: 99%

CD44 ligation induces caspase-independent cell death via a novel calpain/AIF pathway in human erythroleukemia cells

et al. 2006

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“…L Galluzzi et al glutathione levels (Cande et al, 2004b) and allows for optimal assembly or maintenance of respiratory chain complexes I and III (Vahsen et al, 2004). Upon apoptosis induction, AIF translocates to the nucleus where it contributes to chromatin condensation via a direct interaction with DNA (Ye et al, 2002;Vahsen et al, 2006) and recruits other proteins into the 'degradosome', which mediates chromatinolysis Cande et al, 2004a).…”

Section: Chemotherapy and Mitochondriamentioning

confidence: 99%

Mitochondria as therapeutic targets for cancer chemotherapy

et al. 2006

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Mitochondria are vital for cellular bioenergetics and play a central role in determining the point-of-no-return of the apoptotic process. As a consequence, mitochondria exert a dual function in carcinogenesis. Cancer-associated changes in cellular metabolism (the Warburg effect) influence mitochondrial function, and the invalidation of apoptosis is linked to an inhibition of mitochondrial outer membrane permeabilization (MOMP). On theoretical grounds, it is tempting to develop specific therapeutic interventions that target the mitochondrial Achilles' heel, rendering cancer cells metabolically unviable or subverting endogenous MOMP inhibitors. A variety of experimental therapeutic agents can directly target mitochondria, causing apoptosis induction. This applies to a heterogeneous collection of chemically unrelated compounds including positively charged a-helical peptides, agents designed to mimic the Bcl-2 homology domain 3 of Bcl-2-like proteins, ampholytic cations, metals and steroid-like compounds. Such MOMP inducers or facilitators can induce apoptosis by themselves (monotherapy) or facilitate apoptosis induction in combination therapies, bypassing chemoresistance against DNA-damaging agents. In addition, it is possible to design molecules that neutralize inhibitor of apoptosis proteins (IAPs) or heat shock protein 70 (HSP70). Such IAP or HSP70 inhibitors can mimic the action of mitochondrion-derived mediators (Smac/DIABLO, that is, second mitochondria-derived activator of caspases/direct inhibitor of apoptosis-binding protein with a low isoelectric point, in the case of IAPs; AIF, that is apoptosis-inducing factor, in the case of HSP70) and exert potent chemosensitizing effects.

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“…Hence increase in nNOS activity is moderate and less ROS is produced role in mitochondria. AIF deficient cells emphasize the importance of AIF in maintaining mitochondrial function since these cells exhibit a loss of complex 1 stability and activity, and disruption of oxidative phosphorylation [143,144]. In order to separate the function of the mitochondrial AIF from the nuclear functions of AIF during cell death, we constructed anchored AIF mutants which are anchored in the inner membrane of mitochondria and cannot be released during apoptosis.…”

Section: Mitochondrial Cristae Structure and Cell Death: Demolition Fmentioning

confidence: 99%

Mitochondrial dynamics in the regulation of neuronal cell death

2007

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Mitochondria undergo continuous fission and fusion events in physiological situations. Fragmentation of mitochondria during cell death has been shown to play a key role in cell death progression, including release of the mitochondrial apoptotic proteins. Ultrastructural changes in mitochondria, such as cristae remodeling, is also involved in cell death initiation. Here, we emphasize the important role of mitochondrial fission/fusion machinery in neuronal cell death. Unlike many other cell types such as immortalized cell lines, neurons are distinct morphologically and functionally. We will discuss how this uniqueness presents special challenges in the cellular response to neurotoxic stresses, and how this affects the mitochondrial dynamics in the regulation of cell death in neurons.

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AIF deficiency compromises oxidative phosphorylation

Cited by 562 publications

References 51 publications

CD44 ligation induces caspase-independent cell death via a novel calpain/AIF pathway in human erythroleukemia cells

CD44 ligation induces caspase-independent cell death via a novel calpain/AIF pathway in human erythroleukemia cells

Mitochondria as therapeutic targets for cancer chemotherapy

Mitochondrial dynamics in the regulation of neuronal cell death

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