Mitochondrio‐nuclear translocation of AIF in apoptosis and necrosis

  title={Mitochondrio‐nuclear translocation of AIF in apoptosis and necrosis},
  author={Eric Daugas and Santos A. Susin and Naoufal Zamzami and Karine F. Ferri and Theano Irinopoulou and Nathanael Larochette and Marie-Christine Prevost and Brian F. Leber and David William Andrews and Josef M. Penninger and Guido Kroemer},
  journal={The FASEB Journal},
  pages={729 - 739}
Apoptosis inducing factor (AIF) is a novel apoptotic effector protein that induces chro‐matin condensation and large‐scale (—50 kbp) DNA fragmentation when added to purified nuclei in vitro. Confocal and electron microscopy reveal that, in normal cells, AIF is strictly confined to mitochondria and thus colocalizes with heat shock protein 60 (hsp60). On induction of apoptosis by staurosporin, c‐Myc, etoposide, or ceramide, AIF (but not hsp60) translocates to the nucleus. This suggests that only… 

Apoptosis-inducing factor (AIF): key to the conserved caspase-independent pathways of cell death?

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, indicating the central role of mitochondria in the control of physiological and pathological cell demise.

Dominant cell death induction by extramitochondrially targeted apoptosis‐inducing factor

  • M. LoefflerE. Daugas G. Kroemer
  • Biology
    FASEB journal : official publication of the Federation of American Societies for Experimental Biology
  • 2001
Extramitochondrially targeted AIF is a dominant cell death inducer and can favor permeabilization of the outer mitochondrial membrane.

HSP72 inhibits apoptosis-inducing factor release in ATP-depleted renal epithelial cells.

It is suggested that mitochondrial membrane injury and subsequent AIF release contribute to nuclear injury and apoptosis in ATP-depleted renal cells and selective overexpression of human HSP72 reduced the leakage of mitochondrial AIF in a dose-dependent manner.

Nuclear translocation of endonuclease G and apoptosis-inducing factor during acetaminophen-induced liver cell injury.

The data support the conclusion that endonuclease G and AIF translocate to the nucleus in response to AAP-induced mitochondrial dysfunction and may be responsible, at least in part, for the initial DNA fragmentation during AAP hepatotoxicity.

NADH Oxidase Activity of Mitochondrial Apoptosis-inducing Factor*

Biochemical characterization of AIF's redox activity indicates that AIF has a marked oxidoreductase activity which can be dissociated from its apoptosis-inducing function.

Distinct hsp70 Domains Mediate Apoptosis-inducing Factor Release and Nuclear Accumulation*

It is demonstrated that mitochondrial protection against bax-mediated injury requires both intact chaperone and ATPase functions, whereas the ATPase domain is critical for sequestering leaked AIF in the cytosol.

Possible contribution of apoptosis‐inducing factor (AIF) and reactive oxygen species (ROS) to UVB‐induced caspase‐independent cell death in the T cell line Jurkat

It is suggested that caspase‐dependent and ‐independent pathways were involved in UVB‐induced cell death in Jurkat cells, and the mitochondrio‐nuclear translocation of AIF was associated with the latter pathway.

Steroid Receptor Coactivator-interacting Protein (SIP) Inhibits Caspase-independent Apoptosis by Preventing Apoptosis-inducing Factor (AIF) from Being Released from Mitochondria*

It is reported that steroid receptor coactivator-interacting protein (SIP) interacts directly with AIF in mitochondria and specifically inhibits caspase-independent and AIF-dependent apoptosis.



Molecular characterization of mitochondrial apoptosis-inducing factor

The identification and cloning of an apoptosis-inducing factor, AIF, which is sufficient to induce apoptosis of isolated nuclei is reported, indicating that AIF is a mitochondrial effector of apoptotic cell death.

Bcl-2 inhibits the mitochondrial release of an apoptogenic protease

It is shown that mitochondria contain a pre-formed approximately 50-kD protein which is released upon delta psi m disruption and which, in a cell-free in vitro system, causes isolated nuclei to undergo apoptotic changes such as chromatin condensation and internucleosomal DNA fragmentation, and the effect of Bcl-2 on the formation, release, and action of AIF.

The apoptosis-necrosis paradox. Apoptogenic proteases activated after mitochondrial permeability transition determine the mode of cell death

Electron microscopic analysis confirms that cells treated with PT inducers alone undergo apoptosis, whereas cells kept in identical conditions in the presence of Z-VAD.fmk die from necrosis, compatible with the hypothesis that PT would be a rate limiting step in both the apoptotic and the necrotic modes of cell death.

Enforced dimerization of BAX results in its translocation, mitochondrial dysfunction and apoptosis

It is demonstrated that a physiologic death stimulus, the withdrawal of interleukin‐3 (IL‐3), resulted in the translocation of monomeric BAX from the cytosol to the mitochondria where it could be cross‐linked as a BAX homodimer and enforced dimerization of BAX overrode the protection by BCL‐XL and IL‐3 to kill cells.

Mitochondrial control of nuclear apoptosis

Direct evidence is presented indicating that mitochondrial PT constitutes a critical early event of the apoptotic process, and a specific ligand of the mitochondrial adenine nucleotide translocator, bongkreik acid, inhibits PT and reduces apoptosis induction by mitochondria in a cell-free system.

Cleavage of CAD inhibitor in CAD activation and DNA degradation during apoptosis

The results indicate that activation of CAD downstream of the caspase cascade is responsible for internucleosomal DNA degradation during apoptosis, and that ICAD works as an inhibitor of this process.

The Permeability Transition Pore Complex: A Target for Apoptosis Regulation by Caspases and Bcl-2–related Proteins

It is shown that PT pore complexes reconstituted in liposomes exhibit a functional behavior comparable with that of the naturalPT pore present in intact mitochondria.

Bax and adenine nucleotide translocator cooperate in the mitochondrial control of apoptosis.

The proapoptotic molecule Bax and the constitutive mitochondrial protein ANT cooperate within the PTPC to increase mitochondrial membrane permeability and to trigger cell death.

Bcl-2 family proteins regulate the release of apoptogenic cytochrome c by the mitochondrial channel VDAC

The results indicate that the Bcl-2 family of proteins bind to the VDAC in order to regulate the mitochondrial membrane potential and the release of cytochrome c during apoptosis.

Bax directly induces release of cytochrome c from isolated mitochondria.

It is shown that addition of submicromolar amounts of recombinant Bax protein to isolated mitochondria can induce cytochrome c (Cyt c) release, whereas a peptide representing the Bax BH3 domain was inactive, implying that Bax uses an alternative mechanism for triggering release of Cyt c from mitochondria.