Cysteine protease inhibition prevents mitochondrial apoptosis-inducing factor (AIF) release (original) (raw)

Cell Death & Differentiation volume 12, pages 1445–1448 (2005)Cite this article

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During the last years, research on the molecular mechanisms governing caspase-dependent and -independent cell death has yielded a significant quantity of exciting works. As part of those efforts, apoptosis-inducing factor (AIF) was the first identified mitochondrial protein involved in caspase-independent cell death.1 Under physiological conditions, AIF is a mitochondrial FAD-dependent oxidoreductase that plays a role in oxidative phosphorylation.2 However, after a cellular insult, AIF is released from mitochondria and translocates to cytosol and nucleus where it achieves its proapoptotic function.1, 3 Importantly, AIF seems a key factor in neuronal cell death4 and is involved in the early stages of development.5 Although alternative studies demonstrate that AIF could also be released in a caspase-dependent manner,6, 7 AIF has been generally implicated in the caspase-independent mode of cell death. In this context, two recent papers from Otera et al.8 and Uren et al.9 demonstrated that AIF is a membrane-integrated protein that needs to be cleaved for becoming a soluble and apoptogenic protein. In fact, Otera et al.8 states that AIF is released from mitochondria by a two-step process. First, AIF is cleaved in the mitochondrial matrix by the mitochondrial processing peptidase to form an inner-membrane-anchored form. In a second step, AIF is processed, by an unidentified protease, in the intermembrane space of mitochondria (IMS) to yield a soluble and proapoptotic protein released to cytosol. But how is AIF cleaved in the IMS? Is it by a caspase? Apparently not. A third study from Polster et al.10 reported that after incubation of isolated mitochondria with different amounts of Ca2+, mitochondrial AIF release occurs through an N-terminal cleavage mediated by the Ca2+-dependent protease calpain I (also called _μ_-calpain). These data provide a critical clue to understanding the regulation of AIF action. However, we here demonstrate that the mechanism governing AIF cleavage in the mitochondrial IMS is more complex than initially expected.

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Acknowledgements

We thank Marika Sarfati and Luigi Ravagnan for critical comments and review of the manuscript. This work was supported by grants from the Association pour la Recherche sur le Cancer (Contract No. 4812), Fondation de France, and the Pasteur-Weizmann Scientific Council (to SAS). VJY was supported by a Marie Curie Intra-European fellowship within the 6th European Community Framework Programme (contract MEIF-2003-501887). CD and PS hold postdoctoral fellowships from Fondation de France and Fondation Manlio Cantarini, respectively. RSM and MB hold PhD fellowships from Fondation Hariri and MENRT, respectively.

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Authors and Affiliations

  1. Apoptose et Système Immunitaire, CNRS-URA 1961, Institut Pasteur 25 rue du Dr Roux, Paris, 75015, France
    V J Yuste, R S Moubarak, C Delettre, M Bras, P Sancho, N Robert & S A Susin
  2. Plate-Forme d'Analyse et de Microséquençage des Protéines, Institut Pasteur, 25 rue du Dr Roux, Paris, 75015, France
    J d'Alayer

Authors

  1. V J Yuste
  2. R S Moubarak
  3. C Delettre
  4. M Bras
  5. P Sancho
  6. N Robert
  7. J d'Alayer
  8. S A Susin

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Correspondence toS A Susin.

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Yuste, V., Moubarak, R., Delettre, C. et al. Cysteine protease inhibition prevents mitochondrial apoptosis-inducing factor (AIF) release.Cell Death Differ 12, 1445–1448 (2005). https://doi.org/10.1038/sj.cdd.4401687

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