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AIF-mediated caspase-independent cell death: molecular mechanisms – AIFCICD

Submission summary

Programmed cell death (PCD) is essential for the development and maintenance of immune cell homeostasis. Aberrations in apoptosis signaling pathways result in a variety of pathological conditions and are common in cancer cells. In fact, cellular changes leading to inhibition of apoptosis play an essential role in tumor development. The elucidation of the apoptotic pathways is thus an important area of study that may provide insight into the causes of drug resistance and facilitate the development of novel anticancer therapies. In mammalian cells, the onset of apoptosis correlates with the activation of a family of cystein proteases called caspases, which are constitutively expressed as inactive zymogens in the cytosol. Caspases constitute a potent machinery that cleaves key proteins of the nucleus and cytoskeleton producing the phenotypic changes of apoptosis, including advanced chromatin condensation and DNA degradation. However, new evidence indicates that cell elimination does not depend only on caspases. In fact, although caspases are absolutely required for the typical apoptotic morphology, the process of caspase activation is not the sole determinant of the life and death decision. Alternative caspase-independent models have therefore been proposed. Since its creation in 2002, our team is devoted to perform an exhaustive work in characterizing both the principal agents involved and the pathways implicated in Apoptosis-Inducing Factor (AIF)-mediated caspase-independent cell death. AIF is a flavoprotein located in the mitochondrial intermembrane space. Under physiological conditions, AIF is a NADH-oxidase which plays a role in oxidative phosphorylation. Moreover, AIF plays a major role in caspase-independent PCD. Indeed, after a cellular insult, AIF translocates from mitochondria to cytosol and nucleus where it causes chromatin condensation and large-scale (~50 kb) DNA fragmentation in a caspase-independent fashion. This apoptogenic function of AIF seems essential in some types of PCD (more than 1000 references in PubMed). Thus, AIF is a bifunctional protein with both a vital role, via its redox activity in mitochondria, and a lethal role, via its translocation to the nucleus. All these data highlight the role of AIF and the caspase-independent death pathway in the control of PCD. Our previous research project on AIF allows to the understanding of the molecular mechanisms regulating its mitochondrial release and to the characterization of two new AIF isoforms (AIFsh and AIFsh2). More recently, we integrated our results into a caspase-independent cell death pathway controlled by AIF: alkylating DNA-damage mediated death. This work confirms that, similarly to apoptosis, caspase-independent AIF-mediated death is a highly regulated form of PCD. Strikingly, this PCD program can be carried out in cells presenting an intact mechanism of apoptotic cell destruction. This implies the existence of a biochemical AIF pathway that could be modulated independently from the classical apoptotic pathway. In this sense, our results on AIF-dependent PCD pave the way for designing new strategies targeting the caspase-independent cell death pathway. The general aim of the research program submitted to ANR is to assess the contribution of AIF to the execution of PCD. As a continuation of our ongoing effort to functionally characterize AIF, we will focus on the identification of factors that interact with AIF after the apoptotic stimulus, on a better description of caspase-independent PCD involving AIF, and in the generation of an AIF transgenic mutant mouse as a model for the study of this type of programmed cell death. We think that the understanding of caspase-independent mechanisms in normal and pathological regulation of apoptosis should provide conceptual progress for therapeutic interventions in deficient or excessive PCD. For example, the analysis of caspase-independent pathways may provide new options to kill tumor cells. In fact, combination of caspase-directed and alternative therapies based on caspase-independent death effectors, offers a more efficient therapeutic approach to circumvent the commonly observed cell death resistance of transformed cells. Additionally, the unraveling of the mechanisms governing alternative caspase-independent cell death pathways will lead to a better comprehension of programmed cell death.

Project coordination

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

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Beginning and duration of the scientific project: - 0 Months

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