AIFsh, a Novel Apoptosis-inducing Factor (AIF) Pro-apoptotic Isoform with Potential Pathological Relevance in Human Cancer

Delettre, Cécile; Yuste, Vı́ctor J.; Moubarak, Rana S.; Bras, Marlène; Lesbordes-Brion, Jeanne-Claire; Pêtres, Stéphane; Bellalou, Jacques; Susin, Santos A.

doi:10.1074/jbc.m509884200

Cited by 74 publications

(78 citation statements)

References 51 publications

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“…The C-terminal domain (amino acids 508-612) has become the most captivating part of AIF after recent data confirmed that this region encloses its pro-apoptotic function (8)(9)(10)(11) (Fig. 1).…”

Section: Discussionmentioning

confidence: 99%

AIF‐mediated caspase‐independent necroptosis: A new chance for targeted therapeutics

et al. 2011

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SummaryCell death has been initially divided into apoptosis, in which the cell plays an active role, and necrosis, which is considered a passive cell death program. Intense research performed in the last decades has concluded that ''programmed'' cell death (PCD) is a more complex physiological process than initially thought. Indeed, although in most cases the PCD process is achieved via a family of Cys proteases known as caspases, an important number of regulated PCD pathways do not involve this family of proteases. As a consequence, active forms of PCD are initially referred to as caspase-dependent and caspase-independent. More recent data has revealed that there are also active caspase-independent necrotic pathways defined as necroptosis (programmed necrosis). The existence of necroptotic forms of death was corroborated by the discovery of key executioners such as the kinase RIP1 or the mitochondrial protein apoptosis-inducing factor (AIF). AIF is a Janus protein with a redox activity in the mitochondria and a pro-apoptotic function in the nucleus. We have recently described a particular form of AIF-mediated caspase-independent necroptosis that also implicates other molecules such as PARP-1, calpains, Bax, Bcl-2, histone H2AX, and cyclophilin A. From a therapeutic point of view, the unraveling of this new form of PCD poses a question: is it possible to modulate this necroptotic pathway independently of the classical apoptotic paths? Because the answer is yes, a wider understanding of AIF-mediated necroptosis could theoretically pave the way for the development of new drugs that modulate PCD. To this end, we present here an overview of the current knowledge of AIF and AIF-mediated necroptosis. We also summarize the state of the art in some of the most interesting therapeutic strategies that could target AIF or the AIF-mediated necroptotic pathway.

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Section: Discussionmentioning

confidence: 99%

AIF‐mediated caspase‐independent necroptosis: A new chance for targeted therapeutics

et al. 2011

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“…However, the contribution of AIF to RD-associated photoreceptor apoptosis has remained elusive. Furthermore, novel splice variants of AIF have been reported (21), and the role of AIFsh, a proapoptotic short variant that may be transcriptionally induced after apoptotic insults (22), remains largely unknown.…”

Section: Introductionmentioning

confidence: 99%

HIV protease inhibitors provide neuroprotection through inhibition of mitochondrial apoptosis in mice

et al. 2008

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Neuroprotection can be achieved by preventing apoptotic death of postmitotic cells. Apoptotic death can occur by either a caspase-dependent mechanism, involving cytochrome c, apoptosis protease-activating factor-1 (Apaf-1), and caspase-9, or a caspase-independent mechanism, involving apoptosis-inducing factor (AIF). HIV protease inhibitors (PIs) avert apoptosis in part by preventing mitochondrial outer membrane permeabilization (MOMP), but the precise mechanism by which they work is not known. Here, we evaluated the impact of the PIs in a mouse model of retinal detachment (RD) in vivo and in murine primary retinal cell cultures in vitro. Oral administration of the PIs nelfinavir and ritonavir significantly inhibited photoreceptor apoptosis, while preventing the translocation of AIF from mitochondria to the nucleus as well as the activation of caspase-9. RD-induced photoreceptor apoptosis was similarly inhibited in mice carrying hypomorphic mutations of the genes encoding AIF or Apaf-1. Nelfinavir attenuated apoptosis as well as mitochondrial release of AIF and cytochrome c, and subsequent activation of caspase-9 in vitro, in photoreceptor cultures exposed to starvation or monocyte chemoattractant protein-1-stimulated (MCP-1-stimulated) macrophages. Our results suggest that the MOMP inhibition by PIs involved interruption of both caspase-dependent and caspase-independent apoptosis pathways and that PIs may be clinically useful for the treatment of diseases caused by excessive apoptosis.

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“…25 Both short AIF isoforms appear to be low-abundant in normal tissues because they have not been detected by immunoblot, with the exception of AIFsh2 that reportedly is present in the liver extracts. 24,25 By characterizing the tissue expression profile of AIF isoforms, we discovered that AIF2 is specifically expressed in the CNS. Driven by the pathophysiological effect of AIF in neurodegeneration, 9,11,12 we performed an exhaustive functional and biochemical characterization of the AIF2 isoform and importantly, we found that, compared with AIF1, AIF2 possess a stronger anchoring capacity to the inner mitochondrial membrane.…”

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confidence: 99%

“…The transfection-enforced overexpression of AIFsh results in a nuclear protein that causes apoptosis. 24 Moreover, another short form of AIF, AIFsh2, results from the alternative utilization of exon 9b (instead of 9), which contains a stop codon. AIFsh2 is a truncated protein that lacks the C-terminal pro-apoptotic domain, yet conserves its mitochondrial localization and redox function.…”

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A brain-specific isoform of mitochondrial apoptosis-inducing factor: AIF2

et al. 2010

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Apoptosis-inducing factor (AIF) has important supportive as well as potentially lethal roles in neurons. Under normal physiological conditions, AIF is a vital redox-active mitochondrial enzyme, whereas in pathological situations, it translocates from mitochondria to the nuclei of injured neurons and mediates apoptotic chromatin condensation and cell death. In this study, we reveal the existence of a brain-specific isoform of AIF, AIF2, whose expression increases as neuronal precursor cells differentiate. AIF2 arises from the utilization of the alternative exon 2b, yet uses the same remaining 15 exons as the ubiquitous AIF1 isoform. AIF1 and AIF2 are similarly imported to mitochondria in which they anchor to the inner membrane facing the intermembrane space. However, the mitochondrial inner membrane sorting signal encoded in the exon 2b of AIF2 is more hydrophobic than that of AIF1, indicating a stronger membrane anchorage of AIF2 than AIF1. AIF2 is more difficult to be desorbed from mitochondria than AIF1 on exposure to non-ionic detergents or basic pH. Furthermore, AIF2 dimerizes with AIF1, thereby preventing its release from mitochondria. Conversely, it is conceivable that a neuron-specific AIF isoform, AIF2, may have been 'designed' to be retained in mitochondria and to minimize its potential neurotoxic activity. Apoptosis-inducing factor (AIF) has initially been described as a mitochondrial intermembrane protein that is released from mitochondria under conditions of cell death induction and that can induce isolated nuclei to undergo nuclear shrinkage and chromatinolysis, two features that are classically associated with apoptosis. 1 Since its discovery 10 years ago, the AIF protein has been characterized at the structural level, 2,3 and the AIF gene has been subjected to genetic manipulations in mice, flies, nematodes and yeast, revealing the phylogenetically conserved contribution of AIF to cell death in multiple systems. 4,5 After the mitochondrial import of the precursor AIF protein and the removal of its N-terminal 53 amino acids, which includes a mitochondrial localization sequence (MLS), the processed mature human AIF 62 kDa is inserted into the inner mitochondrial membrane, with the N-terminus facing the matrix and with the C-terminal catalytic domain exposed to the intermembrane space. 6 The mitochondrial AIF protein is an NAD(P)H oxidase 7 whose local redox function is essential for optimal oxidative phosphorylation. 8 Knockdown, deletion or hypomorphic mutation of AIF (the harlequin or Hq mutation) reduces the expression of complex I subunits in the respiratory chain, 8 thereby provoking a mitochondriopathy that leads to progressive neurodegeneration, photoreceptor loss and cardiomyopathy. [9][10][11][12][13] The consistent finding that the targeting of AIF mostly affects the central nervous system (CNS) 9 might either be explained by the general tendency of complex I mitochondriopathies to manifest at the level of the CNS 14 and/or by an implication of AIF in the differentiation of neuronal cell p...

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AIFsh, a Novel Apoptosis-inducing Factor (AIF) Pro-apoptotic Isoform with Potential Pathological Relevance in Human Cancer

Cited by 74 publications

References 51 publications

AIF‐mediated caspase‐independent necroptosis: A new chance for targeted therapeutics

AIF‐mediated caspase‐independent necroptosis: A new chance for targeted therapeutics

HIV protease inhibitors provide neuroprotection through inhibition of mitochondrial apoptosis in mice

A brain-specific isoform of mitochondrial apoptosis-inducing factor: AIF2

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