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

Yuste, Vı́ctor J.; Moubarak, Rana S.; Delettre, Cécile; Bras, Marlène; Sancho, Patricia; Robert, N.; d’Alayer, Jacques; Susin, Santos A.

doi:10.1038/sj.cdd.4401687

Cited by 121 publications

(100 citation statements)

References 20 publications

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“…Indeed, AIF needs to be cleaved for becoming a soluble and apoptogenic protein (Otera et al, 2005). Recent studies in isolated mitochondria have shown that AIF cleavage is caspase-independent and involves specific cysteine proteases like calpain I or cathepsins B, L and S (Polster et al, 2005;Yuste et al, 2005). Here, we show that calpain inhibition not only decreases A3D8-induced cell death but also inhibits AIF translocation suggesting that AIF release from mitochondria may be a direct consequence of calpain activity in HEL cells.…”

Section: Cd44-induced Cell Death In Erythroleukemia Cellsmentioning

confidence: 49%

“…Under physiological conditions, AIF is a mitochondrial FAD-dependent oxidoreductase that plays a role in oxidative phosphorylation (Miramar et al, 2001). However, after a cellular insult, AIF is cleaved by calpains and/or cathepsins (Polster et al, 2005;Yuste et al, 2005) and translocates from mitochondria to cytosol and to nucleus where it causes, in a caspase-independent fashion, chromatin condensation and large-scale (B50 kb) DNA fragmentation (Susin et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

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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: Cd44-induced Cell Death In Erythroleukemia Cellsmentioning

confidence: 49%

Section: Introductionmentioning

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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“…Importantly, it appears that the IMSS of AIF1 (IMSS-AIF1), which is encoded by exon 2a, is cleaved during the import of the AIF precursor into mitochondria, in a highly conserved peptide motif, after residue 54 (in humans AIF1) or residue 53 (in mouse AIF). 6,29 This implies that only 29 amino acids of the C-terminal half of IMSS-AIF1 are present in the mature mitochondrial AIF1 protein. Importantly, mature mitochondrial AIF2 (as present in brain tissues or obtained by transfection with a cDNA) showed exactly the same electrophoretic mobility as AIF1, suggesting that AIF2 is trimmed during mitochondrial import by a peptidase that cleaves within the exon 2b-encoded IMSS-AIF2 as well.…”

Section: Resultsmentioning

confidence: 99%

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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“…It has been reported that both calpain and cathepsins can cleave AIF. [20][21][22] In the case of calpain, the subcellular localization of the enzyme responsible for AIF cleavage is not known. Although both m-and m-calpains are generally considered to be cytosolic, mitochondria were also shown to contain Ca 2 þ -dependent calpain 1.…”

Section: Resultsmentioning

confidence: 99%

“…During apoptosis, AIF is further processed and released into the cytosol as a 57 kDa soluble protein. 7,18,19 Several proteases have been proposed to cleave AIF, including Ca 2 þ -dependent calpains and Ca 2 þ -independent cathepsins B, L and S. 20,21 However, the mechanism by which AIF becomes processed and released from mitochondria during apoptosis is not entirely understood. Here, we report that Ca 2 þ import from the extracellular store is required for AIF release during cell death.…”

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confidence: 99%

An increase in intracellular Ca2+ is required for the activation of mitochondrial calpain to release AIF during cell death

et al. 2008

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Apoptosis-inducing factor (AIF), a flavoprotein with NADH oxidase activity anchored to the mitochondrial inner membrane, is known to be involved in complex I maintenance. During apoptosis, AIF can be released from mitochondria and translocate to the nucleus, where it participates in chromatin condensation and large-scale DNA fragmentation. The mechanism of AIF release is not fully understood. Here, we show that a prolonged (B10 min) increase in intracellular Ca 2 þ level is a prerequisite step for AIF processing and release during cell death. In contrast, a transient ATP-induced Ca 2 þ increase, followed by rapid normalization of the Ca 2 þ level, was not sufficient to trigger the proteolysis of AIF. Hence, import of extracellular Ca 2 þ into staurosporine-treated cells caused the activation of a calpain, located in the intermembrane space of mitochondria. The activated calpain, in turn, cleaved membrane-bound AIF, and the soluble fragment was released from the mitochondria upon outer membrane permeabilization through Bax/Bak-mediated pores or by the induction of Ca 2 þ -dependent mitochondrial permeability transition. Inhibition of calpain, or chelation of Ca 2 þ , but not the suppression of caspase activity, prevented processing and release of AIF. Combined, these results provide novel insights into the mechanism of AIF release during cell death.

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

Cited by 121 publications

References 20 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

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

An increase in intracellular Ca2+ is required for the activation of mitochondrial calpain to release AIF during cell death

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