Apoptosis-inducing factor is a major contributor to neuronal loss induced by neonatal cerebral hypoxia-ischemia

Zhu, Changlian; Wang, Xiaoyang; Huang, Zhiheng; Qiu, Lin; Xu, Fanxing; Vahsen, Nicola; Nilsson, Michael; Eriksson, Peter S.; Hagberg, Henrik; Culmsee, Carsten; Plesnila, Nikolaus; Kroemer, Guido; Blomgren, Klas

doi:10.1038/sj.cdd.4402053

Cited by 190 publications

(197 citation statements)

References 34 publications

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“…Furthermore, the prominent apoptosis in immature retinas was related to activation of caspase-dependent pathways, as demonstrated by caspase-3 cleavage. It remained to be determined whether prevention of caspase activation is protective in neonatal retinal injury, similar to previous reports on HI brain injury (24).…”

Section: Hypoxic-ischemic Retinal Injurymentioning

confidence: 88%

Hypoxic–ischemic retinal injury in rat pups

Huang

Hung

et al. 2012

Pediatr Res

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Background: Visual loss associated with brain damage, especially hypoxic-ischemic (hI) encephalopathy, is the most common cause of visual impairment in children in developed countries. We hypothesized that hI insults can cause long-term damage in immature eyes. Methods: In postnatal day 7 rat pups, hI was induced by unilateral common carotid artery ligation followed by hypoxia. Retina damage was assessed by electroretinography (eRG) and cell counting. Neuronal injury and astrogliosis were evaluated by terminal deoxynucleotidyl transferase nick-end labeling, cleaved caspase 3, eD1, and glial fibrillary acidic protein immunostaining. results: We observed rapid and persistently extensive injuries in the ganglia cell layer (GcL), inner plexiform layer, and inner nuclear layer (INL) in ipsilateral retinas after hI injury, corresponding to the marked alteration in eRG. hI insult caused prominent microglial and Műller cell activation in ipsilateral inner retinas. Neuronal death in the GcL and INL after hI injury was mainly apoptotic, involving caspase-dependent pathways. conclusion: Our study demonstrated the first evidence of hI retinal damage at both the pathological and functional level using the Vannucci model in neonatal rats. Because retinal damage is often associated with hI injury, it is important to demonstrate that a particular neuroprotective strategy effectively preserves the retina in addition to the brain.

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Section: Hypoxic-ischemic Retinal Injurymentioning

confidence: 88%

Hypoxic–ischemic retinal injury in rat pups

Huang

Hung

et al. 2012

Pediatr Res

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“…Moreover, cleaved caspase-3 immunoreactivity does not necessarily mean the presence of intact functional subunits, based on recent mass spectroscopy data (Martin et al, 2007). Nevertheless, these biochemical data along with other papers describing activation of caspase and other non-caspase apoptotic mechanisms in neonatal HI (Blomgren et al, 2001, Northington et al, 2001a, Graham et al, 2004, Blomgren and Hagberg, 2006, Zhu et al, 2007 suggest that apoptotic cell death following neonatal HI should be abundant. The obvious question then remains, why is there no evidence for apoptotic cell death following neonatal HI when ultrastructure is examined.…”

Section: (Iv) Discussionmentioning

confidence: 99%

Failure to complete apoptosis following neonatal hypoxia–ischemia manifests as “continuum” phenotype of cell death and occurs with multiple manifestations of mitochondrial dysfunction in rodent forebrain

et al. 2007

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Controversy surrounds proper classification of neurodegeneration occurring acutely following neonatal hypoxia-ischemia. By ultrastructural classification, in the first 24 hours after neonatal hypoxia-ischemia in the p7 rat, the majority of striatal cells die having both apoptotic and necrotic features. There is formation of a functional apoptosome, and activation of caspases 9 and 3 occurring simultaneously with loss of structurally intact mitochondria to 34.7±25% and loss of mitochondrial cytochrome C oxidase activity to 34.7±12.7% of control levels by 3 hours after hypoxia-ischemia. There is also loss of the mitochondrial motor protein, kinesin. This combination of activation of apoptosis pathways simultaneous with significant mitochondrial dysfunction may cause incomplete packaging of nuclear and cytoplasmic contents and a hybrid of necrotic and apoptotic features. Evidence for an intermediate biochemistry of cell death including expression of

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“…8 A key consequence of the activation of these three enzymes is the mitochondrial release of truncated AIF (tAIF), a major effector in caspase-independent PCD. [9][10][11][12][13] Cytosolic tAIF rapidly redistributes to the nuclear compartment where, assisted by gH2AX and cyclophilin A (CypA), it promotes chromatinolysis and cell-viability loss. 14,15 Among the features of MNNG-induced necroptosis, the implication of BCL-2 family members appears as a milestone.…”

mentioning

confidence: 99%

BID regulates AIF-mediated caspase-independent necroptosis by promoting BAX activation

et al. 2011

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Alkylating DNA-damage agents such as N-methyl-N 0 -nitro-N 0 -nitrosoguanidine (MNNG) trigger necroptosis, a newly defined form of programmed cell death (PCD) managed by receptor interacting protein kinases. This caspase-independent mode of cell death involves the sequential activation of poly(ADP-ribose) polymerase-1 (PARP-1), calpains, BAX and AIF, which redistributes from mitochondria to the nucleus to promote chromatinolysis. We have previously demonstrated that the BAX-mediated mitochondrial release of AIF is a critical step in MNNG-mediated necroptosis. However, the mechanism regulating BAX activation in this PCD is poorly understood. Employing mouse embryonic knockout cells, we reveal that BID controls BAX activation in AIF-mediated necroptosis. Indeed, BID is a link between calpains and BAX in this mode of cell death. Therefore, even if PARP-1 and calpains are activated after MNNG treatment, BID genetic ablation abolishes both BAX activation and necroptosis. These PCD defects are reversed by reintroducing the BID-wt cDNA into the BID À/À cells. We also demonstrate that, after MNNG treatment, BID is directly processed into tBID by calpains. In this way, calpain non-cleavable BID proteins (BID-G70A or BID-D68-71) are unable to promote BAX activation and necroptosis. Once processed, tBID localizes in the mitochondria of MNNG-treated cells, where it can facilitate BAX activation and PCD. Altogether, our data reveal that, as in caspase-dependent apoptosis, BH3-only proteins are key regulators of caspase-independent necroptosis. Cell Death and Differentiation (2012) 19, 245-256; doi:10.1038/cdd.2011.91; published online 8 July 2011When and how a cell dies is one of the essential questions to understand the biology of the cell. A cell is considered dead when the integrity of its plasma membrane is compromised, when its fragments are engulfed by an adjacent or a professional cell or when its components, including the nucleus, are fragmented. It is more complicated to outline how a cell could die. Historically, two major types of cell death have been distinguished: apoptosis, a controlled or programmed cell death (PCD), and necrosis, an uncontrolled or accidental death. 1 Cell biologists have particularly focused their attention on apoptotic PCD, helping to characterize it at both genetic and biochemical levels. 2 Fascinatingly, the use of apoptotic inhibitors or cells that are deficient in key apoptotic molecules has revealed the existence of new PCD pathways. As a consequence, active forms of cell death started to be referred to as caspase-dependent or caspase-independent. 3 More recently, it has been accepted that necrosis is more than an unregulated type of death. Indeed, a cell can use different mechanisms/pathways with underlying apoptotic or necrotic features to accomplish its proper demise. 4 The analysis of the tumor necrosis factor (TNF) signaling path has shed new light on the existence of PCD pathways with necrotic features. When TNF binds its receptor, two ways can be engaged: (i) caspase-dependent a...

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Apoptosis-inducing factor is a major contributor to neuronal loss induced by neonatal cerebral hypoxia-ischemia

Cited by 190 publications

References 34 publications

Hypoxic–ischemic retinal injury in rat pups

Hypoxic–ischemic retinal injury in rat pups

Failure to complete apoptosis following neonatal hypoxia–ischemia manifests as “continuum” phenotype of cell death and occurs with multiple manifestations of mitochondrial dysfunction in rodent forebrain

BID regulates AIF-mediated caspase-independent necroptosis by promoting BAX activation

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