Apoptosis-Inducing Factor Triggered by Poly(ADP-Ribose) Polymerase and Bid Mediates Neuronal Cell Death after Oxygen-Glucose Deprivation and Focal Cerebral Ischemia

Culmsee, Carsten; Zhu, Changlian; Landshamer, Stefan; Becattini, Barbara; Wagner, Ernst; Pellecchia, Maurizio; Blomgren, Klas; Plesnila, Nikolaus

doi:10.1523/jneurosci.2818-05.2005

Cited by 309 publications

(296 citation statements)

References 49 publications

Supporting

Mentioning

275

Contrasting

Order By: Relevance

“…5,19 The pivotal role for Bid upstream of such mitochondrial dysfunction is substantiated by experiments demonstrating pronounced neuroprotective effects of the Bid inhibitor BI-6c9 in models of glutamate-induced excitotoxicity and OGD in primary cultured neurons, and similar studies in HT-22 neurons using Bid siRNA. 19,20,30,31 Further, reduced Bid expression attenuated neuronal death in a model of OGD in vitro and reduced brain damage in models of cerebral ischemia and brain trauma in vivo. 21 Recent studies showed that tBid and full-length Bid exert similar effects on mitochondria and AIF-dependent cell death in neurons.…”

Section: Discussionmentioning

confidence: 92%

Inhibition of Drp1 provides neuroprotection in vitro and in vivo

et al. 2012

View full text Add to dashboard Cite

Impaired regulation of mitochondrial dynamics, which shifts the balance towards fission, is associated with neuronal death in age-related neurodegenerative diseases, such as Alzheimer's disease or Parkinson's disease. A role for mitochondrial dynamics in acute brain injury, however, has not been elucidated to date. Here, we investigated the role of dynamin-related protein 1 (Drp1), one of the key regulators of mitochondrial fission, in neuronal cell death induced by glutamate toxicity or oxygen-glucose deprivation (OGD) in vitro, and after ischemic brain damage in vivo. Drp1 siRNA and small molecule inhibitors of Drp1 prevented mitochondrial fission, loss of mitochondrial membrane potential (MMP), and cell death induced by glutamate or tBid overexpression in immortalized hippocampal HT-22 neuronal cells. Further, Drp1 inhibitors protected primary neurons against glutamate excitotoxicity and OGD, and reduced the infarct volume in a mouse model of transient focal ischemia. Our data indicate that Drp1 translocation and associated mitochondrial fission are key features preceding the loss of MMP and neuronal cell death. Thus, inhibition of Drp1 is proposed as an efficient strategy of neuroprotection against glutamate toxicity and OGD in vitro and ischemic brain damage in vivo. Mitochondria play crucial roles in energy metabolism, regulation of free radical formation and calcium storage, thereby determining essential metabolic functions and cell survival. 1 Further, mitochondria are highly dynamic organelles that undergo constant fission and fusion and these morphological changes are required for efficient ATP production, calcium buffering, regulation of signal transduction and apoptosis. 2 In neurons, mitochondrial fission is also essential for axonal transport of the organelles into areas of high metabolic demand, 3 whereas mitochondrial fusion supports substitution and regeneration of mitochondrial proteins, mtDNA repair and functional recovery. 2,4 Consistent with the critical roles of mitochondrial dynamics in neurons, defects in mitochondrial fission and fusion proteins are associated with a wide array of inherited or acquired neurodegenerative diseases such as Charcot-Marie-Tooth disease or Alzheimer's disease, respectively. 2 Fission and fusion defects may limit mitochondrial motility, decrease energy production, promote oxidative stress and lead to accumulating of mtDNA defects, thereby promoting neuronal dysfunction and cell death. 1 Recently, enhanced mitochondrial fragmentation was associated with induction of neuronal death triggered by oxidative stress. 5 These data imply that during neuronal cell death, the tubular mitochondrial network is fragmented into smaller and functionally impaired organelles. 5 It is, however, a matter of ongoing controversy, whether mitochondrial fragmentation is cause or consequence in programmed cell death.Current knowledge of the mechanisms regulating mitochondrial dynamics indicates that fission and fusion of mitochondria are under control of highly conserved dynamin-relate...

show abstract

Section: Discussionmentioning

confidence: 92%

Inhibition of Drp1 provides neuroprotection in vitro and in vivo

et al. 2012

View full text Add to dashboard Cite

show abstract

“…In experimental stroke, both nNOS and PARP activity were found to be increased (Eliasson et al, 1997;Endres et al, 1997;Eliasson et al, 1999;Goyagi et al, 2003), and gene deletion or pharmacologic inhibition of nNOS or PARP-1 reduced infarct volume (Huang et al, 1994;Eliasson et al, 1997;Endres et al, 1997;Goto et al, 2002). In addition, inhibition of PARP decreased AIF translocation, and knockdown of AIF in Harlequin mice reduced infarct volume after 45 minutes of MCAO (Culmsee et al, 2005). Direct exposure of cultured neurons to peroxynitrite stimulates AIF translocation (Zhang et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

“…This design permitted evaluation at early reperfusion, at a mid-range of reperfusion, when many neurons show ischemic morphologic changes, and at late reperfusion, when cell death is widespread throughout the maturing infarct. These timepoints spanned the 1-8 hour range for AIF translocation reported by others (Ferrer et al, 2003;Plesnila et al, 2004;Zhao et al, 2004;Culmsee et al, 2005). Two hemispheres were used per lane.…”

Section: Subcellular Fractionation and Immunoblottingmentioning

confidence: 99%

“…However, translocation of AIF to the nucleus results in irreversible cell death signaling that is independent of caspase activity (Susin et al, 1999;Daugas et al, 2000). In neurons, AIF translocation to the nucleus appears to play an important role in NMDA and kainate excitotoxicity (Yu et al, 2002;Wang et al, 2004;Cheung et al, 2005) and in oxygenglucose deprivation (Cao et al, 2003;Plesnila et al, 2004;Culmsee et al, 2005). In brain, nuclear AIF translocation has been reported after hypoglycemic coma (Ferrand-Drake et al, 2003), global cerebral ischemia (Cao et al, 2003), hypoxia-ischemia in postnatal rats and mice (Matsumori et al, 2005), and traumatic brain injury (Zhang et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

“…After permanent occlusion of the distal middle cerebral artery (MCA) in rats, significant increases in AIF in nuclear subcellular fractions occurred at 48 hours, although localized increases in cortical border regions were evident at 8 hours (Zhao et al, 2004). With 45 minutes of transient MCA occlusion (MCAO) in mice, significant increases in nuclear AIF in cortex occurred by 1 hour (Plesnila et al, 2004) and 2 hours (Culmsee et al, 2005). However, the time course of nuclear AIF translocation has not been evaluated systematically after varying durations of focal ischemia, in which delayed apoptosis is known to be evident after brief ischemia and necrotic cell death rapidly develops with prolonged ischemia (Kametsu et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Influence of duration of focal cerebral ischemia and neuronal nitric oxide synthase on translocation of apoptosis-inducing factor to the nucleus

Nemoto

et al. 2007

Neuroscience

View full text Add to dashboard Cite

Translocation of apoptosis-inducing factor (AIF) from the mitochondria to the nucleus can play a major role in neuronal death elicited by oxidant stress. The time course of nuclear translocation of AIF after experimental stroke may vary with the severity of injury and may be accelerated by oxidant stress associated with reperfusion and nitric oxide (NO) production. Western immunoblots of AIF on nuclear fractions of ischemic hemisphere of male mice showed no significant increase with 1 hour of middle cerebral artery occlusion and no reperfusion, whereas increases were detectable after 6 and 24 hours of permanent ischemia. However, as little as 20 minutes of reperfusion after 1 hour of middle cerebral artery occlusion resulted in an increase in nuclear AIF coincident with an increase in poly(ADP-ribose) polymer (PAR) formation. Further nuclear AIF accumulation was seen at 6 and 24 hours of reperfusion. In contrast, 20 minutes of reperfusion after 2 hours of occlusion did not increase nuclear AIF. In this case, nuclear AIF became detectable at 6 and 24 hours of reperfusion. With brief occlusion of 30 minute duration, nuclear AIF remained undetectable at both 20 minutes and 6 hours and became evident only after 24 hours of reperfusion. Inhibition of neuronal NO synthase attenuated formation of PAR and nuclear AIF accumulation. Gene deletion of neuronal NO synthase also attenuated nuclear AIF accumulation. Therefore, reperfusion accelerates AIF translocation to the nucleus when focal ischemia is of moderate duration (1 hour), but is markedly delayed after brief ischemia (30 minutes). Nuclear translocation of AIF eventually occurs with prolonged focal ischemia with or without reperfusion. Neuronally-derived NO is a major factor contributing to nuclear AIF accumulation after stroke.

show abstract