Mitochondrial Translocation of High Mobility Group Box 1 Facilitates LIM Kinase 2-Mediated Programmed Necrotic Neuronal Death

Abstract

High mobility group box 1 (HMGB1) acts a signaling molecule regulating a wide range of inflammatory responses in extracellular space. HMGB1 also stabilizes nucleosomal structure and facilitates gene transcription. Under pathophysiological conditions, nuclear HMGB1 is immediately transported to the cytoplasm through chromosome region maintenance 1 (CRM1). Recently, we have reported that up-regulation of LIM kinase 2 (LIMK2) expression induces HMGB1 export from neuronal nuclei during status epilepticus (SE)-induced programmed neuronal necrosis in the rat hippocampus. Thus, we investigated whether HMGB1 involves LIMK2-mediated programmed neuronal necrosis, but such role is not reported. In the present study, SE was induced by pilocarpine in rats that were intracerebroventricularly infused with saline, control siRNA, LIMK2 siRNA or leptomycin B (LMB, a CRM1 inhibitor) prior to SE induction. Thereafter, we performed Fluoro-Jade B staining, western blots and immunohistochemical studies. LIMK2 knockdown effectively attenuated SE-induced neuronal death and HMGB1 import into mitochondria accompanied by inhibiting nuclear HMGB1 release and abnormal mitochondrial elongation. LMB alleviated SE-induced neuronal death and nuclear HMGB1 release. However, LMB did not prevent mitochondrial elongation induced by SE, but inhibited the HMGB1 import into mitochondria. The efficacy of LMB was less effective to attenuate SE-induced neuronal death than that of LIMK2 siRNA. These findings indicate that nuclear HMGB1 release and the subsequent mitochondrial import may facilitate and deteriorate programmed necrotic neuronal deaths. The present data suggest that the nuclear HMGB1 release via CRM1 may be a potential therapeutic target for the programmed necrotic neuronal death induced by SE.

HMGB1 Translocation in Neurons after Ischemic Insult: Subcellular Localization in Mitochondria and Peroxisomes

“…The merged pictures of Drp1 with HMGB1 not only supported the colocalization of HMGB1 with Drp1, but also suggested the functional role of surface binding HMGB1 in mitochondrial fission. Interestingly, a recent study using a pilocarpine-induced status epilepticus model suggested that nuclear HMGB1 translocation and the subsequent mitochondrial import might deteriorate programmed necrotic neuronal death [19]. In addition, mitochondrial DNA (mtDNA) has been reported to be released from injured cells as DAMPs (damage associated molecular patterns), and HMGB1 has high affinity to DNA [20].…”

Tau Oligomers Associate with Inflammation in the Brain and Retina of Tauopathy Mice and in Neurodegenerative Diseases

“…In addition, astrocytes and microglia can respond to HMGB1 by producing pro-inflammatory conditions, which is suggested to play an important role in neuroinflammation in neurodegenerative diseases [51–53]. HMGB1 is an important pro-inflammatory cytokine, but it has also been implicated in a necrotic cell death response [54, 55]. Following acute injuries, such as ischemic brain insults, HMGB1 is translocated out of the nucleus and appears to play a role in necrosis or necroptosis (programed cell death in response to injury) [55].…”

p47Phox/CDK5/DRP1-Mediated Mitochondrial Fission Evokes PV Cell Degeneration in the Rat Dentate Gyrus Following Status Epilepticus

“…Dentate hilar neurons and CA1-3 pyramidal cell are extremely vulnerable to insults, while dentate granule cells are resistant ( Ordy et al, 1993 ; Mathern et al, 1995 ; Wittner et al, 2001 ; Kim et al, 2011 ; Ryu et al, 2011 ). Interestingly, hippocampal neurons also show the distinct cell death patterns in the different hippocampal regions following SE: CA1 pyramidal cell death is necrotic rather than apoptotic ( Kim et al, 2014 ; Ko et al, 2015 ; Hyun et al, 2016 ), but PV cells is caspase-3 dependent apoptotic ( Kang et al, 2006 ). Recently, we have reported that the impaired mitochondrial fission induces programmed necrosis in CA1 pyramidal cells following SE ( Kim et al, 2014 ; Ko et al, 2015 ; Hyun et al, 2016 ).…”

“…Interestingly, hippocampal neurons also show the distinct cell death patterns in the different hippocampal regions following SE: CA1 pyramidal cell death is necrotic rather than apoptotic ( Kim et al, 2014 ; Ko et al, 2015 ; Hyun et al, 2016 ), but PV cells is caspase-3 dependent apoptotic ( Kang et al, 2006 ). Recently, we have reported that the impaired mitochondrial fission induces programmed necrosis in CA1 pyramidal cells following SE ( Kim et al, 2014 ; Ko et al, 2015 ; Hyun et al, 2016 ). Unlike CA1 neurons, the present study reveals that SE resulted in PV cell loss through excessive mitochondrial fragmentation, and Mdivi-1 effectively ameliorated SE-induced PV cell loss.…”