Mdivi-1 alleviates blood-brain barrier disruption and cell death in experimental traumatic brain injury by mitigating autophagy dysfunction and mitophagy activation. (January 2018)

• Record Type: Journal Article
• Authors: Wu, Qiong; Gao, Cheng; Wang, Haochen; Zhang, Xinmu; Li, Qianqian; Gu, Zhiya; Shi, Xiuyu; Cui, Yongchun; Wang, Tao; Chen, Xiping; Wang, Xin; Luo, Chengliang; Tao, Luyang
• Is Part Of: International journal of biochemistry & cell biology. Volume 94(2018)
• Page Start: 44
• Page End: 55
• Publication Date: 2018-01
• Subjects: BBB blood–brain barrier -- CQ chloroquine -- Drp1 dynamin-related protein 1 -- EB Evans blue -- LDH lactate dehydrogenase -- MMP-9 matrix metalloproteinases 9 -- PCNs primary cortical neurons -- PINK1 PTEN induced putative kinase 1 -- ROS reactive oxygen species -- TBI traumatic brain injury -- TUNEL terminal deoxynucleotidyl transferase–mediated dUTP nick-end labeling; Dynamin-related protein 1 -- Traumatic brain injury -- Autophagy -- Mitophagy -- Blood-brain barrier; Biochemistry -- Periodicals; Cytology -- Periodicals; Biochemistry -- Periodicals; Cell Biology -- Periodicals; Biochimie -- Périodiques; Cytologie -- Périodiques; Biochimie; Cytologie; Biochemistry; Cytology; Ressource Internet (Descripteur de forme); Périodique électronique (Descripteur de forme); Periodicals; 572.05
• DOI: 10.1016/j.biocel.2017.11.007
• Languages: English
• ISSNs: 1357-2725

Abstract

Highlights: Mdivi-1 inhibits TBI-induced Drp1 up-regulation, autophagy dysfunction and mitophagy activation. Mdivi-1 mitigates TBI-induced BBB disruption and MMP-9 activity. Mdivi-1 reduces scratch injury-induced cell death and loss of mitochondrial membrane potential. Mdivi-1 mitigates scratch injury-induced ROS production and ATP reduction. Chloroquine abrogates the mdivi-1-induced the decrease in autophagosomes accumulation and cell death in PCNs after scratch injury. Abstract: Dynamin-related protein 1 (Drp1) is a key regulator of mitochondrial fission. Our previous studies proved that the inhibition of Drp1 may help attenuate traumatic brain injury (TBI)-induced functional outcome and cell death through maintaining normal mitochondrial morphology and inhibiting activation of apoptosis. However, the molecular mechanisms of Drp1 after TBI remain poorly understood. In this study, we investigated the role of mitochondrial division inhibitor 1 (Mdivi-1), a small molecule inhibitor of Drp1, in underlying mechanisms of general autophagy and mitochondria autophagy (mitophagy) after experimental TBI. In vivo, we found that autophagosomes accumulated in cortical neurons at 24 h after TBI, owing to the enhanced autophagy indicated by the accumulation of LC3 and the decrease of p62; but Mdivi-1 reversed the enhancement. Mdivi-1 also alleviated the number of LC3 puncta and TUNEL-positive structures in cells, indicating that autophagy maybe involved in Mdivi-1′s anti-apoptosis effects. Then, the expression level of mitochondrial dynamics related and mitophagy related proteins was assessed using the isolated mitochondria. The results showed that TBI-induced mitochondrial fission (represented by Drp1), mtDNA concentration down-regulation and PTEN induced putative kinase 1 (PINK1)-Parkin mediated mitophagy activation were all inhibited by Mdivi-1. In addition, TBI-induced blood-brain barrier (BBB) disruption and matrix metalloproteinases (MMP)-9 expression up-regulation were inhibited following Mdivi-1 treatment. In vitro, Mdivi-1 significantly alleviated the scratch injury-induced cell death, loss of mitochondrial membrane potential, reactive oxygen species (ROS) production and ATP reduction in primary cortical neurons (PCNs). Additionally, the lysosome inhibitor chloroquine (CQ) abrogated the Mdivi-1-induced decrease in autophagosomes accumulation and cell death at 24 h both in the basal state and under the conditions of scratch cell injury. Together, these data demonstrate that Mdivi-1 mitigates TBI-induced BBB disruption and cell death at least in part by a mechanism involving inhibiting autophagy dysfunction and mitophagy activation.