PHLDA1 contributes to hypoxic ischemic brain injury in neonatal rats via inhibiting FUNDC1-mediated mitophagy  

作　　者：Xiao-lu Jiang Zu-bin Zhang Chen-xi Feng Chen-jie Lin Hui Yang Lan-lan Tan Xin Ding Li-xiao Xu Gen Li Tao Pan Zheng-hong Qin Bin Sun Xing Feng Mei Li 

机构地区：[1]Pediatrics Research Institute,Children’s Hospital of Soochow University,Suzhou,215025,China [2]Department of Neonatology,Children’s Hospital of Soochow University,Suzhou,215025,China [3]Soochow Key Laboratory of Prevention and Treatment of Child Brain Injury,Children’s Hospital of Soochow University,Suzhou,215025,China [4]Jiangsu Key Laboratory for Translational Research and Therapeutics of NeuroPsycho Diseases,Department of Pharmacology,College of Pharmaceutical Sciences,Soochow University,Suzhou,215123,China [5]Institute of Health Technology,Global Institute of Software Technology,Qingshan Road,Suzhou Science&Technology Tower,Hi-Tech Area,Suzhou,215163,China

出　　处：《Acta Pharmacologica Sinica》2024年第9期1809-1820,共12页中国药理学报（英文版）

基　　金：National Natural Science Foundation of China(82271405,82071379,82171703,82371719);Interdisciplinary Basic Frontier Innovation Program of Suzhou Medical College of Soochow University(YXY2304072);The Natural Science Foundation of the Jiangsu Higher Education Institutions of China(22KJB320021);Training Program Foundation for health talents of Gusu(GSWS2020052,GSWS2019049);Project of Suzhou Science and Technology Development Plan(SKY2021008,SYS2020154).

摘　　要：Hypoxia-ischemia(HI)is one of the main causes of neonatal brain injury.Mitophagy has been implicated in the degradation of damaged mitochondria and cell survival following neonatal brain HI injury.Pleckstrin homology-like domain family A member 1(PHLDA1)plays vital roles in the progression of various disorders including the regulation of oxidative stress,the immune responses and apoptosis.In the present study we investigated the role of PHLDA1 in HI-induced neuronal injury and further explored the mechanisms underlying PHLDA1-regulated mitophagy in vivo and in vitro.HI model was established in newborn rats by ligation of the left common carotid artery plus exposure to an oxygen-deficient chamber with 8%O2 and 92%N2.In vitro studies were conducted in primary hippocampal neurons subjected to oxygen and glucose deprivation/-reoxygenation(OGD/R).We showed that the expression of PHLDA1 was significantly upregulated in the hippocampus of HI newborn rats and in OGD/R-treated primary neurons.Knockdown of PHLDA1 in neonatal rats via lentiviral vector not only significantly ameliorated HI-induced hippocampal neuronal injury but also markedly improved long-term cognitive function outcomes,whereas overexpression of PHLDA1 in neonatal rats via lentiviral vector aggravated these outcomes.PHLDA1 knockdown in primary neurons significantly reversed the reduction of cell viability and increase in intracellular reactive oxygen species(ROS)levels,and attenuated OGD-induced mitochondrial dysfunction,whereas overexpression of PHLDA1 decreased these parameters.In OGD/R-treated primary hippocampal neurons,we revealed that PHLDA1 knockdown enhanced mitophagy by activating FUNDC1,which was abolished by FUNDC1 knockdown or pretreatment with mitophagy inhibitor Mdivi-1(25μM).Notably,pretreatment with Mdivi-1 or the knockdown of FUNDC1 not only increased brain infarct volume,but also abolished the neuroprotective effect of PHLDA1 knockdown in HI newborn rats.Together,these results demonstrate that PHLDA1 contributes to neonatal HI-induced b

关 键 词：neonatal brain injury HYPOXIA-ISCHEMIA PHLDA1 MITOPHAGY FUNDC1 Mdivi-1 

分 类 号：R651.15[医药卫生—外科学]