Mitochondrial ferritin upregulation reduced oxidative stress and blood-brain-barrier disruption by maintaining cellular iron homeostasis in a neonatal rat model of germinal matrix hemorrhage

作者全名："Yuan, Ye; He, Qiuguang; Yang, Xiao; Flores, Jerry J.; Huang, Lei; Luo, Xu; Zhang, Xingyu; Zhang, Zongyi; Li, Ruihao; Gu, Lingui; Dong, Siyuan; Zhu, Shiyi; Yi, Kun; Han, Mingyang; Wu, Lei; Zhou, You; Zhang, John H.; Xie, Zongyi; Tang, Jiping"

作者地址："[Yuan, Ye; He, Qiuguang; Luo, Xu; Zhang, Xingyu; Zhang, Zongyi; Li, Ruihao; Zhou, You; Xie, Zongyi] Chongqing Med Univ, Affiliated Hosp 2, Dept Neurosurg, 76 Linjiang Rd, Chongqing 400010, Peoples R China; [Yuan, Ye; He, Qiuguang; Flores, Jerry J.; Huang, Lei; Dong, Siyuan; Zhu, Shiyi; Han, Mingyang; Wu, Lei; Zhou, You; Zhang, John H.; Tang, Jiping] Loma Linda Univ, Sch Med, Dept Physiol & Pharmacol, Loma Linda, CA 92354 USA; [Yang, Xiao] Chongqing Med Univ, Dept Obstet & Gynecol, Univ Town Hosp, Chongqing 401331, Peoples R China; [Gu, Lingui] Chinese Acad Med Sci & Peking Union Med Coll, Peking Union Med Coll Hosp, Natl Glioma MDT Alliance, Ctr Malignant Brain Tumors,Dept Neurosurg, Beijing 100730, Peoples R China; [Yi, Kun] Chongqing Med Univ, Chongqing Key Lab Ophthalmol, Affiliated Hosp 1, Chongqing 400016, Peoples R China; [Yi, Kun] Chongqing Med Univ, Chongqing Eye Inst, Affiliated Hosp 1, Chongqing 400016, Peoples R China; [Zhang, John H.] Loma Linda Univ, Dept Anesthesiol & Neurol, Sch Med, Loma Linda, CA 92354 USA; [Huang, Lei; Zhang, John H.] Loma Linda Univ, Sch Med, Dept Neurosurg, Loma Linda, CA 92354 USA"

通信作者："Xie, ZY (通讯作者)，Chongqing Med Univ, Affiliated Hosp 2, Dept Neurosurg, 76 Linjiang Rd, Chongqing 400010, Peoples R China.; Tang, JP (通讯作者)，Loma Linda Univ, Sch Med, Dept Physiol & Pharmacol, Loma Linda, CA 92354 USA."

来源：EXPERIMENTAL NEUROLOGY

ESI学科分类：NEUROSCIENCE & BEHAVIOR

WOS号：WOS:001175629500001

JCR分区：Q1

影响因子：5.3

年份：2024

卷号：374

期号：　

开始页：　

结束页：　

文献类型：Article

关键词：Germinal matrix hemorrhage; Mitochondrial ferritin; Iron homeostasis; Oxidative stress; Blood -brain barrier

摘要："Germinal matrix hemorrhage (GMH) is a devasting neurological disease in premature newborns. After GMH, brain iron overload associated with hemoglobin degradation contributed to oxidative stress, causing disruption of the already vulnerable blood-brain barrier (BBB). Mitochondrial ferritin (FTMT), a novel mitochondrial outer membrane protein, is crucial in maintaining cellular iron homeostasis. We aimed to investigate the effect of FTMT upregulation on oxidative stress and BBB disruption associated with brain iron overload in rats. A total of 222 Sprague-Dawley neonatal rat pups (7 days old) were used to establish a collagenase-induced GMH model and an iron-overload model of intracerebral FeCl2 injection. Deferiprone was administered via gastric lavage 1 h after GMH and given daily until euthanasia. FTMT CRISPR Knockout and adenovirus (Ad)-FTMT were administered intracerebroventricularly 48 h before GMH and FeCl2 injection, respectively. Neurobehavioral tests, immunofluorescence, Western blot, Malondialdehyde measurement, and brain water content were performed to evaluate neurobehavior deficits, oxidative stress, and BBB disruption, respectively. The results demonstrated that brain expressions of iron exporter Ferroportin (FPN) and antioxidant glutathione peroxidase 4 (GPX4) as well as BBB tight junction proteins including Claudin-5 and Zona Occulta (ZO)-1 were found to be decreased at 72 h after GMH. FTMT agonist Deferiprone attenuated oxidative stress and preserved BBB tight junction proteins after GMH. These effects were partially reversed by FTMT CRISPR Knockout. Iron overload by FeCl2 injection resulted in oxidative stress and BBB disruption, which were improved by Ad-FTMT mediated FTMT overexpression. Collectively, FTMT upregulation is neuroprotective against brain injury associated with iron overload. Deferiprone reduced oxidative stress and BBB disruption by maintaining cellular iron homeostasis partially by the upregulating of FTMT after GMH. Deferiprone may be an effective treatment for patients with GMH."

基金机构：National Institutes of Health [R01NS117364]; Senior Medical Talents Program of Chongqing for Young and Middle-aged [201911]; Kuanren Talents Program of the Second Affiliated Hospital of Chongqing Medical University [201959]; Chongqing Science and Health Joint Medical Research Project [2020GDRC006]

基金资助正文："This study was supported by the National Institutes of Health (R01NS117364) to Jiping Tang, Senior Medical Talents Program of Chongqing for Young and Middle-aged (No. 201911) , Kuanren Talents Program of the Second Affiliated Hospital of Chongqing Medical University (No. 201959) , and Chongqing Science and Health Joint Medical Research Project (No. 2020GDRC006) to Zongyi Xie."