title: Role of Mitochondrial Calcium Uniporter in Early Brain Injury After Experimental Subarachnoid Hemorrhage.
abstract: Previous studies have shown that mitochondrial Ca(2+) is undertaken by mitochondrial calcium uniporter (MCU), and its accumulation is associated with the development of many diseases. However, little was known about the role of MCU in early brain injury (EBI) after subarachnoid hemorrhage (SAH). MCU can be opened by spermine under a physiological condition and inhibited by ruthenium red (RR). Herein, we investigated the effects of RR and spermine to reveal the role of MCU in SAH animal model. The data obtained with biochemical and histological assays showed that mitochondrial Ca(2+) concentration was significantly increased in the temporal cortex of rats 1, 2, and 3 days after SAH, consistent with constant high levels of cellular Ca(2+) concentration. In agreement with the observation in the acute phase, SAH rats showed an obvious increase of reactive oxygen species (ROS) level and decrease of ATP production. Blockage of MCU prevented Ca(2+) accumulation, abated the level of oxidative stress, and improved the energy supply. Translocation of cytochrome c, increased cleaved caspase-3, and a large amount of apoptotic cells after SAH were reversed by RR administration. Surprisingly, exogenous spermine did not increase cellular Ca(2+) concentration, but lessened the Ca(2+) accumulation after SAH to benefit the rats. Taken together, our results demonstrated that blockage of MCU or prevention of Ca(2+) accumulation after SAH is essential in EBI after SAH. These findings suggest that MCU is considered to be a therapeutic target for patients suffering from SAH.
authors.affiliation: Department of Neurosurgery, Jinling Hospital, School of Medicine, Nanjing University, 305 East Zhongshan Road, Nanjing, 210002, Jiangsu Province, China.
authors.forename: Huiying
authors.initials: H
authors.lastname: Yan
authors.affiliation: Department of Neurosurgery, Jinling Hospital, School of Medicine, Nanjing University, 305 East Zhongshan Road, Nanjing, 210002, Jiangsu Province, China.
authors.forename: Dingding
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Jiangsu Key Laboratory for Molecular Medicine, Medical School of Nanjing University, 22 Hankou Road, Nanjing, 210093, Jiangsu Province, China.
authors.forename: Shuangying
authors.initials: S
authors.lastname: Hao
authors.affiliation: Jiangsu Key Laboratory for Molecular Medicine, Medical School of Nanjing University, 22 Hankou Road, Nanjing, 210093, Jiangsu Province, China. likuanyu@nju.edu.cn.
authors.forename: Kuanyu
authors.initials: K
authors.lastname: Li
authors.affiliation: Department of Neurosurgery, Jinling Hospital, School of Medicine, Nanjing University, 305 East Zhongshan Road, Nanjing, 210002, Jiangsu Province, China. hang_neurosurgery@163.com.
authors.forename: Chun-Hua
authors.initials: CH
authors.lastname: Hang
mesh_terms: D000818:Animals; D001930:Brain Injuries / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000378:metabolism*; D045304:Cytochromes c / Q000378:metabolism; D004195:Disease Models, Animal; D008297:Male; D008928:Mitochondria / Q000378:metabolism*; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D013345:Subarachnoid Hemorrhage / Q000378:metabolism* / Q000473:pathology; D013997:Time Factors
chemical_list: D015220:Calcium Channels; D017382:Reactive Oxygen Species; C034703:mitochondrial calcium uniporter; D045304:Cytochromes c; D002118:Calcium
keywords: Apoptosis; Early brain injury; Mitochondrial calcium uniporter; Oxidative stress; Subarachnoid hemorrhage