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Role of Mitochondrial Calcium Uniporter in Early Brain Injury After Experimental Subarachnoid Hemorrhage

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Abstract

Previous studies have shown that mitochondrial Ca2+ 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 Ca2+ concentration was significantly increased in the temporal cortex of rats 1, 2, and 3 days after SAH, consistent with constant high levels of cellular Ca2+ 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 Ca2+ 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 Ca2+ concentration, but lessened the Ca2+ accumulation after SAH to benefit the rats. Taken together, our results demonstrated that blockage of MCU or prevention of Ca2+ 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.

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Acknowledgments

We would like to thank Dr. Chunxi Wang, Guangbin Xie, and Yuqiu Lu for their technical assistance. This study was supported by the National Natural Science Foundation, China (nos. 81371294, 31071085, and 31371060).

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Authors and Affiliations

  1. Department of Neurosurgery, Jinling Hospital, School of Medicine, Nanjing University, 305 East Zhongshan Road, Nanjing, 210002, Jiangsu Province, China

    Huiying Yan, Dingding Zhang & Chun-Hua Hang

  2. Jiangsu Key Laboratory for Molecular Medicine, Medical School of Nanjing University, 22 Hankou Road, Nanjing, 210093, Jiangsu Province, China

    Shuangying Hao & Kuanyu Li

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  1. Huiying Yan
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Correspondence to Kuanyu Li or Chun-Hua Hang.

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Yan, H., Zhang, D., Hao, S. et al. Role of Mitochondrial Calcium Uniporter in Early Brain Injury After Experimental Subarachnoid Hemorrhage. Mol Neurobiol 52, 1637–1647 (2015). https://doi.org/10.1007/s12035-014-8942-z

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