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Title: Blockage of mitochondrial calcium uniporter prevents iron accumulation in a model of experimental subarachnoid hemorrhage

Highlights: • Iron accumulation was involved in the acute phase following SAH. • Blockage of MCU could attenuate cellular iron accumulation following SAH. • Blockage of MCU could decrease ROS generation and improve cell energy supply following SAH. • Blockage of MCU could alleviate apoptosis and brain injury following SAH. - Abstract: Previous studies have shown that iron accumulation is involved in the pathogenesis of brain injury following subarachnoid hemorrhage (SAH) and chelation of iron reduced mortality and oxidative DNA damage. We previously reported that blockage of mitochondrial calcium uniporter (MCU) provided benefit in the early brain injury after experimental SAH. This study was undertaken to identify whether blockage of MCU could ameliorate iron accumulation-associated brain injury following SAH. Therefore, we used two reagents ruthenium red (RR) and spermine (Sper) to inhibit MCU. Sprague–Dawley (SD) rats were randomly divided into four groups including sham, SAH, SAH + RR, and SAH + Sper. Biochemical analysis and histological assays were performed. The results confirmed the iron accumulation in temporal lobe after SAH. Interestingly, blockage of MCU dramatically reduced the iron accumulation in this area. The mechanism was revealed that inhibition of MCU reversed the down-regulation of iron regulatory protein (IRP) 1/2 andmore » increase of ferritin. Iron–sulfur cluster dependent-aconitase activity was partially conserved when MCU was blocked. In consistence with this and previous report, ROS levels were notably reduced and ATP supply was rescued; levels of cleaved caspase-3 dropped; and integrity of neurons in temporal lobe was protected. Taken together, our results indicated that blockage of MCU could alleviate iron accumulation and the associated injury following SAH. These findings suggest that the alteration of calcium and iron homeostasis be coupled and MCU be considered to be a therapeutic target for patients suffering from SAH.« less
Authors:
 [1] ; ;  [2] ; ; ;  [1] ;  [2] ;  [1]
  1. Department of Neurosurgery, Jinling Hospital, School of Medicine, Nanjing University, 305 East Zhongshan Road, Nanjing 210002, Jiangsu Province (China)
  2. Jiangsu Key Laboratory for Molecular Medicine, Medical School of Nanjing University, 22 Hankou Road, Nanjing 210093, Jiangsu Province (China)
Publication Date:
OSTI Identifier:
22416904
Resource Type:
Journal Article
Resource Relation:
Journal Name: Biochemical and Biophysical Research Communications; Journal Volume: 456; Journal Issue: 4; Other Information: Copyright (c) 2014 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; APOPTOSIS; ATP; BRAIN; CALCIUM; CHELATES; DNA DAMAGES; FERRITIN; HEMORRHAGE; HOMEOSTASIS; IRON; MITOCHONDRIA; MORTALITY; NERVE CELLS; PATHOGENESIS; PATIENTS; PHOSPHATES; RECEPTORS; RUTHENIUM; SPERMINE; TRANSFERRIN