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

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 and 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.

• Authors: Huiying Yan, Shuangying Hao, Xiaoyan Sun, Dingding Zhang, Xin Gao, Zhuang Yu, Kuanyu Li, Chun-Hua Hang
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 456 Issue 4 Pg. 835-40 (Jan 24 2015) ISSN: 1090-2104 [Electronic] United States
• PMID: 25529443 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Inc. All rights reserved.

Chemical References

• Calcium Channels
• mitochondrial calcium uniporter
• Ruthenium Red
• Spermine
• Iron

Topics

• Animals
• Apoptosis (drug effects)
• Brain Injuries (etiology, pathology)
• Calcium Channels (metabolism)
• Disease Models, Animal
• Homeostasis
• Iron (metabolism)
• Male
• Mitochondria (metabolism)
• Oxidative Stress
• Rats, Sprague-Dawley
• Ruthenium Red (administration & dosage, pharmacology)
• Spermine (administration & dosage, pharmacology)
• Subarachnoid Hemorrhage (complications, metabolism, pathology)