Mitochondrial calcium uniporter blocker effectively prevents brain mitochondrial dysfunction caused by iron overload.

Abstract

AIMS:

Although iron overload induces oxidative stress and brain mitochondrial dysfunction, and is associated with neurodegenerative diseases, brain mitochondrial iron uptake has not been investigated. We determined the role of mitochondrial calcium uniporter (MCU) in brain mitochondria as a major route for iron entry. We hypothesized that iron overload causes brain mitochondrial dysfunction, and that the MCU blocker prevents iron entry into mitochondria, thus attenuating mitochondrial dysfunction.

MAIN METHODS:

Isolated brain mitochondria from male Wistar rats were used. Iron (Fe(2+) and Fe(3+)) at 0-286 μM were applied onto mitochondria at various incubation times (5-30 min), and the mitochondrial function was determined. Effects of MCU blocker (Ru-360) and iron chelator were studied.

KEY FINDINGS:

Both Fe(2+) and Fe(3+) entered brain mitochondria and caused mitochondrial swelling in a dose- and time-dependent manner, and caused mitochondrial depolarization and increased ROS production. However, Fe(2+) caused more severe mitochondrial dysfunction than Fe(3+). Although all drugs attenuated mitochondrial dysfunction caused by iron overload, only an MCU blocker could completely prevent ROS production and mitochondrial depolarization.

SIGNIFICANCE:

Our findings indicated that iron overload caused brain mitochondrial dysfunction, and that an MCU blocker effectively prevented this impairment, suggesting that MCU could be the major portal for brain mitochondrial iron uptake.

• Authors: Jirapas Sripetchwandee, Jantira Sanit, Nipon Chattipakorn, Siriporn C Chattipakorn
• Journal: Life sciences (Life Sci) Vol. 92 Issue 4-5 Pg. 298-304 (Mar 12 2013) ISSN: 1879-0631 [Electronic] Netherlands
• PMID: 23333832 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 Elsevier Inc. All rights reserved.

Chemical References

• Calcium Channels
• Citrates
• Ferric Compounds
• Ferrous Compounds
• Iron Chelating Agents
• Quaternary Ammonium Compounds
• Reactive Oxygen Species
• Ru 360
• Ruthenium Compounds
• mitochondrial calcium uniporter
• ammoniacal ferrous citrate
• ferric ammonium citrate

Topics

• Animals
• Brain (drug effects, metabolism, ultrastructure)
• Calcium Channels (metabolism)
• Citrates (pharmacology)
• Dose-Response Relationship, Drug
• Ferric Compounds (pharmacology)
• Ferrous Compounds (pharmacology)
• In Vitro Techniques
• Iron Chelating Agents (pharmacology)
• Iron Overload (complications, metabolism, pathology)
• Male
• Membrane Potential, Mitochondrial (drug effects)
• Microscopy, Electron, Transmission
• Mitochondria (drug effects, metabolism, ultrastructure)
• Mitochondrial Swelling (drug effects)
• Quaternary Ammonium Compounds (pharmacology)
• Rats
• Rats, Wistar
• Reactive Oxygen Species (metabolism)
• Ruthenium Compounds (pharmacology)
• Time Factors