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Mitochondrial uncoupling as a therapeutic target following neuronal injury
P G Sullivan1, Joe E Springer, Edward D Hall
1Spinal Cord and Brain Injury Research Center and Department of Anatomy & Neurobiology, University of Kentucky, Lexington, Kentucky 40536-0305, USA. patsull@uky.edu
Abstract:
Mitochondrial dysfunction is a prominent feature of excitotoxic insult and mitochondria are known to play a pivotal role in neuronal cell survival and death following injury. Following neuronal injury there is a well-documented increase in cytosolic Ca(2+), reactive oxygen species (ROS) production and oxidative damage. In vitro studies have demonstrated these events are dependent on mitochondrial Ca(2+) cycling and that a reduction in membrane potential is sufficient to reduce excitotoxic cell death. This concept has gained additional support from experiments demonstrating that the overexpression of endogenous mitochondrial uncoupling proteins (UCP), which decrease the mitochondrial membrane potential, decreases cell death following oxidative stress. Our group has demonstrated that upregulation of UCP activity can reduce excitotoxic-mediated ROS production and cell death whereas a reduction in UCP levels increases susceptibility to neuronal injury. These findings raise the possibility that mitochondrial uncoupling could be a potential novel treatment for acute CNS injuries.
Insights
Mitochondrial uncoupling proteins (UCP) can protect neurons from excitotoxic injury by reducing reactive oxygen species (ROS) and cell death. Upregulating UCP activity may offer a novel treatment for central nervous system (CNS) injuries.
Area of Science:
- Neuroscience
- Cell Biology
- Biochemistry
Background:
- Mitochondrial dysfunction is central to excitotoxicity and neuronal injury.
- Neuronal injury increases cytosolic Ca(2+), reactive oxygen species (ROS), and oxidative damage.
- Mitochondrial Ca(2+) cycling and membrane potential are critical in excitotoxic cell death.
Purpose of the Study:
- To investigate the role of mitochondrial uncoupling proteins (UCP) in neuronal protection against excitotoxicity.
- To determine if modulating UCP activity impacts ROS production and cell death.
Main Methods:
- In vitro studies examining the effects of mitochondrial Ca(2+) cycling and membrane potential.
- Experiments involving overexpression of UCP to decrease mitochondrial membrane potential.
- Assessing the impact of altered UCP levels on ROS production and neuronal survival following injury.
Main Results:
- Reducing mitochondrial membrane potential is sufficient to decrease excitotoxic cell death.
- Overexpression of UCP reduces cell death following oxidative stress.
- Upregulation of UCP activity decreases excitotoxic ROS production and cell death, while reduced UCP levels increase injury susceptibility.
Conclusions:
- Mitochondrial uncoupling, mediated by UCP, plays a protective role against excitotoxic neuronal injury.
- Modulating UCP activity represents a potential therapeutic strategy for acute central nervous system (CNS) injuries.
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