Mitochondrial uncoupling as a therapeutic target following neuronal injury.
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.
Sullivan
P G
PG
Spinal Cord and Brain Injury Research Center and Department of Anatomy & Neurobiology, University of Kentucky, Lexington, Kentucky 40536-0305, USA. patsull@uky.edu
Springer
Joe E
JE
Hall
Edward D
ED
Scheff
Stephen W
SW
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001930:Brain Injuries / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism*; D016503:Drug Delivery Systems / Q000379:methods; D006801:Humans; D007473:Ion Channels; D008565:Membrane Proteins / Q000378:metabolism*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D028361:Mitochondrial Diseases / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism; D024101:Mitochondrial Proteins; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D017382:Reactive Oxygen Species / Q000378:metabolism; D013119:Spinal Cord Injuries / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism*; D000071256:Uncoupling Protein 1
D002352:Carrier Proteins; D007473:Ion Channels; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D018696:Neuroprotective Agents; D017382:Reactive Oxygen Species; D000071256:Uncoupling Protein 1; D002118:Calcium