Repair of brain energy failure through mitochondrial uncoupling

Deficient brain energy production is associated with aging and neurodegenerative diseases. The complex nature of these diseases and our relatively poor understanding of the molecular pathophysiology is today an obstacle for the development of effective tr eatment, but a key role is attributed to progressing damage of mitochondrial DNA (mtDNA) by reactive oxygen species (ROS) from the nearby electron transport chain. We have established a transgenic mouse model mimicking age and neurodegeneration associated mitochondrial dysfunction. In this model, mitochondrial dysfunction caused by high levels of mtDNA damage is induced specifically in hippocampal pyramidal neurons, cells essential for memory formation and the sense of place. Phenotypically, these mice di splay disturbed mitochondrial dynamics and respiration, reduction of mtDNA copynumber and expression, as well as oxidative stress. The mouse brain shows neurodegeneration and atrophy of the hippocampus, as well as synaptic abnormalities with loss of excit atory receptors. These irregularities are reflected in impaired behavior, and display features comparable to early symptoms in aging and neurodegenerative pathologies like Alzheimer's disease. We now wish to use this model to study mitochondrial uncouplin g proteins (UCPs) in hippocampus. UCPs are known to control the balance between producing enough ATP and reducing levels of reactive oxygen species (ROS), thereby counteracting energy deficiencies and reducing macromolecular damages from ROS. By investiga ting the control and function of the UCPs in neurodegenerative tissue, we believe this model can unravel novel mechanisms of neurodegenerative disease, answer vital scientific questions and offer solutions to new treatment strategies.