Mitochondrial dysfunction and brain energy metabolism in the pathogenesis of Niemann-Pick Type C disease

The brain has one of the highest energy requirements of all organs in the human body. Most energy is generated in specialized compartments in the cells called mitochondria. Defects in mitochondria contribute to many neurodegenerative diseases, by producing less energy and by releasing damaging byproducts of the energy-generating process. Another characteristic of the brain is that it is very rich in cholesterol. Cholesterol is an important part of every cell in the brain, but it has to be in the right place and at the right amount. Alterations in cholesterol distribution seem to play a role in several neurodegenerative disorders. Here, we will focus on Niemann-Pick Type C (NPC) disease, in which a genetic defect leads to progressive brain damage. Most children with NPC disease die before reaching adulthood. Even though this disease is fortunately rare, it can give us insight into general mechanisms that play a role in other neurological diseases and in aging. In the present study we aim to find out how the cholesterol distribution in the brain influences mitochondria and brain energy metabolism, and how defects in mitochondria then cause nerve cell damage. When we know more about the mechanisms involved, we may be able to identify targets for intervention to prevent or slow mitochondrial malfunction or to reduce the damage caused by defective mitochondria.