Role of mitochondrial cholesterol homeostasis in brain energy metabolism and neuronal function

The brain is the most cholesterol-rich organ in the human body, and contains nearly a quarter of total body cholesterol. Cholesterol serves to insulate nerve cells to ensure rapid transmission of signals, and it is present in high levels in nerve cells themselves. Changes in the distribution of cholesterol in the brain and within nerve cells have negative consequences for nerve cell function, and they have been observed in many neurological conditions, including Alzheimer's and Huntington's disease and a rare genetic disorder called Niemann-Pick Type C (NPC) disease. NPC disease is known for severe defects in cholesterol metabolism, which lead to loss of nerve cells, to increasing loss of brain function, and ultimately to death of the patient. Our previous work has shown that one of the different ways how cholesterol might negatively affect nerve cells is by changing energy metabolism in the brain. In NPC disease, cholesterol levels were higher than normal in parts of the cell called mitochondria, which are responsible for generating much of the energy used by nerve cells. This increase in mitochondrial cholesterol can cause defects in mitochondrial energy production; however, we do not know yet, how cholesterol causes this effect, and under what conditions these effects become more pronounced. With our research, we want to find out how mitochondrial cholesterol affects energy production in neurons, what the consequences are for nerve cell function, and whether defects in nerve cells could be improved through addition of energy substrates or special nutrients.