MITOCHONDRIAL GENOME DELETIONS IN THE BRAIN AND THEIR ROLE IN NEURODEGENERATIVE DISEASES

Many of the acute and chronic diseases affecting the central nervous s ystem (CNS) are still of unknown etiology. Given that brain cells are the most aerobic and metabolically active cells in the body, deficits in aerobic energy metabolism may play an important role in many of the se diseases. Over the past decade numerous diseases affecting highly a ctive metabolic tissues including the brain and skeletal musculature h ave been shown to be associated with alterations in the mitochondria, the subcellular organelle responsible for aerobic energy metabolism. I n addition, a number of maternally inherited diseases have been linked to mutations in the circular, 16,569 nucleotide pair mitochondrial ge nome. Mendelian inherited genetic variations and diseases have also be en found to affect the mitochondrial function, structure, and genome i n certain tissues. Specific regions of the brain appear to be more pro ne to the occurrence of mitochondrial DNA (mtDNA) deletion mutations. For example, mtDNA extracted from the putamen from individuals with co nditions associated with chronic hypoxia often contain relatively high levels of mtDNA deletions while such mtDNA deletions are rarely found in the cerebellum. These observations raise the question as to why th ese mutations are region specific and whether they ave primary or seco ndary to pathophysiological processes. The regional specificity of the mtDNA deletions may be due in part to variations in regional blood fl ow, metabolic rates and the presence of known mutagens, such as nitric oxide. If mtDNA mutation events are primary they may serve as trigger mechanisms for disease processes. The loss of critical mitochondrial functions is particularly detrimental to neurons, which require consid erable amounts of energy to restore the transmembrane potentials follo wing each depolarization. In addition, mitochondrial dysfunction can l ead to a metabolic catastrophe in which overproduction of free radical s results in ever increasing damage to the cell's aerobic capacities. If such processes are involved in neurodegenerative diseases, such as Alzheimer's disease, there should be evidence of a genetic association between variations in the mitochondrial genome and the occurrence of this disease. In this regard, deletion and point mutations in the mito chondrial genome have been associated with Alzheimer's disease and the se mutations may in part be responsible for some of the genetic comple xity displayed by this disease.