Mitochondrial genome deletions in the brain and their role in neurodegenerative diseases

Summary

Many of the acute and chronic diseases affecting the central nervous system (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 these diseases. Over the past decade numerous diseases affecting highly active metabolic tissues including the brain and skeletal musculature have been shown to be associated with alterations in the mitochondria, the subcellular organelle responsible for aerobic energy metabolism. In addition, a number of maternally inherited diseases have been linked to mutations in the circular, 16,569 nucleotide pair mitochondrial genome. Mendelian inherited genetic variations and diseases have also been found to affect the mitochondrial function, structure, and genome in certain tissues. Specific regions of the brain appear to be more prone to the occurrence of mitochondrial DNA (mtDNA) deletion mutations. For example, mtDNA extracted from the putamen from individuals with conditions 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 these mutations are region specific and whether they are primary or secondary to pathophysiological processes. The regional specificity of the mtDNA deletions may be due in part to variations in regional blood flow, 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 considerable amounts of energy to restore the transmembrane potentials following each depolarization. In addition, mitochondrial dysfunction can lead to a metabolic catastrophe in which overproduction of free radicals 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 mitochondrial genome have been associated with Alzheimer's disease and these mutations may in part be responsible for some of the genetic complexity displayed by this disease.