Is there a Relationship between Conditions Associated with Chronic Hypoxia, the Mitochondria, and Neurodegenerative Diseases, Such as Alzheimer’s Disease?
The central nervous system (CNS) is extremely sensitive to hypoxia, as neuronal cells require a high rate of energy metabolism to maintain transmembrane potentials. As these cells normally rely on aerobic mitochondrial metabolism to generate the required energy, a lack of oxygen results in a shift toward the anaerobic utilization of glucose. Such a metabolic shift may result in a cascade of potentially deleterious events beginning with an increased production of lactic acid and a decreased rate of ATP production.1 Increased lactic acid concentrations may cause a decrease in cellular pH, followed by the release of iron and the reaction of ferrous ions with hydrogen peroxide to produce hydroxyl radicals. A decrease in ATP may adversely affect DNA replication, transcription,2 and mRNA translation. In addition, the levels of inter-cellular calcium will increase as the ATP dependent calcium ion pump mechanism fails. Increased calcium levels can activate: endonucleases, nitric oxide synthetase, phospholipases and proteases. All of the above alterations in cellular metabolism may result in damage to the cellular DNA, particularly the mitochondrial DNA (Figure 1).
KeywordsChronic Hypoxia Lactic Acid Concentration Parkinson Disease Patient Nitric Oxide Synthetase Increase Calcium Level
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