Oxidative Phosphorylation Enzyme Activities Research Articles

Oxidative phosphorylation defects and Alzheimer's disease.

Abnormalities in cellular bioenergetics have been identified in patients with Alzheimer's disease (AD) as well as in patients with other neurodegenerative diseases. The most commonly reported enzyme abnormalities are in the pyruvate dehydrogenase complex, the alpha-ketoglutarate dehydrogenase complex, and oxidative phosphorylation (OXPHOS). Although genetic evidence supporting primary OXPHOS defects as a cause for AD is weak, functionally important reductions in OXPHOS enzyme activities appear to occur in AD and may be related to beta-amyloid accumulation or other neurodegenerative processes. Since reduced neuronal ATP may enhance susceptibility to glutamate toxicity, OXPHOS defects could play an important role in the pathophysiology of AD.

Oxidative damage and metabolic dysfunction in Huntington's disease: Selective vulnerability of the basal ganglia

The etiology of the selective neuronal death that occurs in Huntington's disease (HD) is unknown. Several lines of evidence implicate the involvement of energetic defects and oxidative damage in the disease process, including a recent study that demonstrated an interaction between huntingtin protein and the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Using spectrophotometric assays in postmortem brain tissue, we found evidence of impaired oxidative phosphorylation enzyme activities restricted to the basal ganglia in HD brain, while enzyme activities were unaltered in three regions relatively spared by HD pathology (frontal cortex, parietal cortex, and cerebellum). Citrate synthase-corrected complex II-III activity was markedly reduced in both HD caudate (-29%) and putamen (-67%), and complex IV activity was reduced in HD putamen (-62%). Complex I and GAPDH activities were unaltered in all regions examined. We also measured levels of the oxidative damage product 8-hydroxydeoxyguanosine (OH8dG) in nuclear DNA, and superoxide dismutase (SOD) activity. OH8dG levels were significantly increased in HD caudate. Cytosolic SOD activity was slightly reduced in HD parietal cortex and cerebellum, whereas particulate SOD activity was unaltered in these regions. These results further support a role for metabolic dysfunction and oxidative damage in the pathogenesis of HD.

Evidence for Physiological Down-regulation of Brain Oxidative Phosphorylation in Alzheimer's Disease

In vivoimaging of patients with Alzheimer's disease using positron emission tomography (PET) demonstrates progressive reductions in brain glucose metabolism and blood flow in relation to dementia severity, more so in association than primary cortical regions. These reductions likely follow regional synaptic loss or dysfunction and reflect physiological down-regulation of gene expression for glucose delivery, oxidative phosphorylation (OXPHOS), and energy consumption in brain. Indeed, the pattern of down-regulation of expression for both mitochondrial and nuclear genes coding for subunits of OXPHOS enzymes in the Alzheimer brain resembles the pattern of down-regulation in normal brain caused by chronic sensory deprivation. In both cases, down-regulation likely is mediated by changes in transcriptional and posttranscriptional regulatory factors. Physiological down-regulation of OXPHOS gene expression in Alzheimer's is consistent with PET evidence that cognitive or psychophysical activation of mildly to moderately demented Alzheimer's patients can augment brain–blood flow and glucose metabolism to the same extent as in control subjects. If the primary neuronal defect that leads to reduced brain energy demand in Alzheimer's disease could be prevented or treated, brain glucose transport and OXPHOS enzyme activities might recover to normal levels.