PDH Role in Disease
Genetic PDH deficiency: Leigh's Syndrome
PDH deficiency is a severe disorder with a broad spectrum of clinical symptoms. A reduction in PDH activity leads to decreased oxidative utilization of pyruvate, which results in accumulation of lactic acid and reduced overall energy production. Alternative metabolic pathways are stimulated to provide energy needs for heart and skeletal muscle but in highly aerobic, glucose-dependent tissues, such as the brain, there is energy insufficiency. The consequence is that, genetic PDH deficiency leads to neurological dysfunction, which often shows in infancy or early childhood. This condition is most often diagnosed as Leigh's disease.
Approximately 90% of reported cases are caused by mutations in the E1α gene (PDHA1), encoded on the X chromosome. Fewer numbers of patients have been reported with deficiencies in the remaining subunits. Interestingly, the first two mutations in the E2 gene, DLAT, were recently described. In both cases, the symptoms were relatively mild compared to patients with E1α mutations.
Clinical and biochemical variability observed in patients is a function of the site of mutation and occurs as a result of X chromosome inactivation; more severe mutations can be tolerated in females than males with only one X chromosome.
Alzheimer's disease is the most common age-related neurodegenerative disease. Research shows that decreased glucose metabolism may be critical in the pathophysiology of Alzheimer's disease. There is evidence of oxidative modification and consequent inhibition of PDH activity in Alzheimer's disease.
Diabetes is fast becoming the most common late onset disease in humans, primarily because of increased food intake and reduced exercising of the human population. PDH functioning is central to regulation of catabolic and anabolic metabolism of carbohydrates and fats. The enzyme regulates the generation of energy equivalents between glycolysis versus oxidative phosphorylation. By producing acetyl-CoA it indirectly regulates β fatty acid oxidation. Regulation involves substrate and product inhibition along with phosphorylation, which inactivates and dephosphorylation, which activates the complex. Four different PDH kinases (PDK1-4) are involved. Altered expression of PDK4 is suspected in Type II diabetes. Overall regulation is insulin sensitive and can be modulated by diet and exercise, as well as by starvation.
It has been suggested based on in vitro experiments that dichloroacetate (DCA) may be effective in treating patients with congenital lactic acidosis, including ones with PDH deficiency and defects in OXPHOS. DCA is a structural analog of pyruvate and inhibits the activity of PDKs, thus keeping PDH in its unphosphorylated, catalytically active form. DCA treatment has remained controversial due to the side-effects.
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