The mammalian
pyruvate dehydrogenase complex (PDHC) is a mitochondrial matrix
enzyme complex (greater than 7 million Daltons) that catalyzes the oxidative decarboxylation of
pyruvate to form
acetyl CoA,
nicotinamide adenine dinucleotide (the reduced form,
NADH), and CO(2). This reaction constitutes the bridge between anaerobic and aerobic cerebral energy metabolism. PDHC
enzyme activity and immunoreactivity are lost in selectively vulnerable neurons after
cerebral ischemia and reperfusion. Evidence from experiments carried out in vitro suggests that reperfusion-dependent loss of activity is caused by oxidative
protein modifications. Impaired
enzyme activity may explain the reduced cerebral
glucose and oxygen consumption that occurs after
cerebral ischemia. This hypothesis is supported by the hyperoxidation of mitochondrial electron transport chain components and
NAD(H) that occurs during reperfusion, indicating that
NADH production, rather than utilization, is rate limiting. Additional support comes from the findings that immediate postischemic administration of
acetyl-L-carnitine both reduces brain
lactate/
pyruvate ratios and improves neurologic outcome after
cardiac arrest in animals. As
acetyl-L-carnitine is converted to
acetyl CoA, the product of the PDHC reaction, it follows that impaired production of
NADH is due to reduced activity of either PDHC or one or more steps in glycolysis. Impaired cerebral energy metabolism and PDHC activity are associated also with
neurodegenerative disorders including
Alzheimer's disease and
Wernicke-Korsakoff syndrome, suggesting that this
enzyme is an important link in the pathophysiology of both
acute brain injury and chronic neurodegeneration.