In the present study, the St. Jude team showed that low levels of CoA trigger the activation of genes that block other biochemical pathways that ordinarily use this molecule. Instead, the cell shifts most of the available CoA activity to producing glucose from the liver. Other organs then break down glucose into a molecule called pyruvate inside structures called mitochondria. In the mitochondria, CoA molecules perform another job: feeding pyruvate into a complex series of chemical reactions that produces molecules of ATP.
"Our results identify the re-arrangements that the cell's metabolism undergoes in order to ensure that the liver keeps CoA levels high enough to produce glucose and the cells of the body maintain enough free CoA for the mitochondria to keep producing ATP," said Yong-Mei Zhang, Ph.D., of the St. Jude Infectious Diseases department and first author of the report.
The investigators demonstrated many of the metabolic changes caused by a shortage of CoA by treating mice with HoPan. The resulting decrease in CoA triggered severe hypoglycemiaa low level of glucose in the blood. Prior to the hypoglycemia, the liver cells adjusted their metabolism in an effort to maintain the glucose output. This study identified several key steps, including a substantial increase in the amount of enzymes that free CoA from molecules called acyl groups, as well as increases in the amount of acylcarnitine, a molecule that grabs those acyl groups, ensuring that CoA remains free and available for energy production.