Lack of medium-chain coenzyme A dehydrogenase (MCAD) leads to the accumulation of CoA esters and decreased free CoA pool, according to a new study presented at the 2023 lecture series of the International Network for Fatty Acid Oxidation Research and Management (INFORM).
In vivo, the lack of the enzyme likely leads to the activation of CoA rescue mechanisms, Ligia Akemi Kiyuna, MSc, explained.
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To explore whether the loss of MCDA in MCDA deficiency has an effect on the availability of coenzyme A, the team led by Barbara M. Bakker, PhD, from the University of Groeningen in The Netherlands, used a computational model as well as in vitro and in vivo models.
Based on the results of the computational model, the researchers hypothesized that the lack of MCAD leads to the accumulation of acyl-CoA esters and decreased levels of free CoA.
To validate the predictions of the model in vitro, the researchers created 3 different MCAD knock out cell lines.
When they incubated these cells in medium containing low amounts of glucose and palmitate, they found that the amount of free CoA was reduced. Interestingly, they also saw that in these cells, the amounts of short and long-chain acyl-CoA were also reduced. This decrease was predicted by the computational model.
Finally, the researchers analyzed the effect of the lack of MCAD in vivo using an MCAD knock-out mouse model. They exposed these animals to overnight fasting followed by a 4-hour cold exposure.
Although there was no difference in the amount of total CoA in the liver of wild type and MCAD knock-out mice, the level of total CoA increased in the liver of MCAD knock-out animals following fasting plus cold exposure.
The researchers hypothesized that this could be due to a compensatory rescue mechanism, either through an increase in CoA synthesis or a decrease in CoA degradation, the hydrolysis of acyl CoA to release free CoA, or the addition of carnitine to acyl-CoA, thereby releasing free CoA as well as acyl-carnitine.
“All the potential mechanisms that might be helping free coA to be released or increased in amount seem to be activated in the liver of these animals,” Kiyuna said.
MCAD deficiency is a type of inherited metabolic disorder characterized by the inability of the body to break down certain fats to produce energy. The disease is caused by a mutation in the ACADM gene, which codes for the MCAD enzyme. Other types of inherited metabolic disorders include long-chain fatty acid oxidation disorders (LCFAOD).
Kiyuna LA. Reduced coenzyme A availability in medium chain acyl-CoA dehydrogenase deficiency (MCADD). Lecture presented at the International Network for Fatty Acid Oxidation Research and Management (INFORM) 2023 lecture series: May 15, 2023; Virtual.