Phenylbutyrate for therapy of pyruvate dehydrogenase deficiency

Posted by & filed under Part 10: DISORDERS OF MITOCHONDRIAL FUNCTION.

My apologies for posting my own work published this month in Science Translational Medicine. The data presented in this paper highlight the potential of phenylbutyrate for therapy of pyruvate dehydrogenase complex (PDHC) deficiency, the most common genetic disorder leading to lactic acidosis, and systemic lactic acidosis. PDHC activity is regulated by phosphorylation of the E1-alpha subunit by pyruvate dehydrogenase kinase (PDK) that inactivates the enzyme, whereas dephosphorylation restores PDHC activity. We found that phenylbutyrate enhances PDHC enzymatic activity in vitro and in vivo by increasing the proportion of unphosphorylated enzyme through inhibition of PDK. Phenylbutyrate resulted in a significant increase in PDHC enzyme activity and a reduction of phosphorylated E1-alpha in mouse brain, muscle, and liver. We showed that phenylbutyrate prevents phosphorylation of E1-alpha through binding and inhibition of PDK, providing a molecular explanation for the effect of phenylbutyrate on PDHC activity. Phenylbutyrate increases PDHC activity in fibroblasts from PDHC-deficient patients harboring various molecular defects and corrects the morphological, locomotor, and biochemical abnormalities in the noa zebrafish model of PDHC deficiency. In mice, phenylbutyrate prevents systemic lactic acidosis induced by partial hepatectomy. Because phenylbutyrate is already approved for human use in other diseases, the findings of this study have the potential to be rapidly translated for treatment of patients with PDHC deficiency and other forms of primary and secondary lactic acidosis.

Posted by Nicola Brunetti-Pierri, MD

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