Ferriero, R., Manco, G., Lamantea, E., Nusco, E., Ferrante, M.I., Sordino, P., Stacpoole, P.W., Lee, B., Zeviani, M., and Brunetti-Pierri, N. (2013) Phenylbutyrate therapy for pyruvate dehydrogenase complex deficiency and lactic acidosis. Science Translational Medicine. 5(175):175ra31.
Lactic acidosis is a buildup of lactic acid in the blood and tissues, which can be due to several inborn errors of metabolism
as well as nongenetic conditions. Deficiency of pyruvate dehydrogenase complex (PDHC) is the most common genetic disorder
leading to lactic acidosis. Phosphorylation of specific serine residues of the E1α subunit of PDHC by pyruvate dehydrogenase
kinase (PDK) 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 given to C57BL/6 wild-type mice results in a significant increase in PDHC enzyme activity and a reduction
of phosphorylated E1α in brain, muscle, and liver compared to saline-treated mice. By means of recombinant enzymes, we showed
that phenylbutyrate prevents phosphorylation of E1α 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
noam631 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.