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 noa(m631) 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.