Phenylbutyrate therapy for pyruvate dehydrogenase complex deficiency and lactic acidosis.

TitlePhenylbutyrate therapy for pyruvate dehydrogenase complex deficiency and lactic acidosis.
Publication TypeJournal Article
Year of Publication2013
AuthorsFerriero, R, Manco, G, Lamantea, E, Nusco, E, Ferrante, MI, Sordino, P, Stacpoole, PW, Lee, B, Zeviani, M, Brunetti-Pierri, N
JournalSci Transl Med
Date Published2013 Mar 06
KeywordsAcidosis, Lactic, Animals, Brain, Liver, Mice, Muscle, Skeletal, Phenylbutyrates, Phosphorylation, Pyruvate Dehydrogenase Complex Deficiency Disease

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.

Alternate JournalSci Transl Med
Citation Key10.1126/scitranslmed.3004986
PubMed ID23467562
PubMed Central IDPMC4102924
Grant ListR01 DK092921 / DK / NIDDK NIH HHS / United States
U54 HD061221 / HD / NICHD NIH HHS / United States
TGM11MT3 / / Telethon / Italy
/ / Howard Hughes Medical Institute / United States
GPP10005 / / Telethon / Italy