Phenylbutyrate Therapy for Pyruvate Dehydrogenase Complex Deficiency and Lactic Acidosis

Abstract

Lactic acidosis is a build-up 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 C57B6/L 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.

Ciprofloxacin Therapy Results in Mitigation of ATP Loss after Irradiation Combined with Wound Trauma: Preservation of Pyruvate Dehydrogenase and Inhibition of Pyruvate Dehydrogenase Kinase 1

“…Combined injury diminished the amount of PDH complex but increased PDK, a symptom similar to that found in PDH deficiency disease (33), which is a genetic disorder. The possibility of combined injury-induced DNA damage on the PDH gene cannot be ruled out, since combined injury has previously demonstrated the ability to increase DNA strand breaks (16).…”

Increasing Pyruvate Dehydrogenase Flux as a Treatment for Diabetic Cardiomyopathy: A Combined 13C Hyperpolarized Magnetic Resonance and Echocardiography Study

“…However, despite the benefits in glycemic control, it has not been widely used as a diabetic treatment because of side effects, which include peripheral neuropathy (53). Although other agents, such as phenylbutyrate (54), are now available to increase PDH activity, their use has, in general, been limited to the treatment of rare conditions of inborn errors in metabolism, including congenital PDH deficiency (55). The findings in our study support further work into the development of PDK and PDH modulators as targets for the treatment of type 2 diabetes.…”

E4F1 controls a transcriptional program essential for pyruvate dehydrogenase activity

“…The diverse clinical manifestations of PDCdeficient patients are significantly, but only partly, improved by ketogenic diets that provide alternative energetic substrates or by treatment with PDK inhibitors, such as dicholoroacetate (DCA). Thiamine/lipoic acid supplementations that favor optimal PDH activity, or bicarbonate treatment that buffers lactate acidosis, have also been tested, although with moderate efficiency (14,15). The design of new and more efficient therapeutic approaches will require a better understanding of PDH regulation and the development of clinically relevant animal models.…”