Dichloroacetate stabilizes the mutant E1alpha subunit in pyruvate dehydrogenase deficiency.

[pyruvate dehydrogenase deficiency]

To determine whether dichloroacetate (DCA ) treatment can increase pyruvate dehydrogenase (PDH ) activity in PDH -deficient cell lines harboring pathogenic mutations in the PDH E 1 alpha gene .P DH deficiency is a nuclear-encoded mitochondrial disorder and a major recognized cause of neonatal encephalomyopathies associated with primary lactic acidosis . Over the last decade , DCA has been used therapeutically , but it has not been clear which patients might benefit . Recent studies suggest that chronic DCA treatment may act by increasing the stability of mutant E 1 alpha polypeptide . The relative effects of DCA treatment on PDH -deficient cell lines with E 1 alpha mutations primarily affecting polypeptide stability or catalytic activity were determined and the mechanism of enhancement of residual PDH activity explored .The effect of chronic 5 -day DCA treatment on PDH activity was assessed in PDH -deficient cell lines containing the R 378 H , R 141 Q , K 387 (FS ), and R 302 C E 1 alpha mutations . PDH subunit turnover and steady-state E 1 alpha levels before and after DCA treatment were measured in the R 378 H mutant line .C hronic DCA treatment resulted in 25 % (p = 0 .0434 ), 31 % (p = 0 .0014 ) increases in PDH activity in the K 387 (FS ) and R 378 H cell lines , both of which are associated with decreased mutant polypeptide stability . In the R 378 H mutant cell line , chronic DCA treatment increased steady-state E 1 alpha levels and slowed the rate of E 1 alpha turnover twofold . In contrast , PDH activity did not change in the chronically DCA-treated R 302 C mutant line , in which the mutant polypeptide has normal stability and reduced catalytic activity .Chronic DCA treatment can increase PDH activity in PDH -deficient cell lines harboring mutations that affect E 1 alpha stability , suggesting a biochemical criterion by which DCA-responsive patients might be selected .

Diseases
Validation

Diseases presenting "deficient cell lines" symptom

pyruvate dehydrogenase deficiency

zellweger syndrome

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