US EPA

7065309 

Journal Article 

Stabilization of the pyruvate dehydrogenase E1 alpha subunit by dichloroacetate 

Morten, KJ; Caky, M; Matthews, PM; , 

1998 

1 

Neurology
ISSN: 0028-3878
EISSN: 1526-632X 

LIPPINCOTT WILLIAMS & WILKINS 

PHILADELPHIA 

1331-1335 

9818855 

WOS:000076906600020 

Objective: To test the effects of dichloroacetate (DCA) treatment on the rate of turnover of pyruvate dehydrogenase (PDH) subunits. Background: PDH deficiency is a nuclear-encoded mitochondrial disorder and a major recognized cause of neonatal encephalomyopathies associated with primary lactic acidosis. DCA has been used for its treatment. The primary mechanism of action of DCA has been thought to increase the proportion of enzyme in the activated, dephosphorylated state. However, this mechanism does not readily account for responses to treatment with mutations that do not obviously affect regulation of the enzyme complex. Methods: PDH subunit turnover rates were measured using pulse-chase methods in a normal fibroblastic cell line before and after chronic (5-day) treatment with 5 mM DCA. Results: Chronic DCA treatment causes a more than twofold decrease in the apparent first-order rate constant for degradation of the PDH E1 alpha subunit (k(E1)alpha(pre-DCA) = 0.025 +/- 0.006 hr(-1), n = 6; k(E1)alpha(post-DCA) = 0.011 +/- 0.002 hr(-1), n = 3; p < 0.01) and a selective, progressive increase in the total cell PDH activity by 150 +/- 5% (p < 0.0005). Conclusion: These results suggest an additional novel mechanism of action for the chronic DCA treatment of lactic acidemia; namely, inhibition of mitochondrial E1 alpha subunit degradation leading to an increase in maximal PDH complex activity.