Regulation of pyruvate dehydrogenase in isolated rat liver mitochondria. Effects of octanoate, oxidation-reduction state, and adenosine triphosphate to adenosine diphosphate ratio.

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Taylor SI, Mukherjee C, Jungas RL

Regulation of pyruvate dehydrogenase in isolated rat liver mitochondria. Effects of octanoate, oxidation-reduction state, and adenosine triphosphate to adenosine diphosphate ratio.

J Biol Chem. 1975 Mar 25;250(6):2028-35.

PubMed ID

1116996 [ View in PubMed

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Abstract

Factors which influence the distribution of pyruvate dehydrogenase between its active, unphosphorylated form (PDHa) and its inactive, phosphorylated form (PDHb) have been examined in isolated rat liver mitochondria. A rapid freezing method was developed for the extraction of pyruvate dehydrogenase from incubated mitochondria which prevented interconversions between PHDa and PDHb which normally occur when mitochondria are collected by centrifugal methods. The intramitochondrial ATP:ADP ration was varied over a 100-fold range by the addition of dinitrophenol, oligomycin, or both substances to mitochondria oxidizing 2-oxoglutarate. PDHa activity was found to be inversely proportional to the intramitochondrial ATP:ADP ratio but was not closely correlated with the extramitochondrial adenine nucleotide levels. When mitochondria were incubated in State 4 with succinate and rotenone, the addition of pyruvate increased PDHa activity more than 10-fold without appreciably altering the mitochondrial ATP:ADP ratio. These observations are most readily explained by the known inhibitory effects of pyruvate and ADP on PDHa kinase. PDHa activity could be maintained at a high level by incubating mitochondria in a condition resembling State 3 by the addition of succinate, glucose, and hexokinase. The further addition of octanoate reduced PDHa activity by 60% without appreciably altering the ATP:ADP ratio. Rotenone had a sililar effect. When added in the presence of octanoate, rotenone further decreased PDHa activity whereas 4-pentenoate led to an increase in activity. The effects of octanoate on PDHa activity were not seen when mitochondria were incubated in the presence of high levels of pyruvate, though pyruvate oxidation was till diminished by over 50%. The data suggest that octanoate addition favors the PDHa kinase reaction leading to inactivation of PDHa, and in addition causes the accumulation of NADH and acetyl-CoA which are recognized competitive inhibitors of pyruvate dehydrogenase.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
NADH	Pyruvate dehydrogenase E1 component subunit beta, mitochondrial	Protein	Humans	Unknown	Not Available	Details