Dihydrolipoamide dehydrogenase, pyruvate oxidation, and acetylation-dependent mechanisms intersecting drug iatrogenesis

The mitochondrial pyruvate dehydrogenase (PDH) complex (PDC) acts as a central metabolic node that mediates pyruvate oxidation and fuels the tricarboxylic acid cycle to meet energy demand. Here, we reveal another level of regulation of the pyruvate oxidation pathway in mammals implicating the E4 transcription factor 1 (E4F1). E4F1 controls a set of four genes [dihydrolipoamide acetlytransferase (Dlat), dihydrolipoyl dehydrogenase (Dld), mitochondrial pyruvate carrier 1 (Mpc1), and solute carrier family 25 member 19 (Slc25a19)] involved in pyruvate oxidation and reported to be individually mutated in human metabolic syndromes. E4F1 dysfunction results in 80% decrease of PDH activity and alterations of pyruvate metabolism. Genetic inactivation of murine E4f1 in striated muscles results in viable animals that show low muscle PDH activity, severe endurance defects, and chronic lactic acidemia, recapitulating some clinical symptoms described in PDC-deficient patients. These phenotypes were attenuated by pharmacological stimulation of PDH or by a ketogenic diet, two treatments used for PDH deficiencies. Taken together, these data identify E4F1 as a master regulator of the PDC.

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Thioctic Acid Content and Pyruvate Oxidation in Ethionine-Damaged Rat Livers.

Experimental Biology and Medicine ◽

10.3181/00379727-90-21967 ◽

1955 ◽

Vol 90 (1) ◽

pp. 153-158 ◽

Cited By ~ 6

Author(s):

G. L. Fischer

Keyword(s):

Acid Content ◽

Thioctic Acid ◽

Pyruvate Oxidation ◽

Rat Livers

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Regulation of glycogen phosphorylase and PDH during exercise in human skeletal muscle during hypoxia

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.2000.278.3.e522 ◽

2000 ◽

Vol 278 (3) ◽

pp. E522-E534 ◽

Cited By ~ 41

Author(s):

Michelle L. Parolin ◽

Lawrence L. Spriet ◽

Eric Hultman ◽

Melanie G. Hollidge-Horvat ◽

Norman L. Jones ◽

...

Keyword(s):

Skeletal Muscle ◽

Glycogen Phosphorylase ◽

Lactate Production ◽

Muscle Metabolism ◽

Lactate Accumulation ◽

Pyruvate Oxidation ◽

Reduced Rate ◽

Rate Limiting ◽

Muscle Biopsies ◽

Elevated Lactate

The present study examined the acute effects of hypoxia on the regulation of skeletal muscle metabolism at rest and during 15 min of submaximal exercise. Subjects exercised on two occasions for 15 min at 55% of their normoxic maximal oxygen uptake while breathing 11% O2 (hypoxia) or room air (normoxia). Muscle biopsies were taken at rest and after 1 and 15 min of exercise. At rest, no effects on muscle metabolism were observed in response to hypoxia. In the 1st min of exercise, glycogenolysis was significantly greater in hypoxia compared with normoxia. This small difference in glycogenolysis was associated with a tendency toward a greater concentration of substrate, free Pi, in hypoxia compared with normoxia. Pyruvate dehydrogenase activity (PDHa) was lower in hypoxia at 1 min compared with normoxia, resulting in a reduced rate of pyruvate oxidation and a greater lactate accumulation. During the last 14 min of exercise, glycogenolysis was greater in hypoxia despite a lower mole fraction of phosphorylase a. The greater glycogenolytic rate was maintained posttransformationally through significantly higher free [AMP] and [Pi]. At the end of exercise, PDHawas greater in hypoxia compared with normoxia, contributing to a greater rate of pyruvate oxidation. Because of the higher glycogenolytic rate in hypoxia, the rate of pyruvate production continued to exceed the rate of pyruvate oxidation, resulting in significant lactate accumulation in hypoxia compared with no further lactate accumulation in normoxia. Hence, the elevated lactate production associated with hypoxia at the same absolute workload could in part be explained by the effects of hypoxia on the activities of the rate-limiting enzymes, phosphorylase and PDH, which regulate the rates of pyruvate production and pyruvate oxidation, respectively.

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Glucose metabolism in perfused skeletal muscle. Pyruvate dehydrogenase activity in starvation, diabetes and exercise

Biochemical Journal ◽

10.1042/bj1580203 ◽

1976 ◽

Vol 158 (2) ◽

pp. 203-210 ◽

Cited By ~ 65

Author(s):

S A Hagg ◽

S I Taylor ◽

N B Ruberman

Keyword(s):

Skeletal Muscle ◽

Dehydrogenase Activity ◽

Pyruvate Dehydrogenase ◽

Preceding Paper ◽

Diabetic Rats ◽

Pyruvate Dehydrogenase Kinase ◽

Lactate Oxidation ◽

Pyruvate Oxidation ◽

Measured Activity ◽

Exercise Induced

1. The interconversion of pyruvate dehydrogenase between its inactive phosphorylated and active dephosphorylated forms was studied in skeletal muscle. 2. Exercise, induced by electrical stimulation of the sciatic nerve (5/s), increased the measured activity of (active) pyruvate dehydrogenase threefold in intact anaesthetized rated within 2 min. No further increase was seen after 15 min of stimulation. 3. In the perfused rat hindquarter, (active) pyruvate dehydrogenase activity was decreased by 50% in muscle of starved and diabetic rats. Exercise produced a twofold increase in its activity in all groups; however, the relative differences between fed, starved and diabetic groups persisted. 4. Perfusion of muslce with acetoacetate (2 mM) decreased (active) pyruvate dehydrogenase activity by 50% at rest but not during exercise. 5. Whole-tissue concentrations of pyruvate and citrate, inhibitors of (active) pyruvate dehydrogenase kinase and (inactive) pyruvate dehydrogenase phosphate phosphatase respectively, were not altered by excerise. A decrease in the ATP/ADP ratio was observed, but did not appear to be sufficient to account for the increase in (active) pyruvate dehydrogenase activity. 6. The results suggest that interconversion of the phosphorylated and dephosphorylated forms of pyruvate dehydrogenase plays a major role in the regulation of pyruvate oxidation by eomparison of enzyme activity with measurements of lactate oxidation in the perfused hindquarter [see the preceding paper, Berger et al. (1976)] suggest that pyruvate oxidation is also modulated by the concentrations of substrates, cofactors and inhibitors of (active) pyruvate dehydrogenase activity.

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