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Control of Hepatic Mitochondrial CO₂ Fixation by Glucagon, Epinephrine, and Cortisol

From the ¹ From the Department of Pharmacology, School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106

Hormonal control of the initial step in hepatic gluconeogenesis from pyruvate was examined following acute administration of epinephrine, glucagon, or cortisol to adult rats. After hormonal treatment of the animals, the mitochondria were isolated for the study of pyruvate metabolism. When pyruvate and bicarbonate were the only substrates provided, mitochondrial fixation of carbon dioxide and production of acetyl coenzyme A accounted for the entire uptake of pyruvate. Although none of the three hormones raised the activity of mitochondrial pyruvate carboxylase, each increased mitochondrial pyruvate uptake and secondarily enhanced both CO₂ fixation and pyruvate-1-¹⁴C decarboxylation. The primary role of mitochondrial pyruvate uptake was confirmed by reducing the osmolality of the suspending medium during incubation of mitochondria with substrate. Increasing mitochondrial uptake of pyruvate by this means enhanced both fixation of CO₂ and decarboxylation of pyruvate-1-¹⁴C, while reducing the observable effect of hormone. Apparently the rate of pyruvate transfer into mitochondria is of primary importance in the control of mitochondrial CO₂ fixation.

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