The quantitative contributions of mitochondrial proton leak and ATP turnover reactions to the changed respiration rates of hepatocytes from rats of different thyroid status

Hepatocytes from hypothyroid rats respire more slowly than those from control animals; cells from hyperthyroid rats respire faster. We have identified the blocks of reactions whose kinetics are significantly affected by thyroid hormones and have quantified the contribution of flux through different blocks of energy-dissipating reactions to the altered oxygen consumption. In cells from hypothyroid rats compared with littermate euthyroid controls, there were significant kinetic effects on non-mitochondrial oxygen consumption reactions and on mitochondrial proton leak but not on ATP turnover. Approximately 50% of the decrease in cellular oxygen consumption of hypothyroid cells was accounted for by a decrease in mitochondrial proton leak rate and approximately 50% by decreased non-mitochondrial oxygen consumption. Metabolic control analysis showed that the distribution of control over oxidative phosphorylation and mitochondrial potential in hepatocytes from hypothyroid animals was broadly similar to its distribution in euthyroid controls. In cells from hyperthyroid rats compared with littermate euthyroid controls, there were significant kinetic effects on mitochondrial proton leak and on the reactions involved in ATP synthesis and consumption but not on non-mitochondrial oxygen consumption. Approximately 50% of the increase in cellular oxygen consumption in hyperthyroid cells was accounted for by an increased mitochondrial proton leak rate and the remainder by increased ATP turnover; there were no changes in non-mitochondrial oxygen consumption.