Alterations of oxidative phosphorylation reactions in mitochondria isolated from hypothyroid rat liver

Abstract

1. Several parameters of oxidative phosphorylation reaction were studied in vitro in isolated liver mitochondria from hypothyroid rats.2. When succinate was employed as a respiratory substrate for mitochondria incubated in a mannitol/sucrose/ phosphate buffer, and measurements were performed during initial additions of ADP, the magnitude of state 3 and state 4 respiration was not different between mitochondria from the hypothyroid and those from the control rats.3. During the course of repetitive additions of ADP and consequently of sequential transitions from state 4 to state 3 and back to state 4, mitochondria from hypothyroid animals showed a gradual decline in the rate of both state 3 and state 4 respiration whereas those from normal animals did not. The total succinate dehydrogenase activity was not different between the two types of mitochondria, and the decline in state 3 and state 4 respiration was not accompanied by any change in the apparent K, for ADP or in the corrected ADPjO ratio [Biochem. Biophys. Res. Commun. (1973) 53, 9881. 4. The amount of oxygen consumed during the state-4-3+4 transition was lower in the hypothyroid than in the control mitochondria.5. These alterations were reversed if the hypothyroid animals were injected with thyroxine intraperitoneally (2 pg/l00 g body weight) for 3 weeks before isolation of mitochondria.6. These results indicate that the fall of respiratory activity in hypothyroidism may result from the decrease not only of respiratory activities of state 3 and state 4, but also of the energy spent in the process of the state-4+3+4 transition, while the coupling efficiencyper se remains normal. These properties become manifest when mitochondria respond to pulses of ADP load, a situation likely to occur in situ.Alteration in the tissue respiratory activity is one of the most characteristic metabolic changes observed in thyroid dysfunction. Various attempts have been made to attribute this change in respiratory activity to an influence of thyroid hormone directly upon the process of oxidative phoshorylation. Earlier reports demonstrated that thyroxine in vitro caused an uncoupling of oxidative phosphorylation [l], and the same hormone in vivo an increase in the transmembrane protonic electrochemical potential difference and the respiratory rate [2].However, in these experiments unphysiologically high doses of thyroxine (up to 1 mM thyroxine in experiments in vitro, and 800 mg of thyroxine subcutaneouslyJkg body weight in vivo experiments) were used [l, 21, and later work has not confirmed this concept. Because thyroid hormone is needed for normal development and maintenance of normal functions of many organs, another naive scepticism concerns with the biological significance of uncoupling of oxidative phosphorylation and of an increase in the transmembrane potential difference.Enq~mex Succinate dehydrogenase or succinate: 2,6-dichloroindophenol oxidoreductase (EC 1.3.99.1); phospholipase A from Crotalus terrificus (EC3.1.1.4).As an attempt to elucidate the mechanism of r...

Effect of Thyroid State on the Morphof unctional Properties of Heart Mitochondria

“…This result indicates that mito chondrial oxidative phosphorylation, in heart, remains tightly coupled in hyperthy roidism as in euthyroid and hypothyroid states. A similar pattern has been found by Ezawa et al [9] and Verhoeven et al [10] for rat liver and by Katyare et al [8] for rat liver, kidney, and brain mitochondria. Therefore, the hormone-induced respiration cannot be attributed to uncoupling of oxidative phos phorylation.…”

“…but as yet the evi dence is inconclusive. Also the mechanism of long-term effects on respiration rate, occur ring over a period of days or weeks [8][9][10], remains unknown, though an increase in the area of mitochondrial inner membrane, in creased amounts of respiratory chain protein, augmentation in activities of various enzymes relevant to energy metabolism, changes in membrane lipids have been suggested [ 11],…”

Mitochondrial DNA transcription regulation and nucleoid organization

“…Hyperthyroidism is associated with increased respiratory enzyme activity in several tissues including liver, heart and skeletal muscle (Short et al 2007). In contrast, decreased mitochondrial activity and oxygen consumption were observed in liver and brain from hypothyroid animals (Ezawa et al 1984) (Martinez et al 2009). Additionally, administration of T3 rescues the mitochondrial deficiency of hypothyroid mice (Sterling et al 1980).…”

Control of Electron Flux Through the Respiratory Chain in Mitochondria and Cells

“…Similarly, hypothyroid rats have depressed amounts of liver inner mitochondrial membrane, cytochromes, succinate-cytochrome c reductase and H+-ATPase (Clot & Baudry, I 982; Dembri et al, 1984). Injection of low levels of thyroxine or triiodothyronine over a period of days or weeks elevates these concentrations by differential stimulation of protein synthesis, and also increases state 3 and state 4 respiration rates of the isolated mitochondria (Nelson, Mutvei & Joste, 1984;Ezawa et al, 1984).…”