The influence of thyroid hormone on the degree of control of oxidative phosphorylation exerted by the adenine nucleotide translocator

Holness, Mark J.; Crespo-Armas, A; Mowbray, John

doi:10.1016/0014-5793(84)81289-2

Cited by 26 publications

(16 citation statements)

References 25 publications

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“…The effect of T3 on state 4 and state 3 of mitochondrial respiration could be the result of its action on: (a) the concentration of some chain components (Bronk, 1966), (b) substrate dehydrogenase (Lee & Lardy, 1965), (c) adenine nucleotide carrier (Babior et al 1973); Holness et al 1984); even if the action on the latter is noticeable at state 3 respiration (Brand & Murphy, 1987). The current opinion is that the action on the con¬ centration of chain components is of lesser import¬ ance than the activation of substrate dehydrogenase, since hyperthyroidism is associated with increased reduction of the electron transport chain (Brand & Murphy, 1987).…”

Section: Discussionmentioning

confidence: 99%

Effect of 3,3′-di-iodothyronine and 3,5-di-iodothyronine on rat liver mitochondria

Lanni

Moreno²,

Cioffi³

et al. 1993

Journal of Endocrinology

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In the present study we report that 3,3',5-tri-iodothyronine (T3) as well as two iodothyronines (3,5-di-iodothyronine (3,5-T2) and 3,3'-di-iodothyronine (3,3'-T2)) significantly influence rat liver mitochondrial activity. Liver oxidative capacity (measured as cytochrome oxidase activity/g wet tissue) in hypothyroid compared with normal rats was significantly reduced (21%, P > 0.01) and the administration of T3 and both iodothyronines restored normal values. At the mitochondrial level, treatment with T3 stimulated respiratory activity (state 4 and state 3) and did not influence cytochrome oxidase activity. On the other hand, both the mitochondrial respiratory rate and specific cytochrome oxidase activity significantly increased in hypothyroid animals after treatment with 3,3'-T2 or 3,5-T2 (about 50 and 40% respectively). The actions of both iodothyronines were rapid and evident by 1 h after the injection. The hepatic mitochondrial protein content which decreased in hypothyroid rats (9.6 mg/g liver compared with 14.1 in normal controls, P < 0.05) was restored by T3 injection, while neither T2 was able to restore it. Our results suggest that T3 and both iodothyronines have different mechanisms of action. T3 acts on both mitochondrial mass and activity; the action on mitochondrial activity was not exerted at the cytochrome oxidase complex level. The action of the iodothyronines, on the other hand, is exerted directly on the cytochrome oxidase complex without any noticeable action on the mitochondrial mass.

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Section: Discussionmentioning

confidence: 99%

Effect of 3,3′-di-iodothyronine and 3,5-di-iodothyronine on rat liver mitochondria

Lanni

Moreno²,

Cioffi³

et al. 1993

Journal of Endocrinology

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“…were reported by . The importance of this to control of electron flux is doubtful, since Holness et al (1984) showed that the flux control coefficient did not drop with short term triiodothyronine treatment, but rose, implying that altered kinetics of the carrier could not be the primary cause of any increase in respiratory rate. These results were similar to those of Verhoeven et al (1985) using 24 h treated rats.…”

Section: ( C ) Short-term Eflectsmentioning

confidence: 99%

“…Mowbray (Palacios-Romero & Mowbray, 1979;Corrigall & Mowbray, 1983 ;Corrigall, Tselentis & Mowbray, 1984;Holness et al, 1984; Mowbray & Crespo-Armas, I 985) has reported that mitochondria from thyroidectomized rats have P/O ratios approximately half that of euthyroid animals, and that treatment with triiodothyronine for 1 5 min reversed this drop. Unfortunately the method of calculation of P/O ratios was that of Chance & Williams (1955), which utilizes extra oxygen consumed in a state 4-3-4 transition, not total oxygen.…”

Section: ( C ) Short-term Eflectsmentioning

confidence: 99%

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

1987

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Summary To answer the question ‘What controls the rate of respiration?’ requires a clear definition of control and an explicit description of the limits of the system to be considered. In this review we use a neutral definition of control in which A controls B if changes in A cause changes in B. A useful system to define when discussing the control of respiration consists of the electron transport chain, the H+‐ATPase, the adenine nucleotide carrier, the intramitochondrial adenine nucleotide and phosphate pools, δp and the proton leak across the mitochondrial inner membrane. Controls operating within this system are designated internal controls and many of them are fairly well characterized. Several models have been advanced to describe the rates of these internal processes in isolated mitochondria, including control of respiration rate by cytochrome oxidase with all other steps near to equilibrium, control by the adenine nucleotide carrier or control by the extent of displacement of individual reactions from equilibrium. More recently, analysis using control theory has shown that in the resting state (state 4) most control over flux is exerted by the leak of protons through the inner membrane, whereas in more active, phosphorylating states (up to state 3) control is distributed between a number of steps, including the proton leak, the adenine nucleotide carrier and cytochrome oxidase. This approach seems a very useful framework within which to pose further questions. This system may be treated as a ‘black box’ interacting with its environment (the rest of the mitochondrion and the experimental cuvette or living cell) through the redox states of NAD, Q and O2 and through the phosphorylation state of the extramitochondrial adenine nucleotides. Very few external effectors cross the system boundary; the only well‐characterized ones are long‐chain fatty acyl‐CoA, which inhibits the adenine nucleotide carrier, and fatty acids, which activate a specific uncoupling protein found only in the inner membrane of mitochondria from brown adipose tissue. At this level respiration rate is determined only by the internal properties of the ‘black box’, by the redox states of NAD, Q and O2, and by the phosphorylation status of the extramitochondrial adenine nucleotide pool. Within a cell the rate of respiration is controlled primarily by the rates of reactions feeding electrons to the electron transport chain (through their effects on NADH/NAD and QH2/Q ratios) and by the rates of reactions consuming or producing ATP (through the cytosolic phosphorylation potential or ATP/ADP ratio). Control of reducing equivalent supply occurs through availability of oxidizable substrates (determined by diet and hormonal status), through regulation of pathways such as glycolysis or fatty acid catabolism and, importantly, through Ca2+ activation of intramitochondrial dehydrogenases. Hormonal control over respiration can occur at all the levels mentioned. Hormones may alter the kinetic properties of the oxidative phosphorylation system by alterin...

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“…To complement this evidence of a putative receptor, rapid effects of hormone on an energy-driven mitochondrial process such as respiratory control, uncoupler sensitivity [2] and calcium transport [4] have been observed. In our laboratory we have found that liver mitochondria from thyroidectomized rats show a number of altered responses to ADP stimulation that hormone addition at near-physiological concentrations both in vivo and in vitro can restore to normal within 15 min [1, [5][6][7][8].…”

Section: Introductionmentioning

confidence: 99%

Direct thyroid hormone signalling via ADP‐ribosylation controls mitochondrial nucleotide transport and membrane leakiness by changing the conformation of the adenine nucleotide transporter

Mowbray

Hardy

1996

FEBS Letters

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Addition of triiodothyronine at 10 pM in vitro to hypothyroid rat liver mitochondria doubles the rate of the adenine nucleotide transporter at low ADP concentrations. Nicotinamide abolishes this effect in parallel with its inhibition of the ADP-ribosylation of an inner membrane protein identical in size to the transporter. Nieotinamide also renders euthyroid preparations indistinguishable from hypothyroid ones. A mechanism is offered to explain these findings in which it is proposed that the adenine nucleotide transporter is a true allosteric protein and that its covalent modification by ADP-ribosylation increases the stability of the less favoured externally-facing C-conformation and thus increases the proportion of transporters in this orientation: although the C-conformation is significantly more leaky to cations than the tight matrix-facing M-conformation, this enhances ADP import. This model is shown to offer an explanation not only for the transport effects of T3 but also for those of oxidative stress and ADP-ribosylation inhibitors on Ca 2+, H ÷ and K + transfer across the mitochondrial inner membrane. Ca 2+ at 30 nM appears to stabilize the Mconformation of the transporter by a mechanism other than ADP-ribosylation.

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The influence of thyroid hormone on the degree of control of oxidative phosphorylation exerted by the adenine nucleotide translocator

Cited by 26 publications

References 25 publications

Effect of 3,3′-di-iodothyronine and 3,5-di-iodothyronine on rat liver mitochondria

Effect of 3,3′-di-iodothyronine and 3,5-di-iodothyronine on rat liver mitochondria

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

Direct thyroid hormone signalling via ADP‐ribosylation controls mitochondrial nucleotide transport and membrane leakiness by changing the conformation of the adenine nucleotide transporter

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