Linear relationships between mitochondrial forces and cytoplasmic flows argue for the organized energy‐coupled nature of cellular metabolism

Berry, Michael N.; Gregory, Roland B.; Grivell, Anthony R.; Henly, Debra C.; Phillips, John W.; Wallace, Patricia G.; Welch, G. Rickey

doi:10.1016/0014-5793(87)80448-9

Cited by 26 publications

(5 citation statements)

References 44 publications

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“…Moreover, very little of the resting respiration was responsive to inhibition by oligomycin (6), strongly suggesting that the elevated temperature exacerbated the proton leak of the inner mitochondrial membrane (3). Mitochondrial uncoupling degrades the cytosolic free energy of ATP hydrolysis (G p ) (9), and hepatic gluconeogenic flux has been shown to vary linearly with cellular energy state (2).…”

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confidence: 99%

Hyperthermia impairs liver mitochondrial function in vitro

Willis

Jackman

Bizeau

et al. 2000

American Journal of Physiology-Regulatory, Integrative and Comp

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The effects of temperature on the relationships among the rates of pyruvate carboxylation, O(2) uptake (J(o)), oxidative phosphorylation (J(p)), and the free energy of ATP hydrolysis (G(p)) were studied in liver mitochondria isolated from 250-g female rats. Pyruvate carboxylation was evaluated at 37, 40, and 43 degrees C. In disrupted mitochondria, pyruvate carboxylase maximal reaction velocity increased from 37 to 43 degrees C with an apparent Q(10) of 2.25. A reduction in ATP/ADP ratio decreased enzyme activity at all three temperatures. In contrast, in intact mitochondria, increasing temperature failed to increase pyruvate carboxylation (malate + citrate accumulation) but did result in increased J(o) and decreased extramitochondrial G(p). J(p) was studied in respiring mitochondria at 37 and 43 degrees C at various fractions of state 3 respiration, elicited with a glucose + hexokinase ADP-regenerating system. The relationship between J(o) and G(p) was similar at both temperatures. However, hyperthermia (43 degrees C) reduced the J(p)/J(o) ratio, resulting in lower G(p) for a given J(p). Fluorescent measurements of membrane phospholipid polarization revealed a transition in membrane order between 40 and 43 degrees C, a finding consistent with increased membrane proton conductance. It is concluded that hyperthermia augments nonspecific proton leaking across the inner mitochondrial membrane, and the resultant degraded energy state offsets temperature stimulation of pyruvate carboxylase. As a consequence, at high temperatures approaching 43 degrees C, the pyruvate carboxylation rate of intact liver mitochondria may fail to exhibit a Q(10) effect.

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confidence: 99%

Hyperthermia impairs liver mitochondrial function in vitro

Willis

Jackman

Bizeau

et al. 2000

American Journal of Physiology-Regulatory, Integrative and Comp

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“…Although this crowded cytosol paradigm has played a major role in the development of major concepts of cell biology, questions have been raised over the years about the validity of this premise (for historical review, see Sols and Marco, 1970;Ottaway and Mowbray, 1977). Extensive research during the last decade has provided even more reason to doubt that view (for selected reviews, see Fulton, 1982;Clegg, 1984;Bhargava, 1985;Welch and Clegg, 1986;Berry et al, 1987;Jones, 1988;Luby-Phelps et al, 1988;Negendank and Edelmann, 1988).…”

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confidence: 99%

Effects of reduced cell volume and water content on glycolysis in L‐929 cells

Clegg

Jackson

Fendl

1990

Journal Cellular Physiology

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Mouse L-929 cells were subjected to increasing concentrations of sorbitol, which remove cell water and reduce volume osmotically. The rate of lactate production from glucose was significantly higher in osmotically perturbed cells than in controls, both in monolayers and in suspensions. L cells can apparently use sorbitol as a glycolytic substrate; however, studies using other solutes (trehalose and sucrose) and permeabilized cells showed that the major effect of sorbitol on glycolysis in intact cells is mediated through a reduction in cell water content and volume. It is possible to explain some of these results by an increase in the chemical potentials of dissolved components of the glycolytic pathway caused by water loss; however, the relationship between water loss and glycolytic rate increase in not a simple linear one, suggesting that the situation is more complex than would result merely from increased concentrations of pathway components. Whatever the complete explanation might be, these studies show that glycolysis continues in an orderly fashion in cells that have lost about 85% of their original water content, suggesting that the operation of this pathway is not unduly sensitive to events taking place in the bulk aqueous phase.

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“…There is evidence that alterations in mitochondrial redox may also have significant effects on hepatocyte function and responsiveness. Prior studies with isolated hepatocytes have suggested that the optimal NAD + /NADH for gluconeogenesis and ureagenesis is approximately 1.3 (Berry et al, 1987). Furthermore, the sensitivity of liver to glucagonmediated cytosolic elevations in cAMP and calcium, which increase the activity of key TCA cycle enzymes such as ␣-ketoglutarate dehydrogenase (Rashed and Patel, 1988) and pyruvate dehydrogenase (Walajtys-Rhode et al, 1992), depends on the oxidation-reduction state of liver, whereby extremely low or elevated redox decrease the sensitivity of the response to glucagon (Rashed and Patel, 1987).…”

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confidence: 99%

Metabolic effects of stress mediators on cultured hepatocytes

Zupke

Stefanovich

Berthiaume

et al. 1998

Biotechnol. Bioeng.

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Stress mediators play a major role in inducing the hypermetabolic stress state in the liver after major injuries. The majority of studies on the effect of mediators on hepatocytes have focused on single factor effects or on the effect of very complex additives (e.g., serum), and there are no reports which have rigorously identified specific interactions between stress mediators. We used a factorial design experimental approach to evaluate the effects of a four to five day exposure to hormone (glucagon, hydrocortisone, and epinephrine) and cytokine [tumor necrosis factor‐α (TNF‐α) interleukin‐1β (IL‐1β) and interleukin‐6 (IL‐6)] stress mediators on stable cultures of rat hepatocytes. Both individual‐factor effects and two factor interactions on the metabolism of urea, glucose, lactate, ketone bodies, albumin, and fibrinogen were evaluated. The cultured hepatocyte model exhibited physiologic responses to the applied stress mediators. While hydrocortisone and epinephrine had no effect, glucagon induced an increase in glucose and urea synthesis. Interleukin‐6 increased fibrinogen and decreased albumin production. Furthermore, IL‐6 and glucagon caused an increase in the ketone‐body ratio (KBR = [acetoacetate]/[β‐hydroxybutyrate]), which is in equilibrium with the intramitochondrial NAD+/NADH. Tumor necrosis factor‐α and IL‐1β, on the other hand, decreased the KBR. An important two‐factor interaction between IL‐1β and IL‐6 was identified, namely that IL‐1β effectively negates the positive effect of IL‐6 on the KBR when both are present. These results provide further understanding of the effect of stress mediators on hepatic function and metabolism. These effects may have important implications in the pathogenesis of progressive organ dysfunction which often follows prolonged inflammatory states triggered by major injuries. © 1998 John Wiley & Sons, Inc. Biotechnol Bioeng 58:222–230, 1998.

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Linear relationships between mitochondrial forces and cytoplasmic flows argue for the organized energy‐coupled nature of cellular metabolism

Cited by 26 publications

References 44 publications

Hyperthermia impairs liver mitochondrial function in vitro

Hyperthermia impairs liver mitochondrial function in vitro

Effects of reduced cell volume and water content on glycolysis in L‐929 cells

Metabolic effects of stress mediators on cultured hepatocytes

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