Role of Zn(II) in the mitochondrial swelling action of insulin

Cash, William D.; Aanning, H L; Carlson, Harold E.; Cox, Springer W.; Ekong, Enobong A.

doi:10.1016/0003-9861(68)90051-9

Cited by 12 publications

(4 citation statements)

References 13 publications

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“…Zn 2ϩ has been implicated in several mitochondrial changes, such as ion transport (55)(56)(57) and membrane swelling (33,56,58,59). Membrane swelling has been associated with the opening of the mitochondrial permeability transition pore, loss of membrane potential, and uncoupling of respiration (60).…”

Section: Discussionmentioning

confidence: 99%

Zn2+ Inhibits α-Ketoglutarate-stimulated Mitochondrial Respiration and the Isolated α-Ketoglutarate Dehydrogenase Complex

Brown¹,

Kristal²,

Effron³

et al. 2000

Journal of Biological Chemistry

145

113

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Section: Discussionmentioning

confidence: 99%

Zn2+ Inhibits α-Ketoglutarate-stimulated Mitochondrial Respiration and the Isolated α-Ketoglutarate Dehydrogenase Complex

Brown¹,

Kristal²,

Effron³

et al. 2000

Journal of Biological Chemistry

145

113

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“…An extension of these studies showed this swelling did not occur in anaerobic conditions (Hunter et al 1956). Initial reports of insulin-induced swelling in liver mitochondria were later attributed to Zn 2+ contamination (Cash et al 1968). In a series of studies using bovine heart mitochondria, Brierley and colleagues showed that Zn 2+ caused swelling and increased permeability to Mg 2+ , K + , Na + , and Cl - (Brierley 1967;Brierley and Knight 1967;Brierley et al 1968).…”

Section: Zn 2+ and Mitochondrial Permeability Transitionmentioning

confidence: 99%

Zinc inhibition of cellular energy production: implications for mitochondria and neurodegeneration

Dineley¹,

Votyakova²,

Reynolds³

2003

Journal of Neurochemistry

315

222

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An increasing body of evidence suggests that high intracellular free zinc promotes neuronal death by inhibiting cellular energy production. A number of targets have been postulated, including complexes of the mitochondrial electron transport chain, components of the tricarboxylic acid cycle, and enzymes of glycolysis. Consequences of cellular zinc overload may include increased cellular reactive oxygen species (ROS) production, loss of mitochondrial membrane potential, and reduced cellular ATP levels. Additionally, zinc toxicity might involve zinc uptake by mitochondria and zinc induction of mitochondrial permeability transition. The present review discusses these processes with special emphasis on their potential involvement in brain injury. Keywords: electron transport chain, glycolysis, metallothionein, permeability transition, reactive oxygen species, tricarboxylic acid cycle. Interest in Zn2+ -mediated brain injury is motivated by evidence implicating Zn 2+ as a neurotoxin in models of stroke, epilepsy, mechanical trauma, and Alzheimer's disease (Choi and Koh 1998). The precise mechanism of cytotoxicity is unknown, but emerging evidence suggests that Zn 2+ kills neurons through the inhibition of ATP synthesis (Weiss et al. 2000). The notion that Zn 2+ affects energy production is admittedly not a new one; indeed, investigators revealed that Zn 2+ impedes mitochondrial function very soon after mitochondria themselves could be properly studied (Hunter and Ford 1955). There has, however, been a resurgence of interest in this general area due to key advances over the last decade. First, a number of seminal reports have allowed a far better understanding of how zinc is regulated under physiological conditions and how disturbances in zinc homeostasis can lead to neuronal injury. Second, neuroscientists have greatly clarified how energy-producing systems such as mitochondria participate in the events leading to neuronal death. Consequently, investigators are now well positioned to explore the impact of zinc on cellular energy production, and how these events may be related to neurodegeneration. This topic is the principal concern of the present review. Initially, we assess data suggesting that zinc interferes with glycolysis, the tricarboxylic acid cycle (TCA), and the mitochondrial electron transport chain. Several related issues also bear consideration, such as mitochondrial generation of reactive oxygen species (ROS) and possible induction of mitochondrial permeability transition (MPT). We then discuss mitochondrial transport of Zn 2+ and possible regulation of metabolism by the metallothionein family of zinc binding proteins. Finally, we examine approaches used in the determination of intracellular free zinc concentrations, which is a critical component of any hypothesis concerning the mechanism of zinc toxicity. More expansive treatments of the neurobiology of Zn 2+ are cited herein. Zinc in the brainZinc is abundant in the brain with levels at 200 ng/mg protein. As suggested by Frederickson (1989), ...

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“…Low concentrations of zinc ( M ) inhibit respiratory activity (14) and induce rapid swelling ( 15) in mitochondria, suggesting a specific effect on functional activity rather than on structural integrity. It is possible that extremely low concentrations of zinc should be used in testing for increased stability of mitochondria1 membranes or decreased lipid peroxidation.…”

mentioning

confidence: 99%

Effect of Zinc on Lipid Peroxidation in Liver Microsomes and Mitochondria

Chvapil¹,

Ryan²,

Zukoski³

1972

Experimental Biology and Medicine

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While studying the role of certain metals and chelating agents in controlling tissue injury, we found that zinc salts stabilize lysosomal membranes in vitro (1, 2) : the rupture of these particles with the resulting release of their enzymes was decreased roughly 50% by low (millimolar) concentrations of zinc. The lysis of cells or subcellular structures is frequently attributed to peroxidation of the lipid components of their membranes (3-5). Thus, one possible explanation of this effect of zinc is that it interferes in some way with peroxidation of unsaturated fatty acids in the lysosomal membrane. This hypothesis was evaluated in in vivo and in vitro experiments using carbon tetrachloride to induce lipid peroxidation.The toxic effects of CC14 in vivo are due to the metabolism of this agent by the liver microsomal drug oxidizing system to the trichloromethyl radical CC13 (6). This free radical attacks unsaturated lipids in intracel-Iular membranes, oxidizing them and causing membrane distortion. This process terminates in cell necrosis (7). Lipid peroxidation can also be induced in vitro by incubating isolated liver microsomes with CC14 in the presence of NADPH or a NADPHgenerating system (8). We have found that zinc prevents or significantly reduces the CCL-induced formation of lipid peroxides both in vEvo and in vitro.Methods. Male rats (Simonson, 200 t 15 g) fed standard Purina lab chow diet were injected sc twice weekly with CC14 at the dose 0.1 m1/100 g. Zinc acetate ( 5 my/100 g) was administered daily by intragastric gavage. Control rats were gavaged accordingly with saline. Rats were sacrificed by decapita-14047 and ES 00790. lThk work was supported by NIH grants AM-tion after 20 and 34 days. The livers were perfused in situ with 20 ml of ice cold saline and homogenized by hand with all-glass homogenizers in three volumes of Tris-KC1 buffer (0.05 M , pH 7.4). The homogenates were fractionated into mitochondria and microsomes by centrifugation: material sedimenting between 800 and 15,OOOg (20 min-mitochondria-and between 15,000 and 105,OOOg (60 min)-microsomes-was collected and resuspended in TrisKCl, 1.5 or 1 .O ml/g liver. The mitochondrial fraction thus obtained includes both mitochondria and lysosomes, although the latter are present in relatively minor amounts. However, for convenience we will refer to the fraction as a crude mitochondrial preparation. Lipid peroxides were measured in both fractions by the formation of malonaldehyde using the thiobarbituric acid (TBA) method (9). The activity of p-glucuronidase was determined (10) in aliquots of the mitochondri-a1 pellet (bound) and supernatant (free enzyme) as a measure of lysosomal membrane stability. For in vitro studies, mitochondria and microsomes were prepared from rat liver and incubated under the conditions described in the Tables. The content of thiol groups was determined according to Elman (1 1) ? and the activity of cytochrome c oxidase by the method of Wharton and Tzagoloff ( 12).Results. The in vivo administration of CCll to rats for 20...

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Role of Zn(II) in the mitochondrial swelling action of insulin

Cited by 12 publications

References 13 publications

Zn2+ Inhibits α-Ketoglutarate-stimulated Mitochondrial Respiration and the Isolated α-Ketoglutarate Dehydrogenase Complex

Zn2+ Inhibits α-Ketoglutarate-stimulated Mitochondrial Respiration and the Isolated α-Ketoglutarate Dehydrogenase Complex

Zinc inhibition of cellular energy production: implications for mitochondria and neurodegeneration

Effect of Zinc on Lipid Peroxidation in Liver Microsomes and Mitochondria

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