Mn2+ sequestration by mitochondria and inhibition of oxidative phosphorylation

Gavin, Claire E.; Gunter, Karlene K.; Gunter, Thomas E.

doi:10.1016/0041-008x(92)90360-5

Cited by 214 publications

(145 citation statements)

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“…For example, the study by Liccione and Maines (1988) determined the activities of mitochondrial GSH-peroxidase, catalase, and gamma-glutamyltranspeptidase, but it did not measure Mn concentrations in mitochondria or cytosol. Other Mn studies with mitochondria are essentially to use mitochondrial preparations for the purpose of studying Mn uptake and efflux kinetics (Gunter and Puskin 1972;Gavin et al, 1999), interaction with Ca 2+ uniporter (Gavin et al, 1992), and speciation catalyzed by isolated mitochondrial preparations (Gunter et al, 2004). The present study, however, directly determined 54 Mn in relatively well-isolated subcellular fractions.…”

Section: Resultsmentioning

confidence: 92%

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Manganese accumulates primarily in nuclei of cultured brain cells

2008

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Manganese (Mn) is known to pass across the blood-brain barrier and interact with dopaminergic neurons. However, the knowledge on the subcellular distribution of Mn in these cell types upon exposure to Mn remained incomplete. This study was designed to investigate the subcellular distribution of Mn in blood-brain barrier endothelial RBE4 cells, blood-cerebrospinal fluid barrier choroidal epithelial Z310 cells, mesencephalic dopaminergic neuronal N27 cells, and pheochromocytoma dopaminergic PC12 cells. The cells were incubated with 100 µM MnCl 2 with radioactive tracer 54 Mn in the culture media for 24 hrs. The subcellular organelles, i.e., nuclei, mitochondria, microsomes, and cytoplasm, were isolated by centrifugation and verified for their authenticity by determining the markers specific to cellular organelles. Data indicated that maximum Mn accumulation was observed in PC12 cells, which was 2.8, 5.2 and 5.9 fold higher than that in N27, Z310 and RBE4 cells, respectively. Within cells, about 92%, 72%, and 52% of intracellular 54 Mn were found to be present in nuclei of RBE4, Z310, and N27 cells, respectively. The recovery of 54 Mn in nuclei and cytoplasm of PC12 cells were 27% and 69% respectively. Surprisingly, less than 0.5% and 2.5% of cellular 54 Mn was found in mitochondrial and microsomal fractions, respectively. This study suggests that the nuclei may serve as the primary pool for intracellular Mn; mitochondria and microsomes may play an insignificant role in Mn subcellular distribution.

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Section: Resultsmentioning

confidence: 92%

“…Mn exposure causes cellular oxidative damage and inhibits oxidative phosphorylation in brain cells (Gavin et al, 1992). Different brain cells exhibit different sensitivity to Mn toxicity; astrocytes sequester more Mn than neurons and thus may have higher tolerance to Mn toxicity than neurons (Zwingmann et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

Manganese accumulates primarily in nuclei of cultured brain cells

2008

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“…Mn 2+ competes with Ca 2+ for the mCU [76,77] (although patch-clamp studies suggest that the selectivity of the mCU for Ca 2+ vs Mn 2+ is > 15-fold [109]) and can be taken up into mitochondria as well [26,33,69,76,77,222], where it may inhibit oxidative phosphorylation [70]. Thus, Mn 2+ could potentially reduce the rate of the mCU, on the one hand by competing with Ca 2+ , on the other hand by reducing Δψ m .…”

Section: Evidence Against Fast Mitochondrial Ca 2+ Uptakementioning

confidence: 99%

Excitation-contraction coupling and mitochondrial energetics

Maack

O’Rourke²

2007

Basic Res Cardiol

221

183

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Cardiac excitation-contraction (EC) coupling consumes vast amounts of cellular energy, most of which is produced in mitochondria by oxidative phosphorylation. In order to adapt the constantly varying workload of the heart to energy supply, tight coupling mechanisms are essential to maintain cellular pools of ATP, phosphocreatine and NADH. To our current knowledge, the most important regulators of oxidative phosphorylation are ADP, P i , and Ca 2+ . However, the kinetics of mitochondrial Ca 2+ -uptake during EC coupling are currently a matter of intense debate. Recent experimental findings suggest the existence of a mitochondrial Ca 2+ microdomain in cardiac myocytes, justified by the close proximity of mitochondria to the sites of cellular Ca 2+ release, i. e., the ryanodine receptors of the sarcoplasmic reticulum. Such a Ca 2+ microdomain could explain seemingly controversial results on mitochondrial Ca 2+ uptake kinetics in isolated mitochondria versus whole cardiac myocytes. Another important consideration is that rapid mitochondrial Ca 2+ uptake facilitated by microdomains may shape cytosolic Ca 2+ signals in cardiac myocytes and have an impact on energy supply and demand matching. Defects in EC coupling in chronic heart failure may adversely affect mitochondrial Ca 2+ uptake and energetics, initiating a vicious cycle of contractile dysfunction and energy depletion. Future therapeutic approaches in the treatment of heart failure could be aimed at interrupting this vicious cycle. Keywords calcium; sodium; microdomain; heart failure; adenosine triphosphate; adenosine diphosphate; respiration; tricarboxylic acid cycle Physiological aspectsThe most important function of the heart is to pump blood to supply the body with oxygen and substrates. In order to adapt cardiac output to the constantly changing demand of blood supply, the heart utilizes three major mechanisms to increase cardiac output: the force-frequency relationship (the Bowditch effect or Treppe; [22]), the Frank-Starling mechanism (sarcomere length-dependent activation of contractile force) [66,149,164], and sympathetic activation [28]. All of these mechanisms increase and accelerate myocardial force generation, and at the same time increase cellular energy demand. By these mechanisms, cardiac output during exertion can be increased more than five-fold compared to resting conditions. © Steinkopff Verlag 2007Correspondence to: Christoph Maack. NIH Public Access Excitation-contraction couplingOf fundamental importance for cardiac contraction and relaxation are the processes of excitation-contraction (EC) coupling (Fig. 1). During the action potential (AP), voltage-gated Na + -channels are activated, and the inward Na + -current (I Na ) induces a rapid depolarization of the cell membrane, facilitating voltage-dependent opening of L-type Ca 2+ -channels (I Ca,L ). The Ca 2+ influx triggers the opening of the ryanodine receptor (RyR2 subtype), inducing the release of even greater amounts of Ca 2+ from the sarcoplasmic reticulum (SR), a process te...

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“…Several reports propose that manganese neurotoxicity is mainly associated with mitochondrial dysfunction (7), leading to decreased oxidative phosphorylation (8). Manganese has also been shown to induce oxidative stress (9 -11).…”

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confidence: 99%

Manganese Induces the Mitochondrial Permeability Transition in Cultured Astrocytes

Rao¹,

Norenberg

2004

Journal of Biological Chemistry

116

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Manganese is known to cause central nervous system injury leading to parkinsonism and to contribute to the pathogenesis of hepatic encephalopathy. Although mechanisms of manganese neurotoxicity are not completely understood, chronic exposure of various cell types to manganese has shown oxidative stress and mitochondrial energy failure, factors that are often implicated in the induction of the mitochondrial permeability transition (MPT). In this study, we examined whether exposure of cultured neurons and astrocytes to manganese induces the MPT. Cells were treated with manganese acetate (10 -100 M), and the MPT was assessed by changes in the mitochondrial membrane potential and in mitochondrial calcein fluorescence. In astrocytes, manganese caused a dissipation of the mitochondrial membrane potential and decreased the mitochondrial calcein fluorescence in a concentration-and time-dependent manner. These changes were completely blocked by pretreatment with cyclosporin A, consistent with induction of the MPT. On the other hand, similarly treated cultured cortical neurons had a delayed or reduced MPT as compared with astrocytes. The manganese-induced MPT in astrocytes was blocked by pretreatment with antioxidants, suggesting the potential involvement of oxidative stress in this process. Induction of the MPT by manganese and associated mitochondrial dysfunction in astrocytes may represent key mechanisms in manganese neurotoxicity.Manganese is an essential element and an integral component of key enzymes such as glutamine synthetase and mitochondrial superoxide dismutase (Mn-SOD) 1 (1). However, excess deposition of manganese in the central nervous system often leads to neurological abnormalities, including manganism, the symptoms of which (hypokinesis, rigidity, and tremor) resemble Parkinson's disease (2). Manganism is an occupational health problem in workers employed in welding factories, manganese mines, and ferro-alloy plants (3). In addition, the widespread use of the manganese derivative methylcyclopentadienyl manganese as an anti-knock agent in gasoline has evolved into a major environmental issue (4). Further, manganese toxicity has been implicated in the mechanism of hepatic encephalopathy, a neurological condition associated with chronic liver failure (5, 6).The mechanisms of manganese neurotoxicity are not completely understood. Several reports propose that manganese neurotoxicity is mainly associated with mitochondrial dysfunction (7), leading to decreased oxidative phosphorylation (8). Manganese has also been shown to induce oxidative stress (9 -11).Oxidative stress is considered a major factor in the induction of the mitochondrial permeability transition (MPT) (12, 13). The MPT is a Ca ϩ2 -dependent process often associated with various other factors (14). The MPT is characterized by opening of the permeability transition pore in the inner mitochondrial membrane, resulting in increased permeability of this membrane to protons, ions, and other solutes Յ1500 Da. This increased permeability leads to a coll...

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Mn2+ sequestration by mitochondria and inhibition of oxidative phosphorylation

Cited by 214 publications

References 41 publications

Manganese accumulates primarily in nuclei of cultured brain cells

Manganese accumulates primarily in nuclei of cultured brain cells

Excitation-contraction coupling and mitochondrial energetics

Manganese Induces the Mitochondrial Permeability Transition in Cultured Astrocytes

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