Manganese stimulates calcium flux through the mitochondrial uniporter

Allshire, Ashley; Bernardi, Paolo; Saris, Nils‐Erik L.

doi:10.1016/0005-2728(85)90123-9

Cited by 55 publications

(31 citation statements)

References 15 publications

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“…The Ca 2+ deregulation seems to occur about five times later in neonatal compared to adult neurons [28]. The mitochondria buffer Ca 2+ once the concentration increases above a critical ''set point'' [40,41], and mitochondrial Ca 2+ overload may result in a nonspecific permeabilization of the inner membrane [42] and depolarization of mitochondrial membrane. Age dependent properties of the mitochondria is also a possible explanation.…”

Section: Discussionmentioning

confidence: 98%

Mitochondria are More Resistant to Hypoxic Depolarization in the Newborn than in the Adult Brain

et al. 2008

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Hypoxic-ischemic brain injury subsequent to asphyxia represents a major cause of morbidity and death in the newborn. The newborn brain has been considered more resistant to hypoxia than the adult brain because of lower energy demand. The mechanisms underlying hypoxic brain injury, in particular the age-related vulnerability, are still only partially understood. The mitochondrial function is pivotal for the function and survival of neurons. Acutely isolated CA1 neurons from neonatal (3-6 days) and adult rats (5-6 weeks) were loaded with Rh 123, and the effect of hypoxia on the inner mitochondrial membrane potential (Delta psi(m)) was compared. During prolonged hypoxia (15 min), Delta psi(m) was lost in a majority of the neonatal neurons (83%) and in all the adult neurons. During hypoxia (5 min) followed by reoxygenation the mitochondria in 23% of the neonatal neurons were completely depolarized, whereas 85% of the adult neurons demonstrated a complete loss of Delta psi(m). In conclusion hippocampal CA1 mitochondria in the newborn rat are more resistant to hypoxic depolarization than in the adult rat.

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Section: Discussionmentioning

confidence: 98%

Mitochondria are More Resistant to Hypoxic Depolarization in the Newborn than in the Adult Brain

et al. 2008

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“…Rat liver mitochondria were prepared by a conventional differential centrifugation method as described elsewhere [16], their protein content was measured by the Lowry procedure [17] with bovine serum albumin as a standard, and respiration was followed polarographically. Changes in [Zn2+] were followed with the metallochromic indicator antipyrylazo III (Fluka AG, Buchs, Switzerland; concentration, 50 PM) employing the wavelength couple 675690 nm [18].…”

Section: Methodsmentioning

confidence: 99%

Is Zn²⁺ transported by the mitochondrial calcium uniporter?

Saris

Niva

1994

FEBS Letters

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Zinc ions were found to inhibit Ca2' uptake by rat liver mitochondria driven by succinate respiration but not that by a valinomycin-induced membrane potential. Zn'+ at 1 PM or higher concentrations induced a lowering of the membrane potential under the former but not the latter conditions. It is concluded that it is the lowered membrane potential in the presence of Zn" that reduces the rate of respiration-driven Car'. Ruthenium red was found to inhibit the uptake of Zn2+ but had no influence on its action upon the membrane potential. Zn2' did not affect the Ruthenium red-insensitive Ca'+ et&ix. Ca" stimulated the uptake of Zn 2+ . It is concluded that Zn" may be transported by the mitochondrial calcium uniporter but that it may have access to sites required for inhibition of respiration by other routes.

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“…Although earlier work has not directly demonstrated the induction of the MPT by manganese either in intact cells or in isolated mitochondria, Allshire et al (31) reported that manganese stimulates Ca 2ϩ flux into isolated mitochondria, a process critical to the induction of the MPT. Studies by Bernardi et al (32) demonstrated a competition between manganese and calcium for the same binding site on the permeability transition pore.…”

Section: Figmentioning

confidence: 96%

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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Manganese stimulates calcium flux through the mitochondrial uniporter

Cited by 55 publications

References 15 publications

Mitochondria are More Resistant to Hypoxic Depolarization in the Newborn than in the Adult Brain

Mitochondria are More Resistant to Hypoxic Depolarization in the Newborn than in the Adult Brain

Is Zn²⁺ transported by the mitochondrial calcium uniporter?

Manganese Induces the Mitochondrial Permeability Transition in Cultured Astrocytes

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Manganese stimulates calcium flux through the mitochondrial uniporter

Cited by 55 publications

References 15 publications

Mitochondria are More Resistant to Hypoxic Depolarization in the Newborn than in the Adult Brain

Mitochondria are More Resistant to Hypoxic Depolarization in the Newborn than in the Adult Brain

Is Zn2+ transported by the mitochondrial calcium uniporter?

Manganese Induces the Mitochondrial Permeability Transition in Cultured Astrocytes

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Is Zn²⁺ transported by the mitochondrial calcium uniporter?