Iron-Mediated Inhibition of Mitochondrial Manganese Uptake Mediates Mitochondrial Dysfunction in a Mouse Model of Hemochromatosis

Jouihan, Hani; Cobine, Paul A.; Cooksey, Robert C.; Hoagland, Emily; Boudina, Sihem; Abel, E. Dale; Winge, Dennis R.; McClain, Donald A.

doi:10.2119/2007-00114.jouihan

Cited by 90 publications

(78 citation statements)

References 56 publications

(55 reference statements)

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“…Since the Mn content was positively correlated with Mn-SOD activity in the cells, we assume that the increase of intracellular Mn is closely related to the activation of Mn-SOD. This concept may be supported by the observation that Mn supplementation increased Mn-SOD activity in mouse tissues [12]. In addition, we found that cellular Mn uptake was enhanced by asbestos exposure.…”

Section: Resultssupporting

confidence: 72%

Alterations in manganese, copper, and zinc contents, and intracellular status of the metal-containing superoxide dismutase in human mesothelioma cells

Hasegawa¹,

Koshikawa²,

Takahashi³

et al. 2008

Journal of Trace Elements in Medicine and Biology

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Section: Resultssupporting

confidence: 72%

Alterations in manganese, copper, and zinc contents, and intracellular status of the metal-containing superoxide dismutase in human mesothelioma cells

Hasegawa¹,

Koshikawa²,

Takahashi³

et al. 2008

Journal of Trace Elements in Medicine and Biology

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“…4a). In a model of hereditary hemochromatosis (Hfe –/– mice), hepatic iron overload was associated with an inhibition of mitochondrial manganese uptake and a reduced activity of MnSOD [57]. Furthermore, several yeast mutants with a high mitochondrial iron, and one mutant with low cellular manganese levels, all misincorporated iron instead of manganese into the MnSOD-active site [58].…”

Section: Discussionmentioning

confidence: 99%

MnSOD Overexpression Prevents Liver Mitochondrial DNA Depletion after an Alcohol Binge but Worsens This Effect after Prolonged Alcohol Consumption in Mice

Mansouri

Tarhuni

Larosche

et al. 2010

Dig Dis

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Both acute and chronic alcohol consumption increase reactive oxygen species (ROS) formation and lipid peroxidation, whose products damage hepatic mitochondrial DNA (mtDNA). To test whether manganese superoxide dismutase (MnSOD) overexpression modulates acute and chronic alcohol-induced mtDNA lesions, transgenic MnSOD-overexpressing (TgMnSOD⁺⁺⁺) mice and wild-type (WT) mice were treated by alcohol, either chronically (7 weeks in drinking water) or acutely (single intragastric dose of 5 g/kg). Acute alcohol administration increased mitochondrial ROS formation, decreased mitochondrial glutathione, depleted and damaged mtDNA, durably increased inducible nitric oxide synthase (NOS) expression, plasma nitrites/nitrates and the nitration of tyrosine residues in complex V proteins and decreased complex V activity in WT mice. These effects were prevented in TgMnSOD⁺⁺⁺ mice. In acutely alcoholized WT mice, mtDNA depletion was prevented by tempol, a superoxide scavenger, L-NAME and 1400W, two NOS inhibitors, or uric acid, a peroxynitrite scavenger. In contrast, chronic alcohol consumption decreased cytosolic glutathione and increased hepatic iron, lipid peroxidation products and respiratory complex I protein carbonyls only in ethanol-treated TgMnSOD⁺⁺⁺ mice but not in WT mice. In chronic ethanol-fed TgMnSOD⁺⁺⁺ mice, but not WT mice, mtDNA was damaged and depleted, and the iron chelator, deferoxamine (DFO), prevented this effect. In conclusion, MnSOD overexpression prevents mtDNA depletion after an acute alcohol binge but aggravates this effect after prolonged alcohol consumption, which selectively triggers iron accumulation in TgMnSOD⁺⁺⁺ mice but not in WT mice. In the model of acute alcohol binge, the protective effects of MnSOD, tempol, NOS inhibitors and uric acid suggested a role of the superoxide anion reacting with NO to form mtDNA-damaging peroxynitrite. In the model of prolonged ethanol consumption, the protective effects of DFO suggested the role of iron reacting with hydrogen peroxide to form mtDNA-damaging hydroxyl radical.

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“…The glutathione (GSH) and oxidized glutathione (GSSG) contents were measured with a specific glutathione assay kit to calculate the mitochondrial redox potential ( E h ) as previously described [26]. In addition, the activities of succinate dehydrogenase (SDH) and cytochrome c oxidase (COX) were quantified by measuring the slope of the absorbance curves [27]. …”

Section: Methodsmentioning

confidence: 99%

Carbon Monoxide-Saturated Hemoglobin-Based Oxygen Carriers Attenuate High-Altitude-Induced Cardiac Injury by Amelioration of the Inflammation Response and Mitochondrial Oxidative Damage

Wang

Hu²,

Hu³

et al. 2016

Cardiology

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Objective: To investigate the therapeutic effect of carbon monoxide (CO) on high-altitude hypoxia-induced cardiac damage. Methods: Forty male C57BL/6 mice were randomly divided into 4 groups. The mice were exposed to normoxia or simulated 5,500-meter high-altitude hypoxia in a hypobaric chamber for 7 days. During the first 3 days, the mice were pretreated with CO-saturated hemoglobin (Hb)-based oxygen carrier (CO-HBOC), oxygen-saturated hemoglobin-based oxygen carrier (O₂-HBOC) at a dose of 0.3 g Hb/kg/day or an equivalent volume of saline. The in vivo left ventricle function, cardiac enzyme release, histopathological changes, apoptosis and inflammation were also measured. Results: High-altitude hypoxia induced significant cardiac damage, as demonstrated by impaired cardiac function and increased proapoptotic, proinflammatory and pro-oxidant markers. Pretreatment with CO-HBOC significantly improved cardiac performance, reduced cardiac enzyme release and limited myocardial apoptosis. The increased inflammatory response was also suppressed. In addition to the preserved mitochondrial structure, hypobaric hypoxia-induced mitochondrial oxidative damage was remarkably attenuated. Moreover, these antiapoptotic and antioxidative effects were accompanied by an upregulated phosphorylation of Akt, ERK and STAT3. Conclusion: This study demonstrated that CO-HBOC provides a promising protective effect on high-altitude hypoxia-induced myocardial injury, which is mediated by the inhibition of inflammation and mitochondrial oxidative damage.

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Iron-Mediated Inhibition of Mitochondrial Manganese Uptake Mediates Mitochondrial Dysfunction in a Mouse Model of Hemochromatosis

Cited by 90 publications

References 56 publications

Alterations in manganese, copper, and zinc contents, and intracellular status of the metal-containing superoxide dismutase in human mesothelioma cells

Alterations in manganese, copper, and zinc contents, and intracellular status of the metal-containing superoxide dismutase in human mesothelioma cells

MnSOD Overexpression Prevents Liver Mitochondrial DNA Depletion after an Alcohol Binge but Worsens This Effect after Prolonged Alcohol Consumption in Mice

Carbon Monoxide-Saturated Hemoglobin-Based Oxygen Carriers Attenuate High-Altitude-Induced Cardiac Injury by Amelioration of the Inflammation Response and Mitochondrial Oxidative Damage

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