Oxidative Phosphorylation In Brain Mitochondria Research Articles

Depleted uranium induces disruption of energy homeostasis and oxidative stress in isolated rat brain mitochondria

Depleted uranium (DU) is emerging as an environmental pollutant primarily due to its military applications. Gulf War veterans with embedded DU showed cognitive disorders that suggest that the central nervous system is a target of DU. Recent evidence has suggested that DU could induce oxidative stress and mitochondrial dysfunction in brain tissue. However, the underlying mechanisms of DU toxicity in brain mitochondria are not yet well understood. Brain mitochondria were obtained using differential centrifugation and were incubated with different concentrations (50, 100 and 200 μM) of uranyl acetate (UA) as a soluble salt of U(238) for 1 h. In this research, mitochondrial ROS production, collapse of mitochondrial membrane potential and mitochondrial swelling were examined by flow cytometry following the addition of UA. Meanwhile, mitochondrial sources of ROS formation were determined using specific substrates and inhibitors. Complex II and IV activity and also the extent of lipid peroxidation and glutathione (GSH) oxidation were detected via spectroscopy. Furthermore, we investigated the concentration of ATP and ATP/ADP ratio using luciferase enzyme and cytochrome c release from mitochondria which was detected by ELISA kit. UA caused concentration-dependent elevation of succinate-linked mitochondrial ROS production, lipid peroxidation, GSH oxidation and inhibition of mitochondrial complex II. UA also induced mitochondrial permeability transition, ATP production decrease and increase in cytochrome c release. Pre-treatment with antioxidants significantly inhibited all the above mentioned toxic effects of UA. This study suggests that mitochondrial oxidative stress and impairment of oxidative phosphorylation in brain mitochondria may play a key role in DU neurotoxicity as reported in Gulf War Syndrome.

Impairment of Brain Mitochondrial Oxidative Phosphorylation Accompanying Vitamin E Oxidation Induced by Iron or Reactive Nitrogen Species: A Selective Review

Mitochondria are exposed to large fluxes of iron, and reactive oxygen and nitrogen species. Hence they are susceptible to oxidative stress, a process inhibited by vitamin E. Our investigations show that iron uncouples oxidative phosphorylation whereas peroxynitrite and nitrite are inhibitors of oxidative phosphorylation. Oxidation of mitochondrial vitamin E is accompanied by generation of lipid peroxidation products, altered enzyme activity and electrical conductance etc., and result in inefficient oxidative phosphorylation. Vitamin E is important for mitochondrial function because: (1) Prior investigations have shown that vitamin E is essential for maintaining mitochondrial respiration. (2) Vitamin E is the most potent, lipid-soluble antioxidant localized ideally in mitochondrial membranes. (3) The decline in respiratory control ratios (RCR) of rat brain mitochondria exposed to peroxynitrite closely paralleled the oxidative elimination of vitamin E. (4) Finally, iron is a strong uncoupler of oxidative phosphorylation in brain mitochondria from vitamin E deficient animals and not from controls.

The protective role of cellular glutathione peroxidase against trauma-induced mitochondrial dysfunction in the mouse brain

Reactive oxygen species are believed to participate in the pathogenesis of traumatic brain injury (TBI). To evaluate the role of cellular glutathione peroxidase (Gpx1), a selenium-containing enzyme functioning in reduction of hydrogen peroxide and alkyl hyperoxides, in protecting animals against TBI, a line of Gpx1 transgenic mice was generated. Overexpression of Gpx1 was found in many organs including the brain of the transgenic mice. This line of transgenic mice and knockout mice deficient in Gpx1 were used in a model of controlled cortical impact injury and the efficiency of oxidative phosphorylation in brain mitochondria was determined. Although a 2-mm depth of mechanical impact caused a drastic decrease in NAD-linked electron transfer activities and energy-coupling capacities in brain mitochondria of nontransgenic mice, the decrease in mitochondrial function was completely prevented by overexpression of Gpx1 in Gpx1 transgenic mice. In addition, a 1-mm deformation depth hardly affected brain mitochondrial function in wild-type (Gpx1 +/+) mice, yet resulted in a significant decrease in mitochondrial bioenergetic capacity in brains of homozygous Gpx1 knockout (Gpx1 −/−) mice. Further experiments showed that inclusion of calcium chelator egtazic acid in measurement of mitochondrial respiration could completely restore the efficiency of mitochondrial respiration in injured brains of nontransgenic mice and Gpx1 −/− mice, suggesting that the observed mitochondrial dysfunction is a direct result of increase in mitochondrion-associated calcium, which is secondary to the increased oxidative stress. These studies not only establish the role of Gpx1 in preventing mitochondrial dysfunction in mouse brain after TBI, but also suggest the species of reactive oxygen responsible for this event.

Iron uncouples oxidative phosphorylation in brain mitochondria isolated from vitamin E-deficient rats.

Few, if any, studies have examined the effect of vitamin E deficiency on brain mitochondrial oxidative phosphorylation. The latter was studied using brain mitochondria isolated from control and vitamin E-deficient rats (13 months of deficiency) after exposure to iron, an inducer of oxidative stress. Mitochondria were treated with iron (2 to 50 microM) added as ferrous ammonium sulfate. Rates of state 3 and state 4 respiration, respiratory control ratios, and ADP/O ratios were not affected by vitamin E deficiency alone. However, iron uncoupled oxidative phosphorylation in vitamin E-deficient mitochondria, but not in controls. In vitamin E-deficient mitochondria, iron decreased ADP/O ratios and markedly stimulated state 4 respiration; iron had only a modest effect on these parameters in control mitochondria. Thus, vitamin E may have an important role in sustaining oxidative phosphorylation. Low concentrations of iron (2 to 5 microM) oxidized mitochondrial tocopherol that exists in two pools. The release of iron in brain may impair oxidative phosphorylation, which would be exacerbated by vitamin E deficiency. The results are important for understanding the pathogenesis of human brain disorders known to be associated with abnormalities in mitochondrial function as well as iron homeostasis (e.g., Parkinson's disease).

Effects of adaptation to intermittent hypoxia on oxidative phosphorylation in brain mitochondria of rats with different sensitivities toward oxygen deficiency

After long-term adaptation to intermittent hypoxia, rats with an initially low resistance to acute oxygen deficiency were 2 to 4 times more resistant to it, while highly resistant rats did not show a significant change in resistance. The adaptation was accompanied by weakening of the electron-transporting function of the respiratory chain and increasing efficiency of oxidative phosphorylation in the brain mitochondria oxidizing NAD-dependent substrates, indicating that energy was produced in a more economical way. The succinate oxidase pathway of oxidation was found to be utilized to only a limited extent as a compensatory mechanism in animals exposed to intermittent hypoxia over a prolonged period. The effects of adaptation were more marked in the brain mitochondria of rats initially highly sensitive to oxygen deficiency.

Oxidative phosphorylation in brain mitochondria of rats differing in their sensitivity to hypoxia

Oxidative phosphorylation in brain mitochondria of rats differing in their sensitivity to hypoxia

Modification of oxidative phosphorylation in brain mitochondria during development and aging by the oxygen analog of ronnel

This paper describes the effect of the oxygen analog of ronnel (OAR) on the respiration of brain mitochondria from 4- and 16-day-old and 2- and 18-month-old rats. The oxygen analog of ronnel seems to be an uncoupler of oxidative phosphorylation in brain mitochondria derived from rats at all ages investigated. The results reported here suggest that the sensitivity of mitochondria to the uncoupling effect of OAR is an age-dependent phenomenon. Most sensitive were mitochondria isolated from brains of 18-month-old animals, while the most resistant were mitochondria derived from newborn rats (4 days old), as compared with young adult rats (2 months old). The relation between membrane structure and insecticide action is discussed.

Effect of halascorbin on oxidative phosphorylation in brain mitochondria of irradiated animals

Effect of halascorbin on oxidative phosphorylation in brain mitochondria of irradiated animals

The effect of bilirubin on the energy metabolism of brain mitochondria.

Abstract— Unconjugated bilirubin caused uncoupling of oxidative phosphorylation in brain mitochondria prepared from mature or weanling rats. Human serum albumin in an amount sufficient to bind 100 per cent of the added bilirubin was able to protect the mitochondria from the inhibitory effects of bilirubin. Bilirubin inhibited both the endogenous and DNP‐activated ATPase activities but had no effect upon the Mg2+‐stimulated ATPase; albumin prevented the inhibition.

Inhibition of oxidative phosphorylation in brain mitochondria by electrical currents and the effect of chelating agents and other substances.

Inhibition of oxidative phosphorylation in brain mitochondria by electrical currents and the effect of chelating agents and other substances.