Generation of hydrogen peroxide by brain mitochondria: The effect of reoxygenation following postdecapitative ischemia

Cino, Maria; Maestro, Rolando F. Del

doi:10.1016/0003-9861(89)90148-3

Cited by 139 publications

(92 citation statements)

References 38 publications

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“…The results of the latter study indicated that reoxygenation with 100% O 2 was associated with significantly more free radical generation than reoxygenation with 21% O 2 . However, two studies have been performed in 840 which hyperoxia after brain ischemia was not found to increase the concentration of reactive oxygen metabolites (5,7).…”

Section: Discussionmentioning

confidence: 99%

Hydrogen Peroxide Production in Leukocytes during Cerebral Hypoxia and Reoxygenation with 100% or 21% Oxygen in Newborn Piglets

et al. 2001

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The aim of this study was to investigate whether reoxygenation with 21% O 2 rather than 100% O 2 results in reduced hydrogen peroxide (H 2 O 2 ) concentrations in neutrophils (PMN). Piglets (2-4 d old) exposed to severe hypoxia (inspired fraction of oxygen, 0.08) were randomized to resuscitation with 21 (n ϭ 13) or 100% O 2 (n ϭ 12). Five animals served as controls. H 2 O 2 concentrations in PMN in terms of rhodamine 123 (Rho 123) fluorescence intensity from arterial and superior sagittal sinus blood were quantified by flow cytometry. Laser Doppler flowmetry (LDF) was used to assess cortical blood perfusion. During hypoxia, Rho 123 increased in arterial PMN in both study groups by 15 and 32%, respectively (p Ͻ 0.05). In cerebral venous PMN, the increase was less dominant (p ϭ 0.06). Reoxygenation with 100 or 21% O 2 had no different effect on Rho 123 in arterial PMN. In cerebral venous PMN, Rho 123 was approximately 40% higher after 60 min and 30% higher after 120 min compared with corresponding data in the 21% O 2 group (p Ͻ 0.05), which were close to baseline levels. Further, O 2 treatment in both groups induced PMN accumulation in arterial blood (p Ͻ 0.05). Laser Doppler flowmetry signals increased during transient hypoxia (p Ͻ 0.0001 compared with baseline) and were normalized after reoxygenation in both study groups. The primary release of products of the sequential reduction of oxygen, superoxide radical (O 2 -) and H 2 O 2 , and the secondary production of hydroxyl radical (HO -) constitute the molecular mechanism of oxygen toxicity. Any system producing O 2 -will, as a result of the dismutase reaction, also produce H 2 O 2 . Although stable, the damaging redox properties of H 2 O 2 and its ability to form highly reactive free radicals in the presence of transition metal ions have caused the body to form defenses against it. The role of oxygen toxicity in the development of perinatal hypoxic-ischemic encephalopathy is still a matter of debate. The principal hypothesis put forward to explain this process is the oxygen free radical theory (1, 2).Stimulation of PMN during hypoxia-reoxygenation may increase the concentration of reactive oxygen species (3) in these cells. To date, the production of H 2 O 2 in PMN during hypoxia and resuscitation with pure or air-mixed O 2 has not been studied in detail. Reoxygenation is necessary to prevent further injury to neuronal tissue, but the renewed availability of O 2 to previously hypoxic brain tissue may also have detrimental effects both with respect to the microcirculation and to the parenchyma of the brain. The production of reactive oxygen metabolites may be proportional to PaO 2 , and the oxygen tension achieved during reactive hyperemia and reoxygenation with O 2 concentrations higher than 21% may generate a correspondingly higher burst of these metabolites. However, we

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Section: Discussionmentioning

confidence: 99%

Hydrogen Peroxide Production in Leukocytes during Cerebral Hypoxia and Reoxygenation with 100% or 21% Oxygen in Newborn Piglets

et al. 2001

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“…The other scenario is called reverse electron transport when the ubiquinol pool increases under high Dp by, for example, respiration on succinate. Electrons are then transferred from QH2 through complex I (Cino and Del Maestro, 1989). It is suggestive to assume that the reduced flavin mononucleotide is then also the site of electron transfer to O 2 but this has not yet been unequivocally proven (Murphy, 2009).…”

Section: Respiratory Chain Complexes and Apoptosismentioning

confidence: 99%

Mitochondrial respiratory chain complexes: apoptosis sensors mutated in cancer?

Lemarié

Grimm

2011

Oncogene

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Mutations in cancer cells affecting subunits of the respiratory chain (RC) indicate a central role of oxidative phosphorylation for tumourigenesis. Recent studies have suggested that such mutations of RC complexes impact apoptosis induction. We review here the evidence for this hypothesis, which in particular emerged from work on how complex I and II mediate signals for apoptosis. Both protein aggregates are specifically inhibited for apoptosis induction through different means by exploiting with protease activation and pH change, two widespread but independent features of dying cells. Nevertheless, both converge on forming reactive oxygen species for the demise of the cell. Investigations into these mitochondrial processes will remain a rewarding area for unravelling the causes of tumourigenesis and for discovering interference options.

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“…These studies revealed that inhibiting complexes I and III of the mitochondrial respiratory chain with specific mitochondrial toxins, such as rotenone and antimycin A, resulted in high rates of ROS production (Turrens, 1997;Murphy et al, 1999;Lenaz, 2001). Similar approaches have been used successfully to study ROS production by isolated (Kwong and Sohal, 1998) and in situ (Sipos et al, 2003) brain mitochondria, but no information is yet available regarding the specific sites or mechanisms of ROS generation in the absence of respiratory chain inhibitors (Sorgato et al, 1974;Patole et al, 1986;Cino and Del Maestro, 1989;Ramsay and Singer, 1992;Hensley et al, 1998;Kwong and Sohal, 1998;Sims et al, 1998;Tretter and Adam-Vizi, 2000;Sipos et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial α-Ketoglutarate Dehydrogenase Complex Generates Reactive Oxygen Species

Starkov¹,

Fiskum²,

Chinopoulos³

et al. 2004

J. Neurosci.

629

472

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Mitochondria-produced reactive oxygen species (ROS) are thought to contribute to cell death caused by a multitude of pathological conditions. The molecular sites of mitochondrial ROS production are not well established but are generally thought to be located in complex I and complex III of the electron transport chain. We measured H 2 O 2 production, respiration, and NADPH reduction level in rat brain mitochondria oxidizing a variety of respiratory substrates. Under conditions of maximum respiration induced with either ADP or carbonyl cyanide p-trifluoromethoxyphenylhydrazone, ␣-ketoglutarate supported the highest rate of H 2 O 2 production. In the absence of ADP or in the presence of rotenone, H 2 O 2 production rates correlated with the reduction level of mitochondrial NADPH with various substrates, with the exception of ␣-ketoglutarate. Isolated mitochondrial ␣-ketoglutarate dehydrogenase (KGDHC) and pyruvate dehydrogenase (PDHC) complexes produced superoxide and H 2 O 2 . NAD ϩ inhibited ROS production by the isolated enzymes and by permeabilized mitochondria. We also measured H 2 O 2 production by brain mitochondria isolated from heterozygous knock-out mice deficient in dihydrolipoyl dehydrogenase (Dld). Although this enzyme is a part of both KGDHC and PDHC, there was greater impairment of KGDHC activity in Dld-deficient mitochondria. These mitochondria also produced significantly less H 2 O 2 than mitochondria isolated from their littermate wild-type mice. The data strongly indicate that KGDHC is a primary site of ROS production in normally functioning mitochondria.

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Generation of hydrogen peroxide by brain mitochondria: The effect of reoxygenation following postdecapitative ischemia

Cited by 139 publications

References 38 publications

Hydrogen Peroxide Production in Leukocytes during Cerebral Hypoxia and Reoxygenation with 100% or 21% Oxygen in Newborn Piglets

Hydrogen Peroxide Production in Leukocytes during Cerebral Hypoxia and Reoxygenation with 100% or 21% Oxygen in Newborn Piglets

Mitochondrial respiratory chain complexes: apoptosis sensors mutated in cancer?

Mitochondrial α-Ketoglutarate Dehydrogenase Complex Generates Reactive Oxygen Species

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