Respiration-dependent Removal of Exogenous H2O2 in Brain Mitochondria

Zoccarato, Franco; Cavallini, Lucia; Alexandre, Adolfo

doi:10.1074/jbc.m308143200

Cited by 120 publications

(122 citation statements)

References 36 publications

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“…Mitochondria are commonly referred to as the most significant source of ROS in the cell. Yet, brain mitochondria have been reported to be capable of a high rate of exogenous H 2 O 2 removal, far exceeding the reported production rates [39] and when ROS was measured in supernatants separated from normal intact mitochondria without respiratory inhibitors no accumulated ROS was detected [40], in accordance with our studies. This calls attention to the question whether mitochondria act as a net sink or a net source of ROS and warrants detailed study of conditions where this balance may shift.…”

Section: Discussionsupporting

confidence: 91%

“…Among them are the regulatory role effect of calcium on several dehydrogenases (although primary substrates for these were not used in the present study), activation of nitric oxide synthase, lipid rearrangements and structural alterations of respiratory complexes as well as inhibition of antioxidative pathways [35][36][37][38][39]. It is important to bear in mind that even though mitochondria can accumulate large amounts of calcium under normal physiological conditions, inactive calcium-phosphates are formed in the alkaline matrix keeping free calcium ions in the low micromolar range [23].…”

Section: Discussionmentioning

confidence: 99%

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Calcium-induced generation of reactive oxygen species in brain mitochondria is mediated by permeability transition

Hansson

Månsson

Morota

et al. 2008

Free Radical Biology and Medicine

110

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Mitochondrial uptake of calcium in excitotoxicity is associated with subsequent increase in reactive oxygen species (ROS) generation and delayed cellular calcium deregulation in ischemic and neurodegenerative insults. The mechanisms linking mitochondrial calcium uptake and ROS production remain unknown but activation of the mitochondrial permeability transition (mPT) may be one such mechanism. In the present study, calcium increased ROS generation in isolated rodent brain and human liver mitochondria undergoing mPT despite an associated loss of membrane potential, NADH and respiration. Unspecific permeabilization of the inner mitochondrial membrane by alamethicin likewise increased ROS independently of calcium, and the ROS increase was further potentiated if NAD(H) was added to the system. Importantly, calcium per se did not induce a ROS increase unless mPT was triggered. Twenty-one cyclosporin A analogs were evaluated for inhibition of calcium-induced ROS and their efficacy clearly paralleled their potency of inhibiting mPT-mediated mitochondrial swelling. We conclude that while intact respiring mitochondria possess powerful antioxidant capability, mPT induces a dysregulated oxidative state with loss of GSH-and NADPH-dependent ROS detoxification. We propose that mPT is a significant cause of pathological ROS generation in excitotoxic cell death.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Calcium-induced generation of reactive oxygen species in brain mitochondria is mediated by permeability transition

Hansson

Månsson

Morota

et al. 2008

Free Radical Biology and Medicine

110

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show abstract

“…Means plus standard deviations, based on triplicate samples, are shown phosphorylation is severely compromised, and this can lead to loss of viability of cells that are highly dependent on mitochondrial ATP production. 14 Defects in respiratory complex I may compromise its contribution to peroxide detoxification, 16,17 providing an additional mechanism whereby AIF can enhance the cellular defense against oxidative damage. Hence, when not exposed to acute apoptogenic stress, cells containing functional wild-type p53 should benefit from the cytoprotective effect of AIF in the mitochondria.…”

Section: Discussionmentioning

confidence: 99%

“…15 Reduced mitochondrial ATP production, as well as specific defects in complex I, is likely to compromise cell viability and render cells more sensitive to the deleterious effects of peroxides and other stress agents. 14,16,17 In support of a cytoprotective role of AIF in vivo, mice that express reduced AIF levels (harlequin mice) display excessive neurodegeneration, accompanied by signs of chronic oxidative stress. 18 In fact, cells derived from such mice are highly prone to peroxide-mediated apoptosis, whereas reconstitution of AIF expression protects them from such apoptosis.…”

Section: Introductionmentioning

confidence: 99%

Regulation of AIF expression by p53

et al. 2006

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The tumor suppressor p53 plays a pivotal role in suppressing tumorigenesis by inducing genomic stability, cell cycle arrest or apoptosis. AIF is a mitochondrial protein, which, upon translocation to the nucleus, can participate in apoptosis, primarily in a caspase-independent contexts. We now report that AIF gene expression is subject to positive transcriptional regulation by p53. Interestingly, unlike most known p53 target genes, the AIF gene is regulated by basal levels of p53, and activation of p53 by genotoxic stress does not result in a substantial further increase in AIF expression. The AIF gene harbors a p53 responsive element, which is bound by p53 within cells. p53 drives efficient induction of large-scale DNA fragmentation, a hallmark of AIF activity. Importantly, caspase-independent death is compromised in cells lacking functional p53, in line with the known role of AIF in this process. Thus, in addition to its documented effects on caspase-dependent apoptosis, p53 may also sensitize cells to caspase-independent death through positive regulation of AIF expression. Moreover, in the absence of overt apoptotic signals, the constitutive induction of AIF by p53 may underpin a cytoprotective maintenance role, based on the role of AIF in ensuring proper mitochondrial function.

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“…This mechanism of ROS formation explains the inhibitory rather than stimulatory action of Ca 2ϩ and P i on mitochondrial oxygen radicals in ⌴IN6 cells by Ca 2ϩ -induced mitochondrial depolarization. In addition, the direct inhibitory action of Ca 2ϩ on the mitochondrial H 2 O 2 -producing site was reported recently (56). The effect of Ca 2ϩ and P i on ROS production, supported by NAD-linked respiratory substrates (glutamate/malate), was also investigated.…”

Section: Fig 2 Effect Of Ca 2؉ On Mitochondrial Function (Respiratimentioning

confidence: 95%

The Characterization of Mitochondrial Permeability Transition in Clonal Pancreatic β-Cells

Koshkin

Bikopoulos

Chan

et al. 2004

Journal of Biological Chemistry

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Mitochondrial permeability transition (MPT), which contributes substantially to the regulation of normal mitochondrial metabolism, also plays a crucial role in the initiation of cell death. It is known that MPT is regulated in a tissue-specific manner. The importance of MPT in the pancreatic ␤-cell is heightened by the fact that mitochondrial bioenergetics serve as the main glucose-sensing regulator and energy source for insulin secretion. In the present study, using MIN6 and INS-1 ␤-cells, we revealed that both Ca 2؉ -phosphate-and oxidant-induced MPT is remarkably different from other tissues. Ca 2؉ -phosphate-induced transition is accompanied by a decline in mitochondrial reactive oxygen species production related to a significant potential dependence of reactive oxygen species formation in ␤-cell mitochondria. Hydroperoxides, which are indirect MPT co-inducers active in liver and heart mitochondria, are inefficient in ␤-cell mitochondria, due to the low mitochondrial ability to metabolize them. Direct cross-linking of mitochondrial thiols in pancreatic ␤-cells induces the opening of a low conductance ion permeability of the mitochondrial membrane instead of the full scale MPT opening typical for liver mitochondria. Low conductance MPT is independent of both endogenous and exogenous Ca 2؉ , suggesting a novel type of nonclassical MPT in ␤-cells. It results in the conversion of electrical transmembrane potential into ⌬pH instead of a decrease in total protonmotive force, thus mitochondrial respiration remains in a controlled state. Both Ca 2؉ -and oxidant-induced MPTs are phosphate-dependent and, through the "phosphate flush" (associated with stimulation of insulin secretion), are expected to participate in the regulation in ␤-cell glucose-sensing and secretory activity.Mitochondrial permeability transition (MPT) 1 is a permeability increase of the inner mitochondrial membrane to solutes of molecular mass up to ϳ1500 Da, which is caused by an opening of specific nonselective proteinaceous pores in the inner mitochondrial membrane (1, 2). Increased permeability of the inner membrane is initiated by an increased level of intramitochondrial Ca 2ϩ and is regulated by multiple effectors, including inorganic phosphate, the redox state of pyridine nucleotides and thiols (oxidative stress), membrane potential, cyclosporin A, and other factors (3). MPT pores are thought to have at least two open conformations and a variable degree of reversibility. Most importantly, MPT in its different forms contributes to both normal cell physiology (regulation of oxidative phosphorylation and Ca 2ϩ metabolism) and to regulatory processes leading to apoptosis (2-4). Specific features of MPT show significant tissue-specific variability (5-8). The most significant and well documented deviation from classical MPT described in liver mitochondria was observed in brain tissue (9). Brain mitochondria demonstrate high resistance to MPT opening (10), low sensitivity to cyclosporin A (5), different responses to MPT modifiers, and a distinctive...

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Respiration-dependent Removal of Exogenous H2O2 in Brain Mitochondria

Cited by 120 publications

References 36 publications

Calcium-induced generation of reactive oxygen species in brain mitochondria is mediated by permeability transition

Calcium-induced generation of reactive oxygen species in brain mitochondria is mediated by permeability transition

Regulation of AIF expression by p53

The Characterization of Mitochondrial Permeability Transition in Clonal Pancreatic β-Cells

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