Mitochondria as a Source of Reactive Oxygen and Nitrogen Species: From Molecular Mechanisms to Human Health

Figueira, Tiago Rezende; Barros, Mário H.; Camargo, Anamaria A.; Castilho, Roger F.; Ferreira, Julio Cesar Batista; Kowaltowski, Alicia J.; Sluse, Francis; Souza-Pinto, Nadja C. de; Vercesi, Anı́bal E.

doi:10.1089/ars.2012.4729

Cited by 360 publications

(288 citation statements)

References 555 publications

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“…Although unclear with AEC, a causal link between mtDNA damage and apoptosis has been established in various cell types (7)(8)(9)(10)12). Compared with nuclear DNA, the mutation and damage rate of mtDNA by oxidative stress is severalfold higher in part because of the close proximity of mtDNA to the electron transport chain-generating ROS, the lack of histone-containing proteins that shield mtDNA, and the limited mtDNA repair systems (1)(2)(3)(4)(5)(6). A novel finding of this study is that mt-hOgg1-Mut, which lacks the crucial amino acids necessary for 8-oxoG DNA repair (25), prevents oxidant-induced AEC mtDNA damage in a manner similar to mt-hOgg1-WT (Fig.…”

Section: Discussionmentioning

confidence: 99%

Mitochondria-targeted Ogg1 and Aconitase-2 Prevent Oxidant-induced Mitochondrial DNA Damage in Alveolar Epithelial Cells

Kim

Cheresh

Williams

et al. 2014

Journal of Biological Chemistry

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Background: Mitochondrial Ogg1 prevents oxidant (H 2 O 2 and asbestos)-induced Aco-2 degradation and apoptosis. Results: Oxidant stress caused preferential AEC mtDNA Ͼ nuclear DNA damage, mt-p53 translocation, and apoptosis; effects were blocked by mt-hOgg1 or Aco-2. Conclusion: mt-hOgg1 and Aco-2 preserve AEC mtDNA, preventing oxidant-induced p53 activation and apoptosis. Significance: mt-hOgg1/Aco-2 effects on mtDNA may be an innovative target for preventing degenerative diseases.

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Section: Discussionmentioning

confidence: 99%

Mitochondria-targeted Ogg1 and Aconitase-2 Prevent Oxidant-induced Mitochondrial DNA Damage in Alveolar Epithelial Cells

Kim

Cheresh

Williams

et al. 2014

Journal of Biological Chemistry

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“…Increased cytosolic Ca 2+ levels feed into the JNK pathway through Ca 2+ /calmodulindependent protein kinase II (CaMKII) and thereby lead to augmented ROS production through NOX2 (also known as CYBB) or NOX4, which in turn leads to oxidative stress and positive-feedback regulation of CHOP through double-stranded RNA-dependent protein kinase (PKR; also known as EIF2AK2) (Li et al, 2010a;Pedruzzi et al, 2004) (Figs 2 and 3). Mitochondrial Ca 2+ elevation, however, increases the generation and release of mitochondrial ROS by various mechanisms, including opening of the mitochondrial permeability transition pore (MPTP) in the inner mitochondrial membrane (Figueira et al, 2013) (see below).…”

Section: Er Stress Can Increase Ros Generationmentioning

confidence: 99%

“…Mitochondrial outer membrane permeabilization (MOMP) is the focal point of the intrinsic apoptosis pathway that is executed by mitochondria-derived endonucleases, caspase-activating factors such as cytochrome c, and ROS (Figueira et al, 2013;Galluzzi et al, 2012). Two pathways mediate MOMP.…”

Section: The Er-stress-mitochondrial Signaling Axismentioning

confidence: 99%

Redox controls UPR to control redox

Eletto

Chevet

Argon

et al. 2014

Journal of Cell Science

149

137

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In many physiological contexts, intracellular reduction-oxidation (redox) conditions and the unfolded protein response (UPR) are important for the control of cell life and death decisions. UPR is triggered by the disruption of endoplasmic reticulum (ER) homeostasis, also known as ER stress. Depending on the duration and severity of the disruption, this leads to cell adaptation or demise. In this Commentary, we review reductive and oxidative activation mechanisms of the UPR, which include direct interactions of dedicated protein disulfide isomerases with ER stress sensors, protein S-nitrosylation and ER Ca 2+ efflux that is promoted by reactive oxygen species. Furthermore, we discuss how cellular oxidant and antioxidant capacities are extensively remodeled downstream of UPR signals. Aside from activation of NADPH oxidases, mitogen-activated protein kinases and transcriptional antioxidant responses, such remodeling prominently relies on ER-mitochondrial crosstalk. Specific redox cues therefore operate both as triggers and effectors of ER stress, thus enabling amplification loops. We propose that redox-based amplification loops critically contribute to the switch from adaptive to fatal UPR.

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“…The ⌬p maintained across the IMM by the activity of the respiratory chain thermodynamically drives the forward NNT reaction to establish an NADPH/NADP ϩ ratio that is at least 500-fold higher than the NADH/NAD ϩ ratio under the conditions present in respiring mitochondria (2). Canonically, the NADP redox potential drives the enzymatic degradation of organic and hydrogen peroxide via peroxidase and reductase systems involving glutathione or thioredoxin as substrates, and thus, NADPH can be considered an ultimate antioxidant against peroxides (1,18). Additionally, the redox state of NADP in the mitochondrial matrix maintained by NNT can drive the otherwise unfavorable reductive carboxylation of ␣-ketoglutarate to isocitrate (i.e.…”

mentioning

confidence: 99%

The Contribution of Nicotinamide Nucleotide Transhydrogenase to Peroxide Detoxification Is Dependent on the Respiratory State and Counterbalanced by Other Sources of NADPH in Liver Mitochondria

Ronchi¹,

Francisco²,

Passos

et al. 2016

Journal of Biological Chemistry

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The forward reaction of nicotinamide nucleotide transhydrogenase (NNT) reduces NADP؉ at the expense of NADH oxida- The coenzymes nicotinamide adenine dinucleotide (NAD) and NAD phosphate (NADP) are soluble electron carriers that are reduced in oxidative reactions during the catabolism of energy substrates in the cytosol and mitochondria. Despite their structural similarity, reduced NAD and NADP are used to drive rather different processes in the cells (1). Given their roles as specific electron donors in diverse metabolic pathways, it is interesting that the redox states of NAD and NADP are linked to each other in the mitochondria of many organisms because the enzyme nicotinamide nucleotide transhydrogenase (NNT) 4 catalyzes the transfer of redox potential between these two coenzymes, reducing one at the expense of the oxidation of the other (2).The academic and clinical interest in the understanding of the role of NNT in redox metabolism (3) has grown substantially because mutations in the gene (Nnt) encoding this protein are present in the most widely used experimental mouse substrain (i.e. C57BL/6J) (4) and in some humans (5). Homozygous mutations of Nnt that are linked to familiar glucocorticoid insufficiency have been documented in humans (5), whereas the C57BL/6J mouse substrains have been shown to exhibit metabolic abnormalities (6 -8) with major implications regarding their use as experimental models in basic research (9 -12). The phenotype of the Nnt mutation in heterozygotes is not clear in humans (13) or mice.NADP ϩ reduction at the expense of NADH oxidation in the mitochondrial matrix is the well known primary role of NNT. Although mitochondria possess three other enzymatic oxidative reactions linked to NADP ϩ reduction (i.e. the enzymes isocitrate dehydrogenase (IDH2), malic enzymes (MEs), and glutamate dehydrogenase (GDH)), as highlighted in Fig. 1

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Mitochondria as a Source of Reactive Oxygen and Nitrogen Species: From Molecular Mechanisms to Human Health

Cited by 360 publications

References 555 publications

Mitochondria-targeted Ogg1 and Aconitase-2 Prevent Oxidant-induced Mitochondrial DNA Damage in Alveolar Epithelial Cells

Mitochondria-targeted Ogg1 and Aconitase-2 Prevent Oxidant-induced Mitochondrial DNA Damage in Alveolar Epithelial Cells

Redox controls UPR to control redox

The Contribution of Nicotinamide Nucleotide Transhydrogenase to Peroxide Detoxification Is Dependent on the Respiratory State and Counterbalanced by Other Sources of NADPH in Liver Mitochondria

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