Essential role of complex II of the respiratory chain in hypoxia-induced ROS generation in the pulmonary vasculature

Paddenberg, Renate; Ishaq, Barat; Goldenberg, Anna; Faulhammer, Petra; Rose, Frank; Weißmann, Norbert; Braun‐Dullaeus, Ruediger C.; Kummer, Wolfgang

doi:10.1152/ajplung.00149.2002

Cited by 158 publications

(113 citation statements)

References 44 publications

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“…Thus, mitochondrial nitrotyrosine clearance may be part of an organelle-specific defense mechanism against oxidative and nitrative stress under conditions of decreasing oxygen tension, because one of the main sources of reactive oxygen species are complexes I-III of the mitochondrial respiratory chain (42). If a protein denitration mechanism is responsible for this clearance of nitrotyrosine, it likely involves either reduction of nitrotyrosine to aminotyrosine or full removal of the nitro group from the tyrosine residue.…”

Section: Resultsmentioning

confidence: 99%

Rapid and Selective Oxygen-regulated Protein Tyrosine Denitration and Nitration in Mitochondria

Koeck

Hazen

et al. 2004

Journal of Biological Chemistry

167

133

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Growing evidence connects a cumulative formation of 3-nitrotyrosyl adducts in proteins as a marker for oxidative damage with the pathogenesis of various diseases and pathological conditions associated with oxidative stress. A physiological signaling role for protein nitration has also been suggested. Controlled "denitration" would be essential for such a contribution of protein nitration to cellular regulatory processes. Thus, we further characterized such a potentially controlled, reversible tyrosine nitration that occurs in respiring mitochondria during oxygen deprivation followed by reoxygenation, which we recently discovered. Mitochondria constitute cellular centers of protein nitration and are leading candidates for a "nitrative" regulation. Mitochondria are capable of completely eliminating 3-nitrotyrosyl adducts during 20 min of hypoxia-anoxia and undergoing a selective partial reduction after only 5 min. This denitration is independent of protein degradation but depends on the oxygen tension. Reoxygenation re-establishes protein tyrosine nitration patterns that are almost identical to the pattern that occurs before hypoxia-anoxia, with nitration levels that depend on the duration of hypoxia-anoxia. The identified mitochondrial targets of this process are critical for energy and antioxidant homeostasis and, therefore, cell and tissue viability. This cycle of protein nitration and denitration shows analogies to protein phosphorylation, and we demonstrate that the cycle meets most of the criteria for a cellular signaling mechanism. Taken together, our data reveal that protein tyrosine nitration in mitochondria can be controlled, is target-selective and rapid, and is dynamic enough to serve as a nitrative regulatory signaling process that likely affects cellular energy, redox homeostasis, and pathological conditions when these features become disturbed.

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Section: Resultsmentioning

confidence: 99%

Rapid and Selective Oxygen-regulated Protein Tyrosine Denitration and Nitration in Mitochondria

Koeck

Hazen

et al. 2004

Journal of Biological Chemistry

167

133

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“…Another aspect is that oxygen tension is low in medullary rays, like it is in the medulla. Low oxygen tension can result in generation of reactive oxygen species (34,35), a possible alternative or additional signal for Pax2 expression. To elucidate how high NaCl levels increase Pax2 mRNA abundance, we measured Pax2 mRNA stability.…”

Section: Discussionmentioning

confidence: 99%

Pax2 expression occurs in renal medullary epithelial cells in vivo and in cell culture, is osmoregulated, and promotes osmotic tolerance

Cai

Dmitrieva

Ferraris

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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Pax2 is a transcription factor that is crucial for kidney development, and it is also expressed in the normal adult kidney, where its physiological function is unknown. In the present study, we find by cDNA microarray analysis that Pax2 expression in second-passage mouse inner-medullary epithelial cells is increased by a high NaCl concentration, which is significant because NaCl levels are normally high in the inner medulla in vivo, and varies with urinary concentration. Furthermore, a high NaCl concentration increases Pax2 mRNA and protein expression in mouse inner medullary collecting duct (mIMCD3) apoptosis ͉ osmotic stress ͉ renal inner medulla

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“…The pharmacologic and genetic data point to the ubiquinone (Q) cycle of complex III as the source of ROS generation during hypoxia to stabilize HIF-1a protein. 41,43,[47][48][49] Unlike complexes I and II, which generate superoxide into the mitochondrial matrix, [52][53][54][55] complex III can also release superoxide into the mitochondrial intermembrane space and subsequently, into the cytosol. [56][57][58] The Q cycle is initiated when complex I and complex II transfer electrons to reduce the lipid moiety ubiquinone to ubiquinol (Figure 3).…”

Section: Regulation Of Hif Functionmentioning

confidence: 99%

Mitochondrial complex III regulates hypoxic activation of HIF

2008

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Decreases in oxygen levels are observed in physiological processes, such as development, and pathological situations, such as tumorigenesis and ischemia. In the complete absence of oxygen (anoxia), mammalian cells are unable to generate sufficient energy for survival, so a mechanism for sensing a decrease in the oxygen level (hypoxia) before it reaches a critical point is crucial for the survival of the organism. In response to decreased oxygen levels, cells activate the transcription factors hypoxiainducible factors (HIFs), which lead to metabolic adaptation to hypoxia, as well as to generate new vasculature to increase oxygen supply. How cells sense decreases in oxygen levels to regulate HIF activation has been hotly debated. Emerging evidence indicates that reactive oxygen species (ROS) generated by mitochondrial complex III are required for hypoxic activation of HIF. This review examines the current knowledge about the role of mitochondrial ROS in HIF activation, as well as implications of ROS-level regulation in pathological processes such as cancer. Oxygen Homeostasis and HIF Maintaining oxygen homeostasis is critical for survival and proper function of cells and organisms. 1 Reduced oxygen levels (hypoxia) initiates proper placental and vascular development. Hypoxia also has a causal role in pathological conditions such as ischemia-related diseases and cancer. A complete absence of oxygen (anoxia) results in cell death. 2 ATP synthesis is ablated, and most cells undergo apoptosis soon after anoxia exposure. 3-5 Cells exposed to hypoxia, or reduced oxygen levels, on the other hand, are able to maintain normal ATP synthesis and survive. 5,6 However, as cells replicate in a hypoxic environment, they reduce the oxygen supply even further and generate levels of local anoxia. Therefore, cells must respond quickly to decreasing oxygen levels before reaching an anoxic state (Figure 1).Mammalian cells respond to hypoxia by activating broadaction transcription factors named hypoxia-inducible factors, or HIFs, which are expressed by virtually all cells of the body. 7-9 Three members of the HIF family exist, named HIF1, HIF2 and HIF-3. 10-13 HIFs bind to hypoxia-responsive elements, consensus sequences in the promoter region of more than one hundred genes, activating the transcription of genes that allow the cell to adapt to and survive in the hypoxic environment. 14,15 Genes regulated by HIFs include glucose transporter that allow the cells to efficiently import glucose to continue generating ATP despite reduced nutrient availability; and genes that reorganize the microenvironment to bring in oxygen, such as vascular endothelial growth factor, which stimulates formation of new blood vessels. [16][17][18] Importantly for tumorigenesis, HIF also turns on genes such as insulin-like growth factor 2,19 which induces cellular survival and proliferation, as well as those that promote tumor invasion and migration, such as matrix metalloproteinase-2. 20 These factors contribute to tumor growth and invasion and metastasis, im...

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Essential role of complex II of the respiratory chain in hypoxia-induced ROS generation in the pulmonary vasculature

Cited by 158 publications

References 44 publications

Rapid and Selective Oxygen-regulated Protein Tyrosine Denitration and Nitration in Mitochondria

Rapid and Selective Oxygen-regulated Protein Tyrosine Denitration and Nitration in Mitochondria

Pax2 expression occurs in renal medullary epithelial cells in vivo and in cell culture, is osmoregulated, and promotes osmotic tolerance

Mitochondrial complex III regulates hypoxic activation of HIF

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