Generation of superoxide anion by the NADH dehydrogenase of bovine heart mitochondria

Turrens, Julio F.; Boveris, Alberto

doi:10.1042/bj1910421

Cited by 1,454 publications

(796 citation statements)

References 30 publications

(31 reference statements)

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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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Section: Regulation Of Hif Functionmentioning

confidence: 99%

Mitochondrial complex III regulates hypoxic activation of HIF

2008

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“…Complex I (CI) and complex III (CIII) are the major sites for ROS production in aging and ischemia-reperfusion injury of the heart [5][6][7]. The NADH dehydrogenase site of CI, which is also the site of electron leakage, is located in the matrix side of the inner mitochondrial membrane [8].…”

Section: Introductionmentioning

confidence: 99%

Age-related alterations in oxidatively damaged proteins of mouse heart mitochondrial electron transport chain complexes

Choksi

Papaconstantinou

2008

Free Radical Biology and Medicine

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Mitochondrial generated ROS increases with age and is a major factor that damages proteins by oxidative modification. Accumulation of oxidatively damaged proteins has been implicated as a causal factor in the age-associated decline in tissue function. Mitochondrial electron transport chain (ETC) complexes I and III are the principle sites of ROS production, and oxidative modifications to their complex subunits inhibit their in vitro activity. We hypothesize that mitochondrial complex subunits may be primary targets for modification by ROS which may impair normal complex activity. This study of heart mitochondria from young, middle-aged and old mice reveals that there is an agerelated decline in complex I and V activities that correlate with increased oxidative modification to their subunits. The data also show a specificity for modifications of the ETC complex subunits, i.e., several proteins have more than one type of adduct. We postulate that the electron leakage from ETC complexes causes specific damage to their subunits and increased ROS generation as oxidative damage accumulates, leading to further mitochondrial dysfunction, a cyclical process that underlies the progressive decline in physiologic function of aged mouse heart.

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“…The major sites of superoxide formation in the respiratory chain lay within respiratory Complexes I and III, with a general consensus that production at Complex I is about half of that at Complex III (6). However, the relative importance and physiological relevance of other sites might also be high.…”

Section: Superoxide Production By Mitochondrial Complexesmentioning

confidence: 99%

The Mitochondrial Production of Reactive Oxygen Species: Mechanisms and Implications in Human Pathology

2001

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SummaryMitochondria are major sources of reactive oxygen species (ROS); the main sites of superoxide radical production in the respiratory chain are Complexes III and I; however, other mitochondrial enzymes, such as Complex II, glycerol-1-phosphate dehydrogenase, and dihydroorotate dehydrogenase, are also involved in production of ROS. ROS appear to be released both in the matrix and in the intermembrane space; however, their appearance outside the mitochondria may not be physiologically relevant. ROS production is increased in State 4 and in all conditions when the respiratory components are substantially in the reduced form. Accordingly, defects inducing decrease of electron transfer in the respiratory chain, as in many pathological conditions, are bound to enhance ROS production.

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Generation of superoxide anion by the NADH dehydrogenase of bovine heart mitochondria

Cited by 1,454 publications

References 30 publications

Mitochondrial complex III regulates hypoxic activation of HIF

Mitochondrial complex III regulates hypoxic activation of HIF

Age-related alterations in oxidatively damaged proteins of mouse heart mitochondrial electron transport chain complexes

The Mitochondrial Production of Reactive Oxygen Species: Mechanisms and Implications in Human Pathology

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