Mitochondrial reactive oxygen species regulate cellular signaling and dictate biological outcomes

Hamanaka, Robert B.; Chandel, Navdeep S.

doi:10.1016/j.tibs.2010.04.002

Cited by 856 publications

(700 citation statements)

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“…The ability of increased ROS to modulate different aspects of cell function has been widely recognized (11,26,37,38,40). Our group has contributed to the knowledge of this regulation by demonstrating that H 2 O 2 induces mesangial cell contraction (6), stimulates cell proliferation (8) To decreased intracellular ROS concentration, CAT was added to the extracellular media of the cells.…”

Section: Discussionmentioning

confidence: 99%

“…The balance between production and elimination is tightly regulated and ensures the proper maintenance of cellular metabolism and homeostasis. In general, moderate levels of ROS are involved in biological processes such as cell proliferation, differentiation and survival (11,37). Exogenous stimuli may also modulate ROS balance and in these cases transient ROS production can act as an intracellular signalling mechanism, regulating a broad variety of genes and cell functions (2,31,39).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Intracellular redox equilibrium is essential for the constitutive expression of AP-1 dependent genes in resting cells: Studies on TGF-β1 regulation

González-Ramos

Mora

Garcı́a

et al. 2012

The International Journal of Biochemistry & Cell Biology

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Intracellular redox equilibrium is essential for the constitutive expression of AP-1 dependent genes in resting cells: Studies on TGF-β1 regulation

González-Ramos

Mora

Garcı́a

et al. 2012

The International Journal of Biochemistry & Cell Biology

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“…ROS as messengers have been associated to signaling by insulin, cytokines and many growth factors [35,36], whose activity regulates classic signaling cascades such as the extracellular ERK, JNK, and MAPK cascades, as well as the PI3-K/Akt, PLC-γ1 and JAK/STAT pathways [37,38]. These pathways in turn exert their phenotypic effects largely by modulating the activities of central transcription factors, among them NF-kB, AP-1, Nrf2, FoxOs, HIF-1α and p53 [39,40]. Furthermore, the activities of enzymes such as catalase, GPxs and Prdx have been shown to be regulated by kinases and phosphatases that are susceptible to oxidative modifications, thus creating a regulatory network [9,10].…”

Section: The Role Of Ros In Signal Transductionmentioning

confidence: 99%

Taking a “good” look at free radicals in the aging process

Hekimi

Lapointe

Yang

2011

Trends in Cell Biology

519

373

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The mitochondrial free radical theory of aging (MFRTA) proposes that aging is caused by damage to macromolecules from mitochondrial reactive oxygen species (ROS). This is based on the observed association of the rate of aging and the aged phenotype with the generation of ROS and with oxidative damage. The theory has led to the strong conviction in the general public that the consumption of antioxidants is crucial to health and beneficial to lifespan. However, a variety of recent findings convincingly demonstrate that ROS generation and oxidative damage cannot be the cause of aging. Here we propose that ROS play a role in mediating a stress response to agedependent damage, which could generate the observed correlation between aging and ROS without implying that ROS cause aging. Redefining our understanding of the relationship between ROS and agingMitochondria are a major source of reactive oxygen species (ROS), a type of molecule that includes free radicals such as superoxide. ROS spontaneously oxidize and damage macromolecules such as proteins, lipids and nucleic acids. Cells and organisms are said to be sustaining oxidative stress when an imbalance between ROS generation and detoxification or repair leads to an increase in the level of ROS-dependent damage. The mitochondrial free radical theory of aging (MFRTA) has provided an attractive framework that integrates numerous observations about the generation, the toxicity and the detoxification of ROS, as well as about how these parameters change with the physiological state of cells and organisms and with chronological age. The theory proposes that aging is actually caused by the toxicity of ROS through a vicious cycle in which ROS damage to the constituents of mitochondria leads to the generation of more ROS. The theory is based on numerous observations, including (1) that there is a strong correlation between chronological age and the level of ROS generation and oxidative damage, (2) that mitochondrial function is gradually lost during aging, (3) that inhibition of mitochondrial function can enhance ROS production, and (4) that several age-dependent diseases are associated with severe increases in oxidative stress.The strength of the MFRTA is that it provides a framework for many observations while also stating a plausible causal theory of aging. Furthermore, it provided a clear research program by proposing a theory to be tested as well as by suggesting that decreasing the generation of ROS will result in health benefits. In fact the MFRTA is often taught in textbooks and in *

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“…•-and • OH) (Radi et al 2002;Boveris et al 2006;Giorgio et al 2007;Hamanaka and Chandel 2010). The diffusion properties of H 2 O 2 likely depend on its site of generation and (local) conversion, since cytoplasmic microdomains of elevated H 2 O 2 levels were demonstrated in cells stimulated with growth factors, suggesting that this type of ROS does not freely diffuse through the cytoplasm (Rhee et al 2012;Mishina et al 2012).…”

Section: Range Of Action Of Rosmentioning

confidence: 99%

“…This strongly suggests that both ROS-induced damage and signaling are affected by restricted diffusion and compartmentalization (Winterbourn 2008). In this respect, it appears that mitochondria-generated O 2•-acts locally, whereas H 2 O 2 and NO • , owing to their membrane permeability and relative stability, can function as both a cytosolic and extracellular messenger (t 1/2 for H 2 O 2 is 10 -2 ms and for NO • between 1-30 s, compared to 10 -3 ms and 10 -6 ms for O 2•-and • OH) (Radi et al 2002;Boveris et al 2006;Giorgio et al 2007;Hamanaka and Chandel 2010). The diffusion properties of H 2 O 2 likely depend on its site of generation and (local) conversion, since cytoplasmic microdomains of elevated H 2 O 2 levels were demonstrated in cells stimulated with growth factors, suggesting that this type of ROS does not freely diffuse through the cytoplasm (Rhee et al 2012;Mishina et al 2012).…”

mentioning

confidence: 99%

Integrated High-Content Quantification of Intracellular ROS Levels and Mitochondrial Morphofunction

Sieprath

Corne

Willems

et al. 2016

Advances in Anatomy, Embryology and Cell Biology

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Oxidative stress arises from an imbalance between the production of reactive oxygen species (ROS) and their removal by cellular antioxidant systems. Especially under pathological conditions, mitochondria constitute a relevant source of cellular ROS. These organelles harbor the electron transport chain, bringing electrons in close vicinity to molecular oxygen. Although a full understanding is still lacking, intracellular ROS generation and mitochondrial function are also linked to changes in mitochondrial morphology. To study the intricate relationships between the different factors that govern cellular redox balance in living cells, we have developed a high-content microscopy-based strategy for simultaneous quantification of intracellular ROS levels and mitochondrial morphofunction. Here, we summarize the principles of intracellular ROS generation and removal, and we explain the major considerations for performing quantitative microscopy analyses of ROS and mitochondrial morphofunction in living cells. Next, we describe our workflow and finally, we illustrate that a multiparametric readout enables the unambiguous classification of chemically perturbed cells as well as laminopathy patient cells. Principles of intracellular ROS generation and removalReactive oxygen species (ROS) are small, short-lived derivatives of molecular oxygen (O 2 ) of radical and non-radical nature (Halliwell and Gutteridge 2007 • ), nitrate radical (NO 3 • ) and many other nitrogen derivatives. ROS were originally described as molecular constituents of the defense system of phagocytic cells, but it has become clear that besides their damaging properties, they also function as signaling molecules and mediate a variety of other cellular responses including cell proliferation, differentiation, gene expression and migration (Lambeth 2004;Bartz and Piantadosi 2010). Intracellular ROS metabolismROS can be generated at various sites in the cell (Fig. 1A). This can be either deliberately, e.g. by NADPH oxidases (NOX), or as a byproduct, e.g. during normal cellular respiration in mitochondria (Babior 1999;Turrens 2003;Murphy 2009). The NOX family of NADPH oxidases (NOX1, NOX2, NOX3, NOX4, NOX5, DUOX1 and DUOX2) are proteins that transport electrons (e -) from NADPH across biological membranes (plasma or endomembranes) (Bedard and Krause 2007;Dupre-Crochet et al. 2013). The activation mechanisms and tissue distribution of the isoforms differ but they all use O 2 as e --acceptor, producing O 2•-. Through ROS generation, they play a role in many cellular processes including host defense, regulation of gene expression and cell differentiation (Bedard and Krause 2007). Despite their sometimes significant contribution to the global ROS pools, NOX are not the predominant source of intracellular ROS. Mitochondria are considered the major culprit, in particular under pathological conditions. Mitochondrial ROS are generated as a byproduct of the oxidative phosphorylation (OXPHOS, cf. below). Irrespective of its source, ROS production generally sta...

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Mitochondrial reactive oxygen species regulate cellular signaling and dictate biological outcomes

Cited by 856 publications

References 97 publications

Intracellular redox equilibrium is essential for the constitutive expression of AP-1 dependent genes in resting cells: Studies on TGF-β1 regulation

Intracellular redox equilibrium is essential for the constitutive expression of AP-1 dependent genes in resting cells: Studies on TGF-β1 regulation

Taking a “good” look at free radicals in the aging process

Integrated High-Content Quantification of Intracellular ROS Levels and Mitochondrial Morphofunction

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