scholarly journals Protein Kinase D Mediates Mitochondrion-to-Nucleus Signaling and Detoxification from Mitochondrial Reactive Oxygen Species

2005 ◽  
Vol 25 (19) ◽  
pp. 8520-8530 ◽  
Author(s):  
Peter Storz ◽  
Heike Döppler ◽  
Alex Toker
Keyword(s):  
Reactive Oxygen Species ◽  
Transcription Factor ◽  
Protein Kinase ◽  
Reactive Oxygen ◽  
Protein Kinase D ◽  
Oxygen Species ◽  
Mitochondrial Reactive Oxygen Species ◽  
Mitochondrial Oxidative Stress ◽  
Cellular Survival ◽  
Mitochondrial Ros

ABSTRACT Efficient elimination of mitochondrial reactive oxygen species (mROS) correlates with increased cellular survival and organism life span. Detoxification of mitochondrial ROS is regulated by induction of the nuclear SOD2 gene, which encodes the manganese-dependent superoxide dismutase (MnSOD). However, the mechanisms by which mitochondrial oxidative stress activates cellular signaling pathways leading to induction of nuclear genes are not known. Here we demonstrate that release of mROS activates a signal relay pathway in which the serine/threonine protein kinase D (PKD) activates the NF-κB transcription factor, leading to induction of SOD2. Conversely, the FOXO3a transcription factor is dispensable for mROS-induced SOD2 induction. PKD-mediated MnSOD expression promotes increased survival of cells upon release of mROS, suggesting that mitochondrion-to-nucleus signaling is necessary for efficient detoxification mechanisms and cellular viability.

Mitochondrial reactive oxygen species contribute to high NaCl-induced activation of the transcription factor TonEBP/OREBP

2006 ◽  
Vol 290 (5) ◽  
pp. F1169-F1176 ◽  
Author(s):  
Xiaoming Zhou ◽  
Joan D. Ferraris ◽  
Maurice B. Burg
Keyword(s):  
Reactive Oxygen Species ◽  
Transcription Factor ◽  
Nuclear Translocation ◽  
Reactive Oxygen ◽  
Hek293 Cells ◽  
Organic Osmolytes ◽  
Ros Production ◽  
Oxygen Species ◽  
Hypertonic Stress ◽  
Mitochondrial Ros

Hypertonicity activates the transcription factor tonicity-responsive enhancer/osmotic response element binding protein (TonEBP/OREBP), resulting in increased expression of genes involved in osmoprotective accumulation of organic osmolytes, including glycine betaine, and in increased expression of osmoprotective heat shock proteins. Our previous studies showed that high NaCl increases reactive oxygen species (ROS), which contribute to activation of TonEBP/OREBP. Mitochondria are a major source of ROS. The purpose of the present study was to examine whether mitochondria produce the ROS that contribute to activation of TonEBP/OREBP. We inhibited mitochondrial ROS production in HEK293 cells with rotenone and myxothiazol, which inhibit mitochondrial complexes I and III, respectively. Rotenone (250 nM) and myxothiazol (12 nM) reduce high NaCl-induced ROS over 40%, whereas apocynin (100 μM), an inhibitor of NADPH oxidase, and allopurinol (100 μM), an inhibitor of xanthine oxidase, have no significant effect. Rotenone and myxothiazol reduce high NaCl-induced increases in TonEBP/OREBP transcriptional activity (ORE/TonE reporter assay) and BGT1 (betaine transporter) mRNA abundance ranging from 53 to 69%. They inhibit high NaCl-induced TonEBP/OREBP transactivating activity, but not its nuclear translocation. Release of ATP into the medium on hypertonic stress has been proposed to be a signal that triggers cellular osmotic responses. However, we do not detect release of ATP into the medium or inhibition of high NaCl-induced ORE/TonE reporter activity by an ATPase, apyrase (20 U/ml), indicating that high NaCl-induced activation of TonEBP/OREBP is not mediated by release of ATP. We conclude that high NaCl increases mitochondrial ROS production, which contributes to the activation of TonEBP/OREBP by increasing its transactivating activity.

Sodium Ion Regulates Mitochondrial ROS

2021 ◽  
Vol 11 ◽  
Author(s):  
Editorial Office ROS
Keyword(s):  
Reactive Oxygen Species ◽  
T Cell Activation ◽  
Solid Phase ◽  
3D Visualization ◽  
Reactive Oxygen ◽  
Sodium Ion ◽  
Calcium Stores ◽  
Oxygen Species ◽  
Mitochondrial Reactive Oxygen Species ◽  
Mitochondrial Ros

In addition to the diverse well-known physiological functions and pathophysiological effects of sodium ion (Na⁺), regulation of mitochondrial reactive oxygen species (ROS) by Na⁺ has recently been demonstrated by several studies published in highly influential journals. The findings from these studies, especially the proposed “cytosolic Na⁺‒Na⁺/Ca²⁺ exchanger‒mitochondrial ROS” axis, have greatly broadened our understanding of this most popular element in physiology and disease. REFERENCES Kohlhaas M, Liu T, Knopp A, Zeller T, Ong MF, Bohm M, et al. Elevated cytosolic Na+ increases mitochondrial formation of reactive oxygen species in failing cardiac myocytes. Circulation 2010; 121(14):1606-13. doi: https://dx.doi.org/10.1161/CIRCULATIONAHA.109.914911. Dey S, DeMazumder D, Sidor A, Foster DB, O'Rourke B. Mitochondrial ROS drive sudden cardiac death and chronic proteome remodeling in heart failure. Circ Res 2018; 123(3):356-71. doi: https://dx.doi.org/10.1161/CIRCRESAHA.118.312708. Murphy E, Eisner DA. Regulation of intracellular and mitochondrial sodium in health and disease. Circ Res 2009; 104(3):292-303. doi: https://dx.doi.org/10.1161/CIRCRESAHA.108.189050. Adrogue HJ, Madias NE. Sodium and potassium in the pathogenesis of hypertension. N Engl J Med 2007; 356(19):1966-78. doi: https://dx.doi.org/10.1056/NEJMra064486. Hernansanz-Agustin P, Choya-Foces C, Carregal-Romero S, Ramos E, Oliva T, Villa-Pina T, et al. Na+ controls hypoxic signalling by the mitochondrial respiratory chain. Nature 2020; 586(7828):287-91. doi: https://dx.doi.org/10.1038/s41586-020-2551-y. Wolf SG, Mutsafi Y, Dadosh T, Ilani T, Lansky Z, Horowitz B, et al. 3D visualization of mitochondrial solid-phase calcium stores in whole cells. Elife 2017; 6. doi: https://dx.doi.org/10.7554/eLife.29929. Shadel GS, Horvath TL. Mitochondrial ROS signaling in organismal homeostasis. Cell 2015; 163(3):560-9. doi: https://dx.doi.org/10.1016/j.cell.2015.10.001. Oberkampf M, Guillerey C, Mouries J, Rosenbaum P, Fayolle C, Bobard A, et al. Mitochondrial reactive oxygen species regulate the induction of CD8+ T cells by plasmacytoid dendritic cells. Nat Commun 2018; 9(1):2241. doi: https://dx.doi.org/10.1038/s41467-018-04686-8. Sena LA, Li S, Jairaman A, Prakriya M, Ezponda T, Hildeman DA, et al. Mitochondria are required for antigen-specific T cell activation through reactive oxygen species signaling. Immunity 2013; 38(2):225-36. doi: https://dx.doi.org/10.1016/j.immuni.2012.10.020.

scholarly journals Survival Signaling by C-RAF: Mitochondrial Reactive Oxygen Species and Ca2+ Are Critical Targets

2008 ◽  
Vol 28 (7) ◽  
pp. 2304-2313 ◽  
Author(s):  
Andrey V. Kuznetsov ◽  
Julija Smigelskaite ◽  
Christine Doblander ◽  
Manickam Janakiraman ◽  
Martin Hermann ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Reactive Oxygen Species ◽  
Cell Death ◽  
Reactive Oxygen ◽  
Ros Production ◽  
Oxygen Species ◽  
Mitochondrial Reactive Oxygen Species ◽  
Mitochondrial Ros ◽  
Survival Signaling ◽  
First Time

ABSTRACT Survival signaling by RAF occurs through largely unknown mechanisms. Here we provide evidence for the first time that RAF controls cell survival by maintaining permissive levels of mitochondrial reactive oxygen species (ROS) and Ca2+. Interleukin-3 (IL-3) withdrawal from 32D cells resulted in ROS production, which was suppressed by activated C-RAF. Oncogenic C-RAF decreased the percentage of apoptotic cells following treatment with staurosporine or the oxidative stress-inducing agent tert-butyl hydroperoxide. However, it was also the case that in parental 32D cells growing in the presence of IL-3, inhibition of RAF signaling resulted in elevated mitochondrial ROS and Ca2+ levels. Cell death is preceded by a ROS-dependent increase in mitochondrial Ca2+, which was absent from cells expressing transforming C-RAF. Prevention of mitochondrial Ca2+ overload after IL-3 deprivation increased cell viability. MEK was essential for the mitochondrial effects of RAF. In summary, our data show that survival control by C-RAF involves controlling ROS production, which otherwise perturbs mitochondrial Ca2+ homeostasis.

scholarly journals Mitochondrial Reactive Oxygen Species Trigger Hypoxia-Inducible Factor-Dependent Extension of the Replicative Life Span during Hypoxia

2007 ◽  
Vol 27 (16) ◽  
pp. 5737-5745 ◽  
Author(s):  
Eric L. Bell ◽  
Tatyana A. Klimova ◽  
James Eisenbart ◽  
Paul T. Schumacker ◽  
Navdeep S. Chandel
Keyword(s):  
Reactive Oxygen Species ◽  
Life Span ◽  
Hypoxia Inducible Factor ◽  
Reactive Oxygen ◽  
Dominant Negative ◽  
Lung Fibroblasts ◽  
Oxygen Species ◽  
Mitochondrial Reactive Oxygen Species ◽  
Replicative Life Span ◽  
Mitochondrial Ros

ABSTRACT Physiological hypoxia extends the replicative life span of human cells in culture. Here, we report that hypoxic extension of replicative life span is associated with an increase in mitochondrial reactive oxygen species (ROS) in primary human lung fibroblasts. The generation of mitochondrial ROS is necessary for hypoxic activation of the transcription factor hypoxia-inducible factor (HIF). The hypoxic extension of replicative life span is ablated by a dominant negative HIF. HIF is sufficient to induce telomerase reverse transcriptase mRNA and telomerase activity and to extend replicative life span. Furthermore, the down-regulation of the von Hippel-Lindau tumor suppressor protein by RNA interference increases HIF activity and extends replicative life span under normoxia. These findings provide genetic evidence that hypoxia utilizes mitochondrial ROS as signaling molecules to activate HIF-dependent extension of replicative life span.

scholarly journals Neutralizing mitochondrial ROS does not rescue muscle atrophy induced by hindlimb unloading in female mice

2020 ◽  
Vol 129 (1) ◽  
pp. 124-132 ◽  
Author(s):  
Hiroaki Eshima ◽  
Piyarat Siripoksup ◽  
Ziad S. Mahmassani ◽  
Jordan M. Johnson ◽  
Patrick J. Ferrara ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Muscle Weakness ◽  
Muscle Atrophy ◽  
Reactive Oxygen ◽  
Hindlimb Unloading ◽  
Oxygen Species ◽  
Mitochondrial Reactive Oxygen Species ◽  
Female Mice ◽  
Mitochondrial Ros ◽  
Genetic Suppression

The premise of this study was to examine the efficacy of genetic suppression of mitochondrial reactive oxygen species (ROS) to attenuate disuse-induced muscle atrophy and muscle weakness. Neutralization of mitochondrial ROS by MCAT expression was insufficient to rescue muscle atrophy and muscle weakness.

scholarly journals Repression of Hypoxia-Inducible Factor-1 Contributes to Increased Mitochondrial Reactive Oxygen Species Production in Diabetes

2021 ◽  
Author(s):  
Xiaowei Zheng ◽  
Sampath Narayanan ◽  
Cheng Xu ◽  
Sofie Eliasson Angelstig ◽  
Jacob Grünler ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Hypoxia Inducible Factor ◽  
Reactive Oxygen ◽  
Pyruvate Dehydrogenase Kinase ◽  
Oxygen Species ◽  
Mitochondrial Reactive Oxygen Species ◽  
Glucose Levels ◽  
Hypoxia Inducible Factor 1 ◽  
Mitochondrial Ros ◽  
Functional Consequences

Background: Excessive production of mitochondrial reactive oxygen species (ROS) is a central mechanism for the development of diabetes complications. Recently, hypoxia has been identified to play an additional pathogenic role in diabetes. In this study, we hypothesized that ROS overproduction was secondary to the impaired responses to hypoxia due to the inhibition of hypoxia-inducible factor-1 (HIF-1) by hyperglycemia. Methods: The dynamic of ROS levels was analysed in the blood of healthy subjects and individuals with type 1 diabetes after exposure to hypoxia (ClinicalTrials.gov registration no. NCT02629406). The relation between HIF-1, glucose levels, ROS production and its functional consequences were analyzed in renal mIMCD-3 cells and in kidneys of mouse models of diabetes. Results: Exposure to hypoxia increased circulating ROS in subjects with diabetes, but not in subjects without diabetes. High glucose concentrations repressed HIF-1 both in hypoxic cells and in kidneys of animals with diabetes, through a HIF prolyl-hydroxylase (PHD) - dependent mechanism. The impaired HIF-1 signaling contributed to excess production of mitochondrial ROS through increased mitochondrial respiration that was mediated by Pyruvate dehydrogenase kinase 1 (PDK1) and was followed by functional consequences. The restoration of HIF-1 function attenuated ROS overproduction despite persistent hyperglycemia, and conferred protection against apoptosis and renal injury in diabetes. Conclusions: We conclude that the repression of HIF-1 plays a central role in mitochondrial ROS overproduction in diabetes and is a potential therapeutic target for diabetic complications. These findings are highly significant and timely since the first PHD inhibitor that can activate HIF-1 has been newly approved for clinical use.

scholarly journals Mitochondrial Reactive Oxygen Species Control the Transcription Factor CHOP-10/GADD153 and Adipocyte Differentiation

2004 ◽  
Vol 279 (39) ◽  
pp. 40462-40469 ◽  
Author(s):  
Audrey Carrière ◽  
Maria-Carmen Carmona ◽  
Yvette Fernandez ◽  
Michel Rigoulet ◽  
Roland H. Wenger ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Transcription Factor ◽  
Adipocyte Differentiation ◽  
Reactive Oxygen ◽  
Oxygen Species ◽  
Mitochondrial Reactive Oxygen Species

scholarly journals Nitrogen Dioxide Inhalation Exposures Induce Cardiac Mitochondrial Reactive Oxygen Species Production, Impair Mitochondrial Function and Promote Coronary Endothelial Dysfunction

2020 ◽  
Vol 17 (15) ◽  
pp. 5526
Author(s):  
Ahmed Karoui ◽  
Clément Crochemore ◽  
Najah Harouki ◽  
Cécile Corbière ◽  
David Preterre ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Risk Factor ◽  
Endothelial Dysfunction ◽  
Mitochondrial Function ◽  
Reactive Oxygen ◽  
Ros Production ◽  
Oxygen Species ◽  
Mitochondrial Reactive Oxygen Species ◽  
Mitochondrial Ros ◽  
Coronary Endothelial Dysfunction

Traffic air pollution is a major health problem and is recognized as an important risk factor for cardiovascular (CV) diseases. In a previous experimental study, we showed that diesel exhaust (DE) exposures induced cardiac mitochondrial and CV dysfunctions associated with the gaseous phase. Here, we hypothesized that NO2 exposures to levels close to those found in DE induce a mitochondrial reactive oxygen species (ROS) production, which contribute to an endothelial dysfunction, an early indicator for numerous CV diseases. For this, we studied the effects of NO2 on ROS production and its impacts on the mitochondrial, coronary endothelial and cardiac functions, after acute (one single exposure) and repeated (three h/day, five days/week for three weeks) exposures in Wistar rats. Acute NO2 exposure induced an early but reversible mitochondrial ROS production. This event was isolated since neither mitochondrial function nor endothelial function were impaired, whereas cardiac function assessment showed a reversible left ventricular dysfunction. Conversely, after three weeks of exposure this alteration was accompanied by a cardiac mitochondrial dysfunction highlighted by an alteration of adenosine triphosphate (ATP) synthesis and oxidative phosphorylation and an increase in mitochondrial ROS production. Moreover, repeated NO2 exposures promoted endothelial dysfunction of the coronary arteries, as shown by reduced acetylcholine-induced vasodilatation, which was due, at least partially, to a superoxide-dependent decrease of nitric oxide (NO) bioavailability. This study shows that NO2 exposures impair cardiac mitochondrial function, which, in conjunction with coronary endothelial dysfunction, contributes to cardiac dysfunction. Together, these results clearly identify NO2 as a probable risk factor in ischemic heart diseases.

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