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 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 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.

scholarly journals Reactive Oxygen Species and Nrf2: Functional and Transcriptional Regulators of Hematopoiesis

2019 ◽  
Vol 2019 ◽  
pp. 1-11 ◽  
Author(s):  
Linping Hu ◽  
Yawen Zhang ◽  
Weimin Miao ◽  
Tao Cheng
Keyword(s):  
Reactive Oxygen Species ◽  
Oxygen Sensor ◽  
Hypoxia Inducible Factor ◽  
Reactive Oxygen ◽  
Ambient Air ◽  
Oxygen Species ◽  
Human Cord Blood ◽  
Hematopoietic Stem ◽  
Hypoxia Inducible Factor 1 ◽  
Cellular Oxygen

Hematopoietic stem cells (HSCs) are characterized by self-renewal and multilineage differentiation potentials. Although they play a central role in hematopoietic homeostasis and bone marrow (BM) transplantation, they are affected by multiple environmental factors in the BM. Here, we review the effects of reactive oxygen species (ROS) and Nrf2 on HSC function and BM transplantation. HSCs reside in the hypoxic microenvironment of BM, and ROS play an important role in HSPC regulation. Recently, an extraphysiologic oxygen shock/stress phenomenon was identified in human cord blood HSCs collected under ambient air conditions. Moreover, Nrf2 has been recently recognized as a master transcriptional factor that regulates multiple antioxidant enzymes. Since several years, the role of Nrf2 in hematopoiesis has been extensively studied, which has functional similarities of cellular oxygen sensor hypoxia-inducible factor-1 as transcriptional factors. Increasing evidence has revealed that abnormally elevated ROS production due to factors such as genetic defects, aging, and ionizing radiation unexceptionally resulted in lethal impairment of HSC function and hematopoiesis. Both experimental and clinical studies have identified elevated ROS levels as a major culprit of ineffective BM transplantation. Lastly, we discuss the possibility of using small molecule antioxidants, such as N-acetyl cysteine, resveratrol, and curcumin, to augment HSC function and improve the therapeutic efficacy of BM transplantation. Further research on the function of ROS levels and improving the efficacy of BM transplantation may have a great potential for broad clinical applications of HSCs.

scholarly journals Hypoxia-inducible Factor-1 Activation in Nonhypoxic Conditions: The Essential Role of Mitochondrial-derived Reactive Oxygen Species

2010 ◽  
Vol 21 (18) ◽  
pp. 3247-3257 ◽  
Author(s):  
David A. Patten ◽  
Véronique N. Lafleur ◽  
Geneviève A. Robitaille ◽  
Denise A. Chan ◽  
Amato J. Giaccia ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Nadph Oxidase ◽  
Hypoxia Inducible Factor ◽  
Reactive Oxygen ◽  
Protein Stabilization ◽  
Complex Iii ◽  
Oxygen Species ◽  
Ang Ii ◽  
Hypoxia Inducible Factor 1

Hypoxia-inducible factor-1 (HIF-1) is a key transcription factor for responses to low oxygen. Different nonhypoxic stimuli, including hormones and growth factors, are also important HIF-1 activators in the vasculature. Angiotensin II (Ang II), the main effecter hormone in the renin-angiotensin system, is a potent HIF-1 activator in vascular smooth muscle cells (VSMCs). HIF-1 activation by Ang II involves intricate mechanisms of HIF-1α transcription, translation, and protein stabilization. Additionally, the generation of reactive oxygen species (ROS) is essential for HIF-1 activation during Ang II treatment. However, the role of the different VSMC ROS generators in HIF-1 activation by Ang II remains unclear. This work aims at elucidating this question. Surprisingly, repression of NADPH oxidase-generated ROS, using Vas2870, a specific inhibitor or a p22phox siRNA had no significant effect on HIF-1 accumulation by Ang II. In contrast, repression of mitochondrial-generated ROS, by complex III inhibition, by Rieske Fe-S protein siRNA, or by the mitochondrial-targeted antioxidant SkQ1, strikingly blocked HIF-1 accumulation. Furthermore, inhibition of mitochondrial-generated ROS abolished HIF-1α protein stability, HIF-1–dependent transcription and VSMC migration by Ang II. A large number of studies implicate NADPH oxidase–generated ROS in Ang II–mediated signaling pathways in VSMCs. However, our work points to mitochondrial-generated ROS as essential intermediates for HIF-1 activation in nonhypoxic conditions.

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 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.

Sign in / Sign up

Export Citation Format

Share Document