Mitochondrial ROS production during ischemia-reperfusion injury

2020 ◽  
pp. 513-538 ◽  
Author(s):  
Hiran A. Prag ◽  
Duvaraka Kula-Alwar ◽  
Timothy E. Beach ◽  
Anja V. Gruszczyk ◽  
Nils Burger ◽  
...  
Keyword(s):  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Ros Production ◽  
Mitochondrial Ros

Abstract P311: Blocking Succinate Release Enhances Mitochondrial Reactive Oxygen Species Generation And Worsens Ischemia-reperfusion Injury

2021 ◽  
Vol 129 (Suppl_1) ◽  
Author(s):  
Alexander S Milliken ◽  
Sergiy M Nadtochiy ◽  
Paul S Brookes
Keyword(s):  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Reactive Oxygen Species Generation ◽  
Ros Generation ◽  
Ros Production ◽  
Succinate Oxidation ◽  
Fluorescence Measurements ◽  
Mitochondrial Ros ◽  
The Impact ◽  
Infarction Heart

Succinate is a metabolite that plays a central role in ischemia-reperfusion (IR) injury,which is relevant to myocardial infarction (heart attack) and stroke. Succinateaccumulates during ischemia and is rapidly consumed at reperfusion driving reactiveoxygen species (ROS) generation at complex-I (Cx-I) and III of the mitochondrial electrontransport chain. This ROS production triggers cell-death, leading to tissue necrosis.Although succinate oxidation has been extensively studied and exploited as a noveltherapeutic target, only 1/3 of the succinate accumulated in ischemia is oxidized atreperfusion, with the remaining 2/3 being released from the cell via monocarboxylatetransporter 1 (MCT1). Extracellular succinate is thought to be pro-inflammatory, and ithas been proposed that preventing succinate release may be therapeutically beneficial.To determine the impact of preventing succinate release on IR injury, we comparedfunctional recovery (i.e. rate x pressure product, RPP) and infarction (i.e. tissue necrosis)of Langendorff perfused mouse hearts treated with an MCT1 inhibitor, AR-C155858,versus vehicle control. This revealed that succinate retention worsens IR injury (i.e.increased infarction and decreased functional recovery) likely due to increased ROS. Totest this hypothesis, we utilized a Langendorff apparatus positioned within aspectrofluorimeter, which permits real-time fluorescence measurements in beatingmouse hearts. Using the mitochondria targeted superoxide probe, MitoSOX red tomeasure ROS production at reperfusion + AR-C155858, demonstrated that succinateretention leads to enhanced mitochondrial ROS generation at the onset of reperfusion.Overall, these results suggest that inhibiting succinate release in the context of IR injurymay not be a viable therapeutic approach, regardless of any downstream anti-inflammatory effects.

Abstract 16598: The Role of Paraoxonase 2 in Myocardial Ischemia/Reperfusion Injury

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Jingyuan Li ◽  
Victor R Grijalva ◽  
Srinivasa T Reddy ◽  
Mansoureh Eghbali
Keyword(s):  
Myocardial Ischemia ◽  
Infarct Size ◽  
Er Stress ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Ros Production ◽  
Myocardial Ischemia Reperfusion Injury ◽  
Myocardial Ischemia Reperfusion

Objectives: Paraoxonases (PON) gene family consists of three proteins PON1, PON2, and PON3. PON2 is an intracellular membrane-associated protein that is widely expressed in vascular cells and many tissues. At the subcellular level, PON2 is localized to both the ER and mitochondria, and protects against oxidative stress. Hypothesis: The aim of this study was to investigate the role of PON2 in myocardial ischemia reperfusion injury. Methods: PON2 deficient (PON2-/-) and WT male mice were subjected to in-vivo ischemia/reperfusion injury. The left anterior descending coronary artery was occluded for 30 min followed by 24 hr of reperfusion. The infarct size, mitochondrial calcium retention capacity (CRC) and reactive oxygen species (ROS) generation were measured. The expression of C/EBP homologous protein (CHOP), GSK3b and phosphate GSK3b protein were examined by Western Blot. The number of animals was 5-7/group and data were expressed as mean±SEM. T test were used for statistical analysis. Probability values <0.05 were considered statistically significant. Results: The infarct size was ~2 fold larger in PON2 deficient mice compared to WT mice (p<0.05). The threshold for opening of mitochondrial permeability transition pore (mPTP) in response to calcium overload was much lower in PON2-/- mice compared with WT mice (173±19 in PON2-/-, 250±41 in WT, nmol/mg-mitochondrial protein, p<0.05). The ROS production was ~2 fold higher in isolated cardiac mitochondria from PON2-/- mice compared with WT mice (p<0.05). ER stress protein CHOP increased significantly in PON2-/- mice compared to WT mice (normalized to WT: 1±0.05 in WT, 1.66±0.08 in PON2-/-, p<0.001). Phospho-GSK3b level was significantly downregulated in in PON2-/- mice compared to WT mice (pGSK3b/GSK3b normalized to WT: 1±0.06 in WT 0.67±0.08 in PON2-/-, p<0.05). Conclusions: PON2 regulates myocardial ischemia/reperfusion injury via inhibiting the opening of mPTP, which is associated with reduced mitochondria ROS production, deactivation of ER stress signaling CHOP and GSK3b.

scholarly journals Restoring Mitochondrial Function While Avoiding Redox Stress: The Key to Preventing Ischemia/Reperfusion Injury in Machine Perfused Liver Grafts?

2020 ◽  
Vol 21 (9) ◽  
pp. 3132 ◽  
Author(s):  
Julia Hofmann ◽  
Giorgi Otarashvili ◽  
Andras Meszaros ◽  
Susanne Ebner ◽  
Annemarie Weissenbacher ◽  
...  
Keyword(s):  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ex Vivo ◽  
Ischemia Reperfusion ◽  
Graft Function ◽  
Ros Production ◽  
Machine Perfusion ◽  
Redox Stress ◽  
Molecular Events ◽  
Regulate Cell Death

Mitochondria sense changes resulting from the ischemia and subsequent reperfusion of an organ and mitochondrial reactive oxygen species (ROS) production initiates a series of events, which over time result in the development of full-fledged ischemia-reperfusion injury (IRI), severely affecting graft function and survival after transplantation. ROS activate the innate immune system, regulate cell death, impair mitochondrial and cellular performance and hence organ function. Arresting the development of IRI before the onset of ROS production is currently not feasible and clinicians are faced with limiting the consequences. Ex vivo machine perfusion has opened the possibility to ameliorate or antagonize the development of IRI and may be particularly beneficial for extended criteria donor organs. The molecular events occurring during machine perfusion remain incompletely understood. Accumulation of succinate and depletion of adenosine triphosphate (ATP) have been considered key mechanisms in the initiation; however, a plethora of molecular events contribute to the final tissue damage. Here we discuss how understanding mitochondrial dysfunction linked to IRI may help to develop novel strategies for the prevention of ROS-initiated damage in the evolving era of machine perfusion.

scholarly journals SIRT3 a Major Player in Attenuation of Hepatic Ischemia-Reperfusion Injury by Reducing ROS via Its Downstream Mediators: SOD2, CYP-D, and HIF-1α

2018 ◽  
Vol 2018 ◽  
pp. 1-13 ◽  
Author(s):  
Gaurav Katwal ◽  
Dilip Baral ◽  
Xiaoli Fan ◽  
He Weiyang ◽  
Xinjiang Zhang ◽  
...  
Keyword(s):  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Bibliographic Databases ◽  
Molecular Pathways ◽  
Remnant Liver ◽  
Ros Production ◽  
Hepatic Ischemia ◽  
Major Player ◽  
Hepatic Ischemia Reperfusion

Reactive oxygen species (ROS) production in hepatic ischemia-reperfusion injury (IRI) is a complex process where multiple cellular and molecular pathways are involved. Few of those molecular pathways are under the direct influence of SIRT3 and its downstream mediators. SIRT3 plays a major role in the mechanism of IRI, and its activation has been shown to attenuate the deleterious effect of ROS during IRI via SOD2-, CYP-D-, and HIF-1α-mediated pathways. The objective of this review is to analyze the current knowledge on SIRT3 and its downstream mediators: SOD2, CYP-D, and HIF-1α, and their role in IRI. For the references of this review article, we have searched the bibliographic databases of PubMed, Web of Science databases, MEDLINE, and EMBASE with the headings “SIRT3,” “SOD2,” “CYP-D,” “HIF-1α,” and “liver IRI.” Priority was given to recent experimental articles that provide information on ROS modulation by these proteins. All the recent advancement demonstrates that activation of SIRT3 can suppress ROS production during IRI through various pathways and few of those are via SOD2, CYP-D, and HIF-1α. This effect can improve the quality of the remnant liver following resection as well as a transplanted liver. More research is warranted to disclose its role in IRI attenuation via this pathway.

Tetrahydrobiopterin compounds modulate intracellular signaling and reactive oxygen species levels in an in vitro model of ischemia-reperfusion injury

Pteridines ◽  
2013 ◽  
Vol 24 (3) ◽  
pp. 225-235
Author(s):  
Peter Santer ◽  
Thomas Ratschiller ◽  
Muhammad Imtiaz Ashraf ◽  
Ernst R. Werner ◽  
Gabriele Werner-Felmayer ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Reperfusion Injury ◽  
Intracellular Signaling ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Reactive Oxygen ◽  
Solid Organ ◽  
Oxygen Species ◽  
Prolonged Incubation ◽  
Mitochondrial Ros

AbstractTetrahydrobiopterin (BH4) and 4-amino-tetrahydrobiopterin (ABH4) prevent acute rejection after solid organ transplantation. Moreover, BH4 also attenuates ischemia-reperfusion injury (IRI). The mechanisms underlying these protective effects are poorly defined. Activation of intracellular signaling proteins, including the mitogen-activated protein kinases (MAPKs) ERK, p38, and JNK, and the excessive production of mitochondrial reactive oxygen species (ROS) are observed mainly during early reperfusion. While the role of ROS in the initiation and progression of IRI is well understood, the contribution of individual signaling pathways is less clear. Here, we tested the potential effects of BH4 and ABH4 on MAPK activity and mitochondrial ROS levels. During hypoxia and reoxygenation (H/R), all three MAPKs were activated during early reoxygenation in cardiomyocytes and endothelial cells. p38 and JNK activation were further augmented by BH4 and ABH4, whereas ERK activation was not affected. Pretreatment with BH4 and ABH4 reduced the basal mitochondrial ROS levels as well as the H/R-induced increase in ROS. Prolonged incubation with ABH4, however, showed pro-apoptotic effects in cardiomyocytes. These data suggest that a protective effect of BH4 and ABH4 pretreatment may be attributed mainly to their antioxidant capacity. The effects on intracellular signaling are complex and warrant further investigations.

scholarly journals Enhancing Glycolysis Protects against Ischemia-Reperfusion Injury by Reducing ROS Production

Metabolites ◽  
2020 ◽  
Vol 10 (4) ◽  
pp. 132
Author(s):  
Claudia Beltran ◽  
Rosario Pardo ◽  
Diana Bou-Teen ◽  
Marisol Ruiz-Meana ◽  
Josep A. Villena ◽  
...  
Keyword(s):  
Cell Death ◽  
Myocardial Ischemia ◽  
Reperfusion Injury ◽  
Glucose Oxidation ◽  
Ischemia Reperfusion Injury ◽  
Aerobic Glycolysis ◽  
Ischemia Reperfusion ◽  
Ros Production ◽  
Metabolic Shift ◽  
Myocardial Ischemia Reperfusion

After myocardial ischemia-reperfusion, fatty acid oxidation shows fast recovery while glucose oxidation rates remain depressed. A metabolic shift aimed at increasing glucose oxidation has shown to be beneficial in models of myocardial ischemia-reperfusion. However, strategies aimed at increasing glucose consumption in the clinic have provided mixed results and have not yet reached routine clinical practice. A better understanding of the mechanisms underlying the protection afforded by increased glucose oxidation may facilitate the transfer to the clinic. The purpose of this study was to evaluate if the modulation of reactive oxygen species (ROS) was involved in the protection afforded by increased glucose oxidation. Firstly, we characterized an H9C2 cellular model in which the use of glucose or galactose as substrates can modulate glycolysis and oxidative phosphorylation pathways. In this model, there were no differences in morphology, cell number, or ATP and PCr levels. However, galactose-grown cells consumed more oxygen and had an increased Krebs cycle turnover, while cells grown in glucose had increased aerobic glycolysis rate as demonstrated by higher lactate and alanine production. Increased aerobic glycolysis was associated with reduced ROS levels and protected the cells against simulated ischemia-reperfusion injury. Furthermore, ROS scavenger N-acetyl cysteine (NAC) was able to reduce the amount of ROS and to prevent cell death. Lastly, cells grown in galactose showed higher activation of mTOR/Akt signaling pathways. In conclusion, our results provide evidence indicating that metabolic shift towards increased glycolysis reduces mitochondrial ROS production and prevents cell death during ischemia-reperfusion injury.

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