scholarly journals Peroxisomal support of mitochondrial respiratory efficiency promotes ER stress survival

2021 ◽  
Author(s):  
Imadeddin Hijazi ◽  
Emily Wang ◽  
Michelle Orozco ◽  
Sarah Pelton ◽  
Amy Chang
Keyword(s):  
Cell Survival ◽  
Tca Cycle ◽  
Mitochondrial Proteins ◽  
Oxygen Species ◽  
Respiratory Response ◽  
The Tca Cycle ◽  
Mitochondrial Pyruvate Carrier ◽  
Ros Accumulation ◽  
Stress Survival ◽  
Respiratory Efficiency

Endoplasmic reticulum stress (ERS) occurs when cellular demand for protein folding exceeds the capacity of the organelle. Adaptation and cell survival in response to ERS requires a critical contribution by mitochondria and peroxisomes. During ERS response, mitochondrial respiration increases to ameliorate reactive oxygen species (ROS) accumulation; we now show in yeast that peroxisome abundance also increases to promote an adaptive response. In pox1▵ cells, defective in peroxisomal ß oxidation of fatty acids, respiratory response to ERS is impaired, and ROS accrues. However, respiratory response to ERS is rescued, and ROS production is mitigated in pox1▵ cells by overexpression of Mpc1, the mitochondrial pyruvate carrier that provides another source of acetyl CoA to fuel the TCA cycle and oxidative phosphorylation. Using proteomics, select mitochondrial proteins were identified that undergo upregulation by ERS to remodel respiratory machinery. Several peroxisome-based proteins were also increased, corroborating the peroxisomal role in ERS adaptation. Finally, ERS stimulates assembly of respiratory complexes into higher order supercomplexes, underlying increased electron transfer efficiency. Our results highlight peroxisomal and mitochondrial support for ERS adaptation to favor cell survival.

scholarly journals Glutamine Oxidation Maintains the TCA Cycle and Cell Survival during Impaired Mitochondrial Pyruvate Transport

2014 ◽  
Vol 56 (3) ◽  
pp. 414-424 ◽  
Author(s):  
Chendong Yang ◽  
Bookyung Ko ◽  
Christopher T. Hensley ◽  
Lei Jiang ◽  
Ajla T. Wasti ◽  
...  
Keyword(s):  
Cell Survival ◽  
Tca Cycle ◽  
The Tca Cycle

scholarly journals Reactive Oxygen Species, Metabolic Plasticity, and Drug Resistance in Cancer

2020 ◽  
Vol 21 (10) ◽  
pp. 3412 ◽  
Author(s):  
Vikas Bhardwaj ◽  
Jun He
Keyword(s):  
Reactive Oxygen Species ◽  
Cancer Cells ◽  
Reactive Oxygen ◽  
Tca Cycle ◽  
Metabolic Adaptation ◽  
Oxygen Species ◽  
Metabolic Plasticity ◽  
The Tca Cycle ◽  
Clinical Benefits ◽  
High Level

The metabolic abnormality observed in tumors is characterized by the dependence of cancer cells on glycolysis for their energy requirements. Cancer cells also exhibit a high level of reactive oxygen species (ROS), largely due to the alteration of cellular bioenergetics. A highly coordinated interplay between tumor energetics and ROS generates a powerful phenotype that provides the tumor cells with proliferative, antiapoptotic, and overall aggressive characteristics. In this review article, we summarize the literature on how ROS impacts energy metabolism by regulating key metabolic enzymes and how metabolic pathways e.g., glycolysis, PPP, and the TCA cycle reciprocally affect the generation and maintenance of ROS homeostasis. Lastly, we discuss how metabolic adaptation in cancer influences the tumor’s response to chemotherapeutic drugs. Though attempts of targeting tumor energetics have shown promising preclinical outcomes, the clinical benefits are yet to be fully achieved. A better understanding of the interaction between metabolic abnormalities and involvement of ROS under the chemo-induced stress will help develop new strategies and personalized approaches to improve the therapeutic efficiency in cancer patients.

scholarly journals UK5099 inhibits macrophage activation independent of mitochondrial pyruvate carrier mediated metabolism

2021 ◽  
Author(s):  
Linyu Ran ◽  
Song Zhang ◽  
Pei Zhao ◽  
Jiaqi Zhou ◽  
Haiyun Gan ◽  
...  
Keyword(s):  
Macrophage Activation ◽  
Cytokine Production ◽  
Inflammatory Responses ◽  
Tca Cycle ◽  
Metabolic Reprogramming ◽  
M1 Macrophages ◽  
Inflammatory Cytokine Production ◽  
The Tca Cycle ◽  
Mitochondrial Pyruvate Carrier ◽  
High Doses

Abstract Glycolysis is essential for the classical activation of macrophages (M1), but how glycolytic pathway metabolites engage in this process remains to be elucidated. Glycolysis culminates in the production of pyruvate, which can be transported into the mitochondria by the mitochondrial pyruvate carrier (MPC) followed by conversion to citrate and utilization in the TCA cycle. Alternatively, pyruvate can be metabolized to lactate under aerobic conditions, which had been considered to be the dominant route in the setting of classical macrophage activation. However, based on studies that used UK5099 as a MPC inhibitor and showed reduction in key inflammatory cytokines, the mitochondrial route has been considered to be of significance for M1 activation as well. Herein, using a genetic depletion model, we found that MPC is dispensable for metabolic reprogramming and the activation of M1. While UK5099 reaches maximal MPC inhibitory capacity at approximately 2–5µM, higher concentrations are required to inhibit inflammatory cytokine production in M1 and this is independent of MPC expression. Apart from MPC inhibition, UK5099 at high doses impairs glutamate oxidation, mitochondrial membrane potential and HIF-1α stabilization. Taken together, UK5099 inhibits inflammatory responses in M1 macrophages due to effects other than MPC inhibition.

scholarly journals A non-canonical convergence of carbohydrate and glutamine metabolism is required after metabolic rewiring in 3D environment

2021 ◽  
Author(s):  
Peng Wei ◽  
Alex J Bott ◽  
Ahmad A Cluntun ◽  
Jeffrey T Morgan ◽  
Corey N Cunningham ◽  
...  
Keyword(s):  
Tca Cycle ◽  
Glutamine Metabolism ◽  
Glutamate Pyruvate Transaminase ◽  
Solid Culture ◽  
3D Environment ◽  
The Tca Cycle ◽  
Mitochondrial Pyruvate Carrier ◽  
Metabolic Feature ◽  
Glutamate Pyruvate ◽  
Culture Environment

The fate of pyruvate, which is modulated mitochondrial pyruvate carrier (MPC) activity, is a defining metabolic feature in many cancers. Diffuse large B-cell lymphomas (DLBCLs) are a genetically and metabolically heterogenous cancer. Although MPC expression and activity differed between DLBCL subgroups, mitochondrial pyruvate oxidation was uniformly minimal. Mitochondrial pyruvate was instead robustly consumed by glutamate pyruvate transaminase 2 to support α-ketoglutarate production as part of glutamine catabolism. This led us to discover that glutamine exceeds pyruvate as a carbon source for the TCA cycle, but, MPC function is required to enable GPT2-mediated glutamine catabolism. Furthermore, we found that MPC inhibition only decreased DLBCL proliferation in a solid culture environment, but not in a suspension environment. Thus, the non-canonical connection between the consumption and assimilation of carbohydrates and glutamine in DLBCLs enables their proliferation in a solid 3D environment.

scholarly journals The mitochondrial pyruvate carrier (MPC) complex is one of three pyruvate-supplying pathways that sustain Arabidopsis respiratory metabolism

2021 ◽  
Author(s):  
Xuyen H. Le ◽  
Chun-Pong Lee ◽  
A. Harvey Millar
Keyword(s):  
Plant Growth ◽  
Plant Mitochondria ◽  
Complex Function ◽  
Tca Cycle ◽  
Respiratory Metabolism ◽  
The Tca Cycle ◽  
Mitochondrial Pyruvate Carrier ◽  
The Matrix ◽  
Branched Chain ◽  
Malate Oxidation

AbstractMalate oxidation by plant mitochondria enables the generation of both oxaloacetate (OAA) and pyruvate for tricarboxylic acid (TCA) cycle function, potentially eliminating the need for pyruvate transport into mitochondria in plants. Here we show that the absence of the mitochondrial pyruvate carrier 1 (MPC1) causes the co-commitment loss of its orthologs, MPC3/MPC4, and eliminates pyruvate transport into Arabidopsis mitochondria, proving it is essential for MPC complex function. While the loss of either MPC or mitochondrial pyruvate-generating NAD-malic enzyme (NAD-ME) did not cause vegetative phenotypes, the lack of both reduced plant growth and caused an increase in cellular pyruvate levels, indicating a block in respiratory metabolism, and elevated the levels of branched-chain amino acids at night, a sign of alterative substrate provision for respiration. 13C-pyruvate feeding of leaves lacking MPC showed metabolic homeostasis were largely maintained except for alanine and glutamate, indicating that transamination contributes to restoration of the metabolic network to an operating equilibrium by delivering pyruvate independently of MPC into the matrix. Inhibition of alanine aminotransferases (AlaAT) when MPC1 is absent resulted in extremely retarded phenotypes in Arabidopsis, suggesting all pyruvate-supplying enzymes work synergistically to support the TCA cycle for sustained plant growth.

scholarly journals NADPH and glutathione redox link TCA cycle activity to endoplasmic reticulum stress

2019 ◽  
Author(s):  
Erica R. Gansemer ◽  
Kyle S. McCommis ◽  
Michael Martino ◽  
Abdul Qaadir King-McAlpin ◽  
Matthew J. Potthoff ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Tca Cycle ◽  
The Tca Cycle ◽  
Mitochondrial Pyruvate Carrier ◽  
Glutathione Oxidation ◽  
Mouse Hepatocytes ◽  
Redox Metabolites ◽  
Er Homeostasis ◽  
Mitochondrial Oxidative Metabolism

AbstractEndoplasmic reticulum (ER) stress is associated with dysregulated metabolism, but little is known about how the ER responds to metabolic activity. Here, working primarily in mouse hepatocytes, we show that decreasing the availability of substrate for the TCA cycle diminished NADPH production and attenuated ER stress in a manner that depended on glutathione oxidation. ER stress was also alleviated by impairing either TCA-dependent NADPH production or Glutathione Reductase. Conversely, stimulating TCA activity favored NADPH production, glutathione reduction, and ER stress. Validating these findings, we show that deletion of the mitochondrial pyruvate carrier, which is known to decrease TCA cycle activity and protect the liver from diet-induced injury, also diminished NADPH, elevated glutathione oxidation, and alleviated ER stress. These results provide independent genetic evidence that mitochondrial oxidative metabolism is linked to ER homeostasis. Our results demonstrate a novel pathway of communication between mitochondria and the ER, through relay of redox metabolites.

Liquid-liquid extraction of succinate using a dicopper cryptate

2020 ◽  
Author(s):  
Riccardo Mobili ◽  
Sonia La Cognata ◽  
Francesca Merlo ◽  
Andrea Speltini ◽  
Massimo Boiocchi ◽  
...  
Keyword(s):  
Aqueous Phase ◽  
Visible Spectrum ◽  
Tca Cycle ◽  
Residual Concentration ◽  
Waste Products ◽  
Liquid Liquid Extraction ◽  
The Tca Cycle ◽  
Quantitative Extraction ◽  
Uv Visible

<div> <p>The extraction of the succinate dianion from a neutral aqueous solution into dichloromethane is obtained using a lipophilic cage-like dicopper(II) complex as the extractant. The quantitative extraction exploits the high affinity of the succinate anion for the cavity of the azacryptate. The anion is effectively transferred from the aqueous phase, buffered at pH 7 with HEPES, into dichloromethane. A 1:1 extractant:anion adduct is obtained. Extraction can be easily monitored by following changes in the UV-visible spectrum of the dicopper complex in dichloromethane, and by measuring the residual concentration of succinate in the aqueous phase by HPLC−UV. Considering i) the relevance of polycarboxylates in biochemistry, as e.g. normal intermediates of the TCA cycle, ii) the relevance of dicarboxylates in the environmental field, as e.g. waste products of industrial processes, and iii) the recently discovered role of succinate and other dicarboxylates in pathophysiological processes including cancer, our results open new perspectives for research in all contexts where selective recognition, trapping and extraction of polycarboxylates is required. </p> </div>

Danshensu Rescues Ischemia/Reperfusion Caused Human Hepatocyte Death

2018 ◽  
Vol 17 (2) ◽  
pp. 117-121
Author(s):  
Sun Maw-Sheng ◽  
Liang Chun-Ya ◽  
Hsieh Po-Chun ◽  
Kuo Chan-Yen
Keyword(s):  
Oxidative Stress ◽  
Reactive Oxygen Species ◽  
Caspase 3 ◽  
Ischemia Reperfusion ◽  
Oxygen Species ◽  
Good Strategy ◽  
Ros Accumulation ◽  
Dichlorofluorescin Diacetate ◽  
Hepatocyte Damage ◽  
Hepatocyte Death

Apoptosis of hepatocyte, under ischemia/reperfusion (IR) conditions, has been identified as an essential process in the progression of liver transplantation. Under these conditions, mitochondria can become a threat to the cell because of their capacity to generate reactive oxygen species (ROS). Additionally, ROS overproduction may induce inflammation. As ROS accumulation appears to cause hepatocyte damage or death, there has been considerable interest in identifying the candidate natural products involved and in developing strategies to reduce oxidative stress. In this study, we use Danshensu as a candidate product to speculate whether has the protective effect on apoptotic hepatocyte upon IR. To speculate the apoptotic phenomena was reversed by Danshensu, we detected the p53, cleaved-caspase 3 expression by western blotting, as well as caspase-3 activity. Additionally, we analyzed the ROS levels by 2′,7′-dichlorofluorescin diacetate (DCF-DA) staining. We also detected the cell viability by WST-1. Results showed that Danshensu alleviated hypoxia-caused cell apoptosis via ROS overproduction. We suggested that Danshensu is a good strategy for treating hepatocyte damage upon IR.

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