Numerical modelling of the effects of cold atmospheric plasma on mitochondrial redox homeostasis and energy metabolism

AbstractA biochemical reaction model clarifies for the first time how cold atmospheric plasmas (CAPs) affect mitochondrial redox homeostasis and energy metabolism. Fundamental mitochondrial functions in pyruvic acid oxidation, the tricarboxylic acid (TCA) cycle and oxidative phosphorylation involving the respiratory chain (RC), adenosine triphosphate/adenosine diphosphate (ATP/ADP) synthesis machinery and reactive oxygen species/reactive nitrogen species (ROS/RNS)-mediated mechanisms are numerically simulated. The effects of CAP irradiation are modelled as 1) the influx of hydrogen peroxide (H$${}_{2}$$2O$${}_{2}$$2) to an ROS regulation system and 2) the change in mitochondrial transmembrane potential induced by RNS on membrane permeability. The CAP-induced stress modifies the dynamics of intramitochondrial H$${}_{2}$$2O$${}_{2}$$2 and superoxide anions, i.e., the rhythm and shape of ROS oscillation are disturbed by H$${}_{2}$$2O$${}_{2}$$2 infusion. Furthermore, CAPs control the ROS oscillatory behaviour, nicotinamide adenine dinucleotide redox state and ATP/ADP conversion through the reaction mixture over the RC, the TCA cycle and ROS regulation system. CAPs even induce a homeostatic or irreversible state transition in cell metabolism. The present computational model demonstrates that CAPs crucially affect essential mitochondrial functions, which in turn affect redox signalling, metabolic cooporation and cell fate decision of survival or death.

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Lipid Catabolism and ROS in Cancer: A Bidirectional Liaison

Cancers ◽

10.3390/cancers13215484 ◽

2021 ◽

Vol 13 (21) ◽

pp. 5484

Author(s):

Serena Castelli ◽

Pamela De De Falco ◽

Fabio Ciccarone ◽

Enrico Desideri ◽

Maria Rosa Ciriolo

Keyword(s):

Cancer Cells ◽

Cell Metabolism ◽

Second Messengers ◽

Tumor Therapy ◽

Redox Homeostasis ◽

Antioxidant Systems ◽

Acid Oxidation ◽

Antioxidant Compounds ◽

Tumor Type ◽

Lipid Catabolism

Although cancer cell metabolism was mainly considered to rely on glycolysis, with the concomitant impairment of mitochondrial metabolism, it has recently been demonstrated that several tumor types are sustained by oxidative phosphorylation (OXPHOS). In this context, endogenous fatty acids (FAs) deriving from lipolysis or lipophagy are oxidised into the mitochondrion, and are used as a source of energy through OXPHOS. Because the electron transport chain is the main source of ROS, cancer cells relying on fatty acid oxidation (FAO) need to be equipped with antioxidant systems that maintain the ROS levels under the death threshold. In those conditions, ROS can act as second messengers, favouring proliferation and survival. Herein, we highlight the different responses that tumor cells adopt when lipid catabolism is augmented, taking into account the different ROS fates. Many papers have demonstrated that the pro- or anti-tumoral roles of endogenous FA usage are hugely dependent on the tumor type, and on the capacity of cancer cells to maintain redox homeostasis. In light of this, clinical studies have taken advantage of the boosting of lipid catabolism to increase the efficacy of tumor therapy, whereas, in other contexts, antioxidant compounds are useful to reduce the pro-survival effects of ROS deriving from FAO.

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Metabolic determinants of embryonic development and stem cell fate

Reproduction Fertility and Development ◽

10.1071/rd14383 ◽

2015 ◽

Vol 27 (1) ◽

pp. 82 ◽

Cited By ~ 33

Author(s):

Clifford D. L. Folmes ◽

Andre Terzic

Keyword(s):

Stem Cell ◽

Energy Metabolism ◽

Cell Fate ◽

Epigenetic Regulation ◽

Cell Biology ◽

Metabolic Flux ◽

Cell Metabolism ◽

Cell Signalling ◽

Regulation Of Gene Expression ◽

Stem Cell Differentiation

Decoding stem cell metabolism has implicated a tight linkage between energy metabolism and cell fate regulation, a dynamic interplay vital in the execution of developmental and differentiation programs. The inherent plasticity in energy metabolism enables prioritisation of metabolic pathways in support of stage-specific demands. Beyond traditional support of energetic needs, intermediate metabolism may also dictate cell fate choices through regulation of cellular signalling and epigenetic regulation of gene expression. The notion of a ‘metabolism-centric’ control of stem cell differentiation has been informed by developmental embryogenesis based upon an on-demand paradigm paramount in defining diverse developmental behaviours, from a post-fertilisation nascent zygote to complex organogenesis leading to adequate tissue formation and maturation. Monitored through natural or bioengineered stem cell surrogates, nutrient-responsive metabolites are identified as mediators of cross-talk between metabolic flux, cell signalling and epigenetic regulation charting, collectively, whether a cell will self-renew to maintain progenitor pools, lineage specify to ensure tissue (re)generation or remain quiescent to curb stress damage. Thus, bioenergetics are increasingly recognised as integral in governing stemness and associated organogenic decisions, paving the way for metabolism-defined targets in control of embryology, stem cell biology and tissue regeneration.

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Angiogenesis revisited from a metabolic perspective: role and therapeutic implications of endothelial cell metabolism

Open Biology ◽

10.1098/rsob.170219 ◽

2017 ◽

Vol 7 (12) ◽

pp. 170219 ◽

Cited By ~ 35

Author(s):

Nihed Draoui ◽

Pauline de Zeeuw ◽

Peter Carmeliet

Keyword(s):

Endothelial Cell ◽

Cell Metabolism ◽

Redox Homeostasis ◽

Acid Oxidation ◽

Therapeutic Implications ◽

Angiogenic Switch ◽

Vessel Normalization ◽

Promising Therapeutic Target ◽

Health And Disease

Endothelial cell (EC) metabolism has lately emerged as a novel and promising therapeutic target to block vascular dysregulation associated with diseases like cancer and blinding eye disease. Glycolysis, fatty acid oxidation (FAO) and, more recently, glutamine/asparagine metabolism emerged as key regulators of EC metabolism, able to impact angiogenesis in health and disease. ECs are highly glycolytic as they require ATP and biomass for vessel sprouting. Notably, a regulator of the glycolytic pathway, 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3, controls vessel sprouting during the angiogenic switch and its inhibition in tumour ECs leads to vessel normalization, thereby reducing metastasis and ameliorating chemotherapy. Moreover, FAO promotes EC proliferation through DNA synthesis, and plays an essential role in lymphangiogenesis via epigenetic regulation of histone acetylation. Pathological angiogenesis was decreased upon blockade of carnitine palmitoyltransferase 1, a regulator of FAO in ECs. More recently, metabolism of glutamine, in conjunction with asparagine, was reported to maintain EC sprouting through TCA anaplerosis, redox homeostasis, mTOR activation and endoplasmic stress control. Inactivation or blockade of glutaminase 1, which hydrolyses glutamine into ammonia and glutamate, impairs angiogenesis in health and disease, while silencing of asparagine synthetase reduces vessel sprouting in vitro . In this review, we summarize recent insights into EC metabolism and discuss therapeutic implications of targeting EC metabolism.

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Blood progenitor redox homeostasis through GABA control of TCA cycle in Drosophila hematopoiesis

10.1101/2021.02.23.432543 ◽

2021 ◽

Author(s):

Manisha Goyal ◽

Ajay Tomar ◽

Sukanya Madhwal ◽

Tina Mukherjee

Keyword(s):

Progenitor Cells ◽

Pyruvate Dehydrogenase ◽

Cell Metabolism ◽

Redox Homeostasis ◽

Myeloid Cell ◽

Tca Cycle ◽

Lymph Gland ◽

Pyruvate Dehydrogenase Kinase ◽

Hematopoietic Organ ◽

Ros Homeostasis

AbstractThe importance of reactive oxygen species (ROS) in myeloid cell development and function is well-established. However, a comprehensive understanding of metabolic states controlling ROS levels during hematopoiesis remains elusive. Myeloid-like blood progenitor cells of the Drosophila larvae reside in a specialized hematopoietic organ called the lymph gland. We find that these progenitors in homeostasis, utilize TCA to generate ROS. Excessive activation of TCA however raises ROS levels causing them to precociously differentiate and leads to retardation of lymph gland size. Thus, to maintain ROS homeostasis, progenitor cells utilize systemically derived GABA. GABA internalization and catabolism via inhibiting hydroxy prolyl hydroxylase (Hph) activity, promotes pyruvate dehydrogenase kinase enzyme activity (PDK). PDK controls inhibitory phosphorylation of pyruvate dehydrogenase (PDH), the rate-limiting enzyme, connecting pyruvate to TCA cycle and OXPHOS. Thus, by regulating PDK, GABA regulates progenitor TCA activity and ROS levels. In addition to this, GABA-catabolism/Hph axis via Hifα/Sima drives a glycolytic state in progenitor cells. The dual control established by GABA on PDK and Sima maintains progenitor cell metabolism and sustains ROS homeostasis necessary for their development. Taken together, our study demonstrates the metabolic underpinnings of GABA in myeloid ROS regulation and their development, the relevance of which may be broadly conserved.

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Reprogramming of arachidonate metabolism confers drug resistance to glioblastoma through Enhancing Mitochondrial Activity in Fatty Acid Oxidation

10.21203/rs.3.rs-965026/v1 ◽

2021 ◽

Author(s):

Yu-Ting Tsai ◽

Wei-Lun Lo ◽

Pin-Yuan Chen ◽

Chiung-Yuan Ko ◽

Tzu-Jen Kao ◽

...

Keyword(s):

Drug Resistance ◽

Fatty Acid ◽

Stress Test ◽

Tca Cycle ◽

Metabolic Reprogramming ◽

Pge2 Production ◽

Acid Oxidation ◽

Mitochondrial Activity ◽

Rna Seq ◽

Mitochondrial Functions

Abstract Background Sp1 is involved in the recurrence of glioblastoma (GBM) due to the acquirement of resistance to temozolomide (TMZ). Particularly, the role of Sp1 in metabolic reprogramming for drug resistance remains unknown. Methods RNA-Seq and mass spectrometry were used to analyze gene expression and metabolites amounts in paired GBM specimens (primary vs. recurrent) and in paired GBM cells (sensitive vs. resistant). ω-3/6 fatty acid and arachidonic acid (AA) metabolism in GBM patients were analyzed by targeted metabolome. Mitochondrial functions were determined by Seahorse XF Mito Stress Test, RNA-Seq, metabolome and substrate utilization for producing ATP. Therapeutic options targeting prostaglandin (PG) E2 in TMZ-resistant GBM were validated in vitro and in vivo. Results Among the metabolic pathways, Sp1 increased the prostaglandin-endoperoxide synthase 2 expression and PGE2 production in TMZ-resistant GBM. Mitochondrial genes and metabolites were obviously increased by PGE2, and these characteristics were required for developing resistance in GBM cells. For inducing TMZ resistance, PGE2 activated mitochondrial functions, including fatty acid β-oxidation (FAO) and tricarboxylic acid (TCA) cycle progression, through PGE2 receptors, E-type prostanoid (EP)1 and EP3. Additionally, EP1 antagonist ONO-8713 inhibited the survival of TMZ-resistant GBM synergistically with TMZ. Conclusion Sp1-regulated PGE2 production activates FAO and TCA cycle in mitochondria, through EP1 and EP3 receptors, resulting in TMZ resistance in GBM. These results will provide us a new strategy to attenuate drug resistance or to re-sensitize recurred GBM.

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Schisandrin Restores the Amyloid β-Induced Impairments on Mitochondrial Function, Energy Metabolism, Biogenesis, and Dynamics in Rat Primary Hippocampal Neurons

Pharmacology ◽

10.1159/000507818 ◽

2021 ◽

pp. 1-11

Author(s):

Zhongyuan Piao ◽

Lin Song ◽

Lifen Yao ◽

Limei Zhang ◽

Yichan Lu

Keyword(s):

Energy Metabolism ◽

Cytochrome C ◽

Mitochondrial Biogenesis ◽

Mitochondrial Function ◽

Hippocampal Neurons ◽

Citrate Synthase ◽

Mitochondrial Permeability Transition ◽

Amyloid Β ◽

Mitochondrial Functions ◽

Primary Hippocampal Neurons

Introduction: Schisandrin which is derived from Schisandra chinensis has shown multiple pharmacological effects on various diseases including Alzheimer’s disease (AD). It is demonstrated that mitochondrial dysfunction plays an essential role in the pathogenesis of neurodegenerative disorders. Objective: Our study aims to investigate the effects of schisandrin on mitochondrial functions and metabolisms in primary hippocampal neurons. Methods: In our study, rat primary hippocampal neurons were isolated and treated with indicated dose of amyloid β1–42 (Aβ1–42) oligomer to establish a cell model of AD in vitro. Schisandrin (2 μg/mL) was further subjected to test its effects on mitochondrial function, energy metabolism, mitochondrial biogenesis, and dynamics in the Aβ1–42 oligomer-treated neurons. Results and Conclusions: Our findings indicated that schisandrin significantly alleviated the Aβ1–42 oligomer-induced loss of mitochondrial membrane potential and impaired cytochrome c oxidase activity. Additionally, the opening of mitochondrial permeability transition pore and release of cytochrome c were highly restricted with schisandrin treatment. Alterations in cell viability, ATP production, citrate synthase activity, and the expressions of glycolysis-related enzymes demonstrated the relief of defective energy metabolism in Aβ-treated neurons after the treatment of schisandrin. For mitochondrial biogenesis, elevated expression of peroxisome proliferator-activated receptor γ coactivator along with promoted mitochondrial mass was found in schisandrin-treated cells. The imbalance in the cycle of fusion and fission was also remarkably restored by schisandrin. In summary, this study provides novel mechanisms for the protective effect of schisandrin on mitochondria-related functions.

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Production of succinate by engineered strains of Synechocystis PCC 6803 overexpressing phosphoenolpyruvate carboxylase and a glyoxylate shunt

Microbial Cell Factories ◽

10.1186/s12934-021-01529-y ◽

2021 ◽

Vol 20 (1) ◽

Author(s):

Claudia Durall ◽

Kateryna Kukil ◽

Jeffrey A. Hawkes ◽

Alessia Albergati ◽

Peter Lindblad ◽

...

Keyword(s):

Phosphoenolpyruvate Carboxylase ◽

Isocitrate Lyase ◽

Tricarboxylic Acid Cycle ◽

Cell Metabolism ◽

Tca Cycle ◽

Malate Synthase ◽

Glyoxylate Shunt ◽

Control Strain ◽

Genes Encoding ◽

Pcc 6803

Abstract Background Cyanobacteria are promising hosts for the production of various industrially important compounds such as succinate. This study focuses on introduction of the glyoxylate shunt, which is naturally present in only a few cyanobacteria, into Synechocystis PCC 6803. In order to test its impact on cell metabolism, engineered strains were evaluated for succinate accumulation under conditions of light, darkness and anoxic darkness. Each condition was complemented by treatments with 2-thenoyltrifluoroacetone, an inhibitor of succinate dehydrogenase enzyme, and acetate, both in nitrogen replete and deplete medium. Results We were able to introduce genes encoding the glyoxylate shunt, aceA and aceB, encoding isocitrate lyase and malate synthase respectively, into a strain of Synechocystis PCC 6803 engineered to overexpress phosphoenolpyruvate carboxylase. Our results show that complete expression of the glyoxylate shunt results in higher extracellular succinate accumulation compared to the wild type control strain after incubation of cells in darkness and anoxic darkness in the presence of nitrate. Addition of the inhibitor 2-thenoyltrifluoroacetone increased succinate titers in all the conditions tested when nitrate was available. Addition of acetate in the presence of the inhibitor further increased the succinate accumulation, resulting in high levels when phosphoenolpyruvate carboxylase was overexpressed, compared to control strain. However, the highest succinate titer was obtained after dark incubation of an engineered strain with a partial glyoxylate shunt overexpressing isocitrate lyase in addition to phosphoenolpyruvate carboxylase, with only 2-thenoyltrifluoroacetone supplementation to the medium. Conclusions Heterologous expression of the glyoxylate shunt with its central link to the tricarboxylic acid cycle (TCA) for acetate assimilation provides insight on the coordination of the carbon metabolism in the cell. Phosphoenolpyruvate carboxylase plays an important role in directing carbon flux towards the TCA cycle.

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LONP1 and ClpP cooperatively regulate mitochondrial proteostasis for cancer cell survival

Oncogenesis ◽

10.1038/s41389-021-00306-1 ◽

2021 ◽

Vol 10 (2) ◽

Author(s):

Yu Geon Lee ◽

Hui Won Kim ◽

Yeji Nam ◽

Kyeong Jin Shin ◽

Yu Jin Lee ◽

...

Keyword(s):

Cell Death ◽

Cell Growth ◽

Cell Survival ◽

Cancer Cell ◽

Stress Responses ◽

Molecular Mechanisms ◽

Tca Cycle ◽

Mitochondrial Matrix ◽

Mitochondrial Functions ◽

Cancer Cell Survival

AbstractMitochondrial proteases are key components in mitochondrial stress responses that maintain proteostasis and mitochondrial integrity in harsh environmental conditions, which leads to the acquisition of aggressive phenotypes, including chemoresistance and metastasis. However, the molecular mechanisms and exact role of mitochondrial proteases in cancer remain largely unexplored. Here, we identified functional crosstalk between LONP1 and ClpP, which are two mitochondrial matrix proteases that cooperate to attenuate proteotoxic stress and protect mitochondrial functions for cancer cell survival. LONP1 and ClpP genes closely localized on chromosome 19 and were co-expressed at high levels in most human cancers. Depletion of both genes synergistically attenuated cancer cell growth and induced cell death due to impaired mitochondrial functions and increased oxidative stress. Using mitochondrial matrix proteomic analysis with an engineered peroxidase (APEX)-mediated proximity biotinylation method, we identified the specific target substrates of these proteases, which were crucial components of mitochondrial functions, including oxidative phosphorylation, the TCA cycle, and amino acid and lipid metabolism. Furthermore, we found that LONP1 and ClpP shared many substrates, including serine hydroxymethyltransferase 2 (SHMT2). Inhibition of both LONP1 and ClpP additively increased the amount of unfolded SHMT2 protein and enhanced sensitivity to SHMT2 inhibitor, resulting in significantly reduced cell growth and increased cell death under metabolic stress. Additionally, prostate cancer patients with higher LONP1 and ClpP expression exhibited poorer survival. These results suggest that interventions targeting the mitochondrial proteostasis network via LONP1 and ClpP could be potential therapeutic strategies for cancer.

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Butyrate Prevents TGF-β1-Induced Alveolar Myofibroblast Differentiation and Modulates Energy Metabolism

Metabolites ◽

10.3390/metabo11050258 ◽

2021 ◽

Vol 11 (5) ◽

pp. 258

Author(s):

Hyo Yeong Lee ◽

Somi Nam ◽

Mi Jeong Kim ◽

Su Jung Kim ◽

Sung Hoon Back ◽

...

Keyword(s):

Energy Metabolism ◽

Pulmonary Fibrosis ◽

Transforming Growth Factor ◽

Mitochondrial Dynamics ◽

Tca Cycle ◽

Lung Fibroblasts ◽

Myofibroblast Differentiation ◽

Pulmonary Fibroblasts ◽

Matrix Deposition ◽

Tgf Β1

Idiopathic pulmonary fibrosis (IPF) is a serious lung disease characterized by excessive collagen matrix deposition and extracellular remodeling. Signaling pathways mediated by fibrotic cytokine transforming growth factor β1 (TGF-β1) make important contributions to pulmonary fibrosis, but it remains unclear how TGF-β1 alters metabolism and modulates the activation and differentiation of pulmonary fibroblasts. We found that TGF-β1 lowers NADH and NADH/NAD levels, possibly due to changes in the TCA cycle, resulting in reductions in the ATP level and oxidative phosphorylation in pulmonary fibroblasts. In addition, we showed that butyrate (C4), a short chain fatty acid (SCFA), exhibits potent antifibrotic activity by inhibiting expression of fibrosis markers. Butyrate treatment inhibited mitochondrial elongation in TGF-β1-treated lung fibroblasts and increased the mitochondrial membrane potential (MMP). Consistent with the mitochondrial observations, butyrate significantly increased ADP, ATP, NADH, and NADH/NAD levels in TGF-β1-treated pulmonary fibroblasts. Collectively, our findings indicate that TGF-β1 induces changes in mitochondrial dynamics and energy metabolism during myofibroblast differentiation, and that these changes can be modulated by butyrate, which enhances mitochondrial function.

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Metabolomic Analysis to Elucidate Mechanisms of Sunitinib Resistance in Renal Cell Carcinoma

Metabolites ◽

10.3390/metabo11010001 ◽

2020 ◽

Vol 11 (1) ◽

pp. 1

Author(s):

Tomonori Sato ◽

Yoshihide Kawasaki ◽

Masamitsu Maekawa ◽

Shinya Takasaki ◽

Kento Morozumi ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Energy Metabolism ◽

Cell Carcinoma ◽

Cell Line ◽

Cell Lines ◽

Cancer Progression ◽

Renal Cell ◽

Treatment Resistance ◽

Tca Cycle ◽

Glutamine Uptake

Metabolomics analysis possibly identifies new therapeutic targets in treatment resistance by measuring changes in metabolites accompanying cancer progression. We previously conducted a global metabolomics (G-Met) study of renal cell carcinoma (RCC) and identified metabolites that may be involved in sunitinib resistance in RCC. Here, we aimed to elucidate possible mechanisms of sunitinib resistance in RCC through intracellular metabolites. We established sunitinib-resistant and control RCC cell lines from tumor tissues of RCC cell (786-O)-injected mice. We also quantified characteristic metabolites identified in our G-Met study to compare intracellular metabolism between the two cell lines using liquid chromatography-mass spectrometry. The established sunitinib-resistant RCC cell line demonstrated significantly desuppressed protein kinase B (Akt) and mesenchymal-to-epithelial transition (MET) phosphorylation compared with the control RCC cell line under sunitinib exposure. Among identified metabolites, glutamine, glutamic acid, and α-KG (involved in glutamine uptake into the tricarboxylic acid (TCA) cycle for energy metabolism); fructose 6-phosphate, D-sedoheptulose 7-phosphate, and glucose 1-phosphate (involved in increased glycolysis and its intermediate metabolites); and glutathione and myoinositol (antioxidant effects) were significantly increased in the sunitinib-resistant RCC cell line. Particularly, glutamine transporter (SLC1A5) expression was significantly increased in sunitinib-resistant RCC cells compared with control cells. In this study, we demonstrated energy metabolism with glutamine uptake and glycolysis upregulation, as well as antioxidant activity, was also associated with sunitinib resistance in RCC cells.

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