scholarly journals DDRE-01. METABOLIC PLASTICITY AND HETEROGENEITY IN IDH1MUT CELL LINES PRODUCES RESISTANCE TO GLUTAMINASE INHIBITION BY CB839

2020 ◽  
Vol 3 (Supplement_1) ◽  
pp. i6-i6
Author(s):  
Mioara Larion ◽  
Victor Ruiz-Rodado
Keyword(s):  
Cell Lines ◽  
Metabolic Profiling ◽  
Cellular Proliferation ◽  
Lactate Production ◽  
Tca Cycle ◽  
Heterogeneous Landscape ◽  
The Tca Cycle ◽  
A Cell ◽  
Metabolic Tracing ◽  
Mutant Idh1

Abstract BACKGROUND Mutant IDH1 (IDH1mut) gliomas have characteristic genetic and metabolic profiles and exhibit phenotype that is distinct from their wild-type counterparts. The glutamine/glutamate pathway has been hypothesized as a selective therapeutic target in IDH1mut gliomas. However, little information exists on the contribution of this pathway to the formation of D-2-hydroxyglutarate (D-2HG), a hallmark of IDHmut cells, and the metabolic consequences of inhibiting this pathway. METHODS We employed an untargeted metabolic profiling approach in order to detect metabolic changes arising from glutaminase (GLS) inhibition treatment. Subsequently, 13C metabolic tracing analysis through a combined Nuclear Magnetic Resonance and Liquid Chromatography-Mass Spectrometry approach, we explored the fate of glutamine and glucose under treatment with CB839 a glutaminase-GLS-inhibitor and their respective contributions to D-2HG formation. RESULTS AND CONCLUSIONS The effects of CB839 on cellular proliferation differed among the cell lines tested, leading to designations of GLS-inhibition super-sensitive, -sensitive or -resistant. Our data indicates a decrease in the production of downstream metabolites of glutamate, including those involved in the TCA cycle, when treating the sensitive cells with CB839 (glutaminase -GLS- inhibitor). Notably, CB839-sensitive IDH1mutcells respond to GLS inhibition by upregulating glycolysis and lactate production. In contrast, CB839-resistantIDH1mut cell lines do not rely only on glutamine for the sustenance of TCA cycle. In these cells, glucose contribution to TCA is enough to compensate the downregulation of glutamine-derived TCA metabolites. This investigation reveals that the glutamine/glutamate pathway contributes differentially to D-2HG in a cell-line dependent fashion on a panel of IDHmut cell lines. Further, these results demonstrate that there is a heterogeneous landscape of IDH1mut metabolic phenotypes. This underscores the importance of detailed metabolic profiling of IDH1mut patients prior to the decision to target glutamine/glutamate pathway clinically.

scholarly journals O-GlcNAcylation of PGK1 coordinates glycolysis and TCA cycle to promote tumor growth

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Hao Nie ◽  
Haixing Ju ◽  
Jiayi Fan ◽  
Xiaoliu Shi ◽  
Yaxian Cheng ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Cancer Cells ◽  
Tumor Development ◽  
Lactate Production ◽  
Phosphoglycerate Kinase ◽  
Tca Cycle ◽  
Human Colon ◽  
Colon Cancers ◽  
The Tca Cycle ◽  
Promote Tumor Growth

AbstractMany cancer cells display enhanced glycolysis and suppressed mitochondrial metabolism. This phenomenon, known as the Warburg effect, is critical for tumor development. However, how cancer cells coordinate glucose metabolism through glycolysis and the mitochondrial tricarboxylic acid (TCA) cycle is largely unknown. We demonstrate here that phosphoglycerate kinase 1 (PGK1), the first ATP-producing enzyme in glycolysis, is reversibly and dynamically modified with O-linked N-acetylglucosamine (O-GlcNAc) at threonine 255 (T255). O-GlcNAcylation activates PGK1 activity to enhance lactate production, and simultaneously induces PGK1 translocation into mitochondria. Inside mitochondria, PGK1 acts as a kinase to inhibit pyruvate dehydrogenase (PDH) complex to reduce oxidative phosphorylation. Blocking T255 O-GlcNAcylation of PGK1 decreases colon cancer cell proliferation, suppresses glycolysis, enhances the TCA cycle, and inhibits tumor growth in xenograft models. Furthermore, PGK1 O-GlcNAcylation levels are elevated in human colon cancers. This study highlights O-GlcNAcylation as an important signal for coordinating glycolysis and the TCA cycle to promote tumorigenesis.

scholarly journals SIRT3 Is a Novel Metabolic Driver of and Therapeutic Target for Chemotherapy Resistant Dlbcls

Blood ◽  
2017 ◽  
Vol 130 (Suppl_1) ◽  
pp. 643-643
Author(s):  
Meng Li ◽  
Ying-Ling Chiang ◽  
Costas Lyssiotis ◽  
Matthew Teater ◽  
Hao Shen ◽  
...  
Keyword(s):  
B Cells ◽  
Cell Lines ◽  
Therapeutic Target ◽  
Research Funding ◽  
Solid Phase ◽  
Tricarboxylic Acid Cycle ◽  
Unmet Need ◽  
Tca Cycle ◽  
Autophagic Flux ◽  
The Tca Cycle

Abstract Understanding the molecular basis of therapy-resistant DLBCL is a critical unmet need. We explored whether the family of Sirtuin proteins might contribute to such effects. Analysis of four independent clinically annotated patient cohorts revealed that higher SIRT3 expression was linked to inferior outcome (p=4.7e-5). This was not the case for any other of the sirtuins. SIRT3 mRNA and protein expression were also much higher in DLBCL patients as compared to normal germinal center (GC) B-cells. Among the seven sirtuins, only SIRT3 depletion universally suppressed proliferation, induced cell cycle arrest, suppressed colony formation, and induced apoptosis in a large panel of DLBCL cell lines regardless of cell of origin, OxPhos status, or somatic mutation profiles. Constitutive Sirt3-/- mice manifested completely normal GC formation after T-cell dependent antigen immunization. However SIRT3 depleted human DLBCL cells manifested inferior engraftment and tumor formation in mice (p=0.023 for hairpin#1, p=0.045 for hairpin#2). Sirt3 inducible knockdown caused strong regression of established DLBCL xenografts. We examined whether SIRT3 was important in lymphoma initiation by crossing VavP-Bcl2 mice with Sirt3-/- animals. As compared to VavP-Bcl2 controls, the VavP-Bcl2/Sirt3-/- mice manifested significantly longer overall survival (P=0.0035), and greatly reduced tumor burden and systemic lymphoma infiltration of organs. SIRT3 is exclusively localized to mitochondria and hence its actions are likely metabolic. We therefore performed metabolomic profiling in SIRT 3 depleted DLBCL cell lines. This analysis revealed profound suppression of the TCA (tricarboxylic acid) cycle, with reduced TCA metabolites such as citrate, alpha-ketoglutarate, succinate, fumarate, malate, etc. SIRT3 depletion caused significant reduction in acetyl-CoA pools as measured by solid phase extraction and LC-MS, indicating that SIRT3 is required to maintain the production of key metabolic intermediates from the TCA cycle. To define the nature of the TCA defect we performed metabolic tracing studies using 13C-labeled glutamine and glucose. The results revealed that SIRT3 drives the TCA cycle through glutaminolysis. We showed that SIRT3 mediates this effect by directly deacetylating and hence hyper-activating the enzymatic activity of mitochondrial glutamine dehydrogenase (GDH). Indeed GDH overexpression could fully rescue the collapse of the TCA, cell proliferation arrest and apoptosis induced by SIRT3 depletion. SIRT3 knockdown was also rescued by feeding cells DMKG (which mimics alpha-ketoglutarate) and hence bypasses the need for SIRT3 mediated glutaminolysis. Because SIRT3 depletion caused metabolic collapse, DLBCL cells manifested potent induction of autophagy, as shown by ratios of LC3II/LC3I in DLBCL cells and using a mCherry-EGFP-LC3 reporter to measure autophagic flux. This autophagy effect was rescued by feeding cells with DMKG or by overexpressing GDH, which uncouple the TCA cycle from SIRT3 dependency. Notably the ratio of LC3II/LCI and perturbed autophagy flux was also Increased in lymphoma cells from VavP-Bcl2;sirt3-/- vs. VavP-Bcl2;sirt3+/+ mice. These data nominate SIRT3 as a putative therapeutic target. Therefore we designed a nanomolar-potency SIRT3 selective small molecule inhibitor including a mitochondrial-targeting motif that concentrates drug in the mitochondrial matrix. This compound (called YC8-02), phenocopied all the effects of SIRT3 depletion including proliferation arrest, apoptosis, TCA collapse by metabolomics study, hyperacetylation of mitochondrial proteins, suppression of GDH activity, and induction of autophagy. Yet YC8-02 had no effect on normal B-cells. Moreover, YC8-02 treatment of chemotherapy resistant DLBCL cell lines restored their sensitivity to clinically relevant doxorubicin concentrations. In summary, SIRT3 is a novel metabolic oncoprotein widely required for DLBCL cells to satisfy their metabolic needs by enhancing the activity of the TCA cycle through glutaminolysis. SIRT3 is a crucial new therapeutic vulnerability especially impactful for the most resistant DLBCLs regardless of their somatic mutations. YC8-02 and its newer derivatives are a promising and entirely new mechanism-based approach to help these patients. Disclosures Cerchietti: Leukemia and Lymphoma Society: Research Funding; Lymphoma Research Foundation: Research Funding; Weill Cornell Medicine - New York Presbyterian Hospital: Employment; Celgene: Research Funding.

scholarly journals Dysregulated Provision of Oxidisable Substrates to the Mitochondria in ME/CFS Lymphoblasts

2021 ◽  
Vol 22 (4) ◽  
pp. 2046
Author(s):  
Daniel Missailidis ◽  
Oana Sanislav ◽  
Claire Y. Allan ◽  
Paige K. Smith ◽  
Sarah J. Annesley ◽  
...  
Keyword(s):  
Amino Acids ◽  
Fatty Acid ◽  
Cell Lines ◽  
Tca Cycle ◽  
Whole Cell ◽  
Energy Stress ◽  
The Tca Cycle ◽  
Mitochondrial Fatty Acid ◽  
Mtorc1 Signaling ◽  
Signaling Activity

Although understanding of the biomedical basis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is growing, the underlying pathological mechanisms remain uncertain. We recently reported a reduction in the proportion of basal oxygen consumption due to ATP synthesis by Complex V in ME/CFS patient-derived lymphoblast cell lines, suggesting mitochondrial respiratory inefficiency. This was accompanied by elevated respiratory capacity, elevated mammalian target of rapamycin complex 1 (mTORC1) signaling activity and elevated expression of enzymes involved in the TCA cycle, fatty acid β-oxidation and mitochondrial transport. These and other observations led us to hypothesise the dysregulation of pathways providing the mitochondria with oxidisable substrates. In our current study, we aimed to revisit this hypothesis by applying a combination of whole-cell transcriptomics, proteomics and energy stress signaling activity measures using subsets of up to 34 ME/CFS and 31 healthy control lymphoblast cell lines from our growing library. While levels of glycolytic enzymes were unchanged in accordance with our previous observations of unaltered glycolytic rates, the whole-cell proteomes of ME/CFS lymphoblasts contained elevated levels of enzymes involved in the TCA cycle (p = 1.03 × 10−4), the pentose phosphate pathway (p = 0.034, G6PD p = 5.5 × 10−4), mitochondrial fatty acid β-oxidation (p = 9.2 × 10−3), and degradation of amino acids including glutamine/glutamate (GLS p = 0.034, GLUD1 p = 0.048, GOT2 p = 0.026), branched-chain amino acids (BCKDHA p = 0.028, BCKDHB p = 0.031) and essential amino acids (FAH p = 0.036, GCDH p = 0.006). The activity of the major cellular energy stress sensor, AMPK, was elevated but the increase did not reach statistical significance. The results suggest that ME/CFS metabolism is dysregulated such that alternatives to glycolysis are more heavily utilised than in controls to provide the mitochondria with oxidisable substrates.

Production of lactic acid and energy metabolism in vascular smooth muscle: effect of dichloroacetate

1995 ◽  
Vol 268 (2) ◽  
pp. H713-H719 ◽  
Author(s):  
J. T. Barron ◽  
J. E. Parrillo
Keyword(s):  
Smooth Muscle ◽  
Lactic Acid ◽  
Vascular Smooth Muscle ◽  
Energy Demand ◽  
Glucose Oxidation ◽  
Lactate Production ◽  
Muscle Metabolism ◽  
Tca Cycle ◽  
The Tca Cycle ◽  
Optimal Coordination

Vascular smooth muscle metabolism is characterized by substantial production of lactic acid even under fully oxygenated conditions. The role the aerobic production of lactate plays in the energetics of smooth muscle is obscure and was investigated in this study. Helical strips of porcine carotid arteries were incubated in medium containing 1 mM dichloroacetate (DCA), an agent that stimulates pyruvate dehydrogenase and promotes the oxidation of glucose. Lactate production in resting muscle was decreased in the presence of DCA (0.033 +/- 0.006 vs. 0.111 +/- 0.014 mumol.g-1.min-1, P < 0.02), indicating diversion of glucose metabolism from lactate production to enhanced glucose oxidation. This was associated with reduction in the level of ATP+phosphocreatine (PCr) (0.99 +/- 0.01 vs. 1.40 +/- 0.09 mumol/g, P < 0.05) and cataplerosis of the tricarboxylic acid (TCA) cycle. Contraction by KCl was also associated with reduced lactate production in the presence of DCA (0.086 +/- 0.017 vs. 0.20 +/- 0.002 mumol.g-1.min-1, P < 0.01), but ATP+PCr normalized, and there was anaplerosis of the TCA cycle. Glycogen in control arteries declined by approximately 1.3 mumol/g over 30 min K+ contraction but was unchanged in the presence of DCA. By calculation, the glycogen spared could be accounted for by the quantity of glucose diverted from lactate production to glucose oxidation during contraction. It is concluded that the aerobic production of lactate is a mechanism affording optimal coordination and modulation of glucose supply and oxidative energy production with energy demand.

scholarly journals Targeting Glutamine Metabolism Overcomes Resistance to Targeted Therapies in Refractory Mantle Cell Lymphoma

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 25-26
Author(s):  
Lingzhi Li ◽  
Changying Jiang ◽  
Lucy Jayne Navsaria ◽  
Yang Liu ◽  
Angela Leeming ◽  
...  
Keyword(s):  
Cell Viability ◽  
B Cell ◽  
Cell Lines ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Tca Cycle ◽  
Glutamine Metabolism ◽  
Metabolomic Profiling ◽  
The Tca Cycle ◽  
Mantle Cell

Background: Mantle cell lymphoma (MCL) is an incurable B cell non-Hodgkin's lymphoma characterized by high refractory occurrence following drug treatment. Despite the encouraging initial MCL tumor response to ibrutinib (IBN), relapse occurs only after few months of treatment due to multiple resistance mechanisms. Thus, the novel therapeutic strategies targeting resistant mechanisms are crucial. Our group has recently shown that among the highly proliferative MCL population, a subpopulation of IBN-R cells exhibits increased OXPHOS activity that is fueled by increased glutaminolysis and rely more on mitochondrial respiration for their grow and survival. The aim of this work was to uncover potential targets responsible for the upregulation of OXPHOS pathway in the refractory/relapsed (R/R) MCL by using multiple biochemical and biological strategies. We focused the present study on glutaminase (GLS), the enzyme that converts glutamine to glutamate, a precursor of α-ketoglutarate (α-KG) that links glutamate to the TCA cycle. Incorporation of α-KG into the TCA cycle is a major anaplerotic step in proliferating cells and is critical for the maintenance of TCA cycle function. To further demonstrate the reliance of OXPHOS on glutamine anaplerosis, we have further tested the combinatory effects of targeting GLS and OXPHOS using their respective inhibitors, CB-839 and IACS-010759, on tumor killing activity in R/R MCL. Methods:Primary MCL cells from patient leukapheresis or whole blood specimens, as well as established MCL cell lines were used as experimental models of MCL. Metabolomic profiling was used to determine intracellular metabolite fluxes and levels. Cell Titer Glo assay was used to measure cell proliferation/viability after treatment with inhibitors. Annexin V and propidium iodide were used to measure cell apoptosis and cell cycle arrestviaflow cytometry analysis. Magnetic microbeads-based B-cell isolation method were used for the purification of malignant B cells from patient samples. Western blot analysis was used to evaluate protein level expression. Patient-derived Xenograft (PDX) mouse model created from patients with MCL was used to evaluate the in vivo anti-tumor activity and potential clinical value of GLS and OXPHOS inhibitors. Results:Our recent metabolomic profiling studies have demonstrated that glutaminolysis and OXPHOS are upregulated in IBN-R MCL, manifested by increased glutamine uptake in the ibrutinib-resistant MCL cell lines (p=0.03).Inhibition of glutamine metabolism with the allosteric GLS1-selective inhibitor BPTES resulted in inhibition of cell viability (0.2381uM-9.98uM), indicating that MCL cells are dependent on glutamine metabolism for their proliferation. To corroborate with the above finding, we also presented evidence that GLS1 is highly increased in IBN-R and CART-R MCL patient samples and cell lines confirmed by immunoblotting. Inhibiting of GLS would lead to significant reduction in OXPHOS, mitochondria membrane potential and ATP production, as either single drug or in combination with other targeting agents. To identify a clinical actionable GLS inhibitor for the treatment of MCL, we chose a GLS1 specific inhibitor CB-839 (Selleckchem), currently under several phase II and III clinical trials investigation on solid tumors. Inhibiting GLS1 with CB-839 leads to the decreased cell viability in MCL (0.5626nM-308.4nM). Of note, the treatment with CB-839 to MCL cell lines induces S phase reduction in both Jeko-1 (17.23%) and Z-138 (14.01%), as well as induces significant apoptosis (p=0.013 and p=0.002 in Jeko-1 and Z-138 cells). GLS inhibition will be further explored in the context of mitochondria defect or hypoxia, where OXPHOS maybe deficient. Importantly, while CB-839 is continuing its validation in several solid tumor models, this is the first study providing data on its efficacy in preclinical models of MCL. Conclusion:In conclusion, we report that glutaminolysis and OXPHOS are upregulated in IBN-R MCL that could be partially due to high expression of GLS1. Our preliminary results revealed that the new GLS inhibitor, GCB-839, may present a clinical potential for a new indication and warrants more in-depth investigation. Deciphering the mechanisms involved in MCL metabolic heterogeneity and adaptability during drug resistance development would be crucial to identify key actors enabling MCL cells to escape from therapy. Disclosures Wang: Acerta Pharma:Research Funding;Molecular Templates:Research Funding;InnoCare:Consultancy;Oncternal:Consultancy, Research Funding;Celgene:Consultancy, Other: Travel, accommodation, expenses, Research Funding;Targeted Oncology:Honoraria;MoreHealth:Consultancy;Kite Pharma:Consultancy, Other: Travel, accommodation, expenses, Research Funding;Lu Daopei Medical Group:Honoraria;OMI:Honoraria, Other: Travel, accommodation, expenses;Verastem:Research Funding;Nobel Insights:Consultancy;BioInvent:Research Funding;Guidepoint Global:Consultancy;AstraZeneca:Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding;Pharmacyclics:Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding;Janssen:Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding;Juno:Consultancy, Research Funding;Dava Oncology:Honoraria;Loxo Oncology:Consultancy, Research Funding;Pulse Biosciences:Consultancy;OncLive:Honoraria;Beijing Medical Award Foundation:Honoraria;VelosBio:Research Funding.

Abstract WP268: Roles And Regulation Of Ketogenesis In Cultured Astroglia And Neurons Under Hypoxia

Stroke ◽  
2013 ◽  
Vol 44 (suppl_1) ◽  
Author(s):  
Shinichi Takahashi ◽  
Takuya Iizumi ◽  
Takato Abe ◽  
Norihiro Suzuki
Keyword(s):  
Alternative Energy ◽  
Ketone Bodies ◽  
Cell Damage ◽  
Tca Cycle ◽  
Neural Cells ◽  
Lactate Oxidation ◽  
Energy Substrates ◽  
The Tca Cycle ◽  
A Cell ◽  
Neuronal Energy Metabolism

Purpose: Although exogenous ketone bodies (KBs), acetoacetate (AA) and β-hydroxybutyrate (BHB) can serve as alternative energy substrates in neural cells under starvation, the exact roles and the regulation of ketogenesis in the brain remain uncertain. The present study examined the ketogenic capacity of cultured rat astroglia under hypoxia and possible roles and the regulation of KBs in neuronal energy metabolism. Methods: Primary neurons and secondary astroglia were prepared from SD rats. Palmitic acid (PA) and L-carnitine (LC) were added to the nutrient medium. AA and BHB produced and released in the medium during 24h were measured using the cyclic thio-NADH method. 14 C-labeled acid-soluble products (i.e., KBs) and 14 CO 2 produced from [1- 14 C]PA were measured to assess the role of PA and KBs as energy substrates in the TCA cycle. [U- 14 C]lactate or [1- 14 C]BHB was used to compare the oxidative metabolism of the end-products of glycolysis with those of the β-oxidation of fatty acid. Some cells were placed in a hypoxic chamber (1%O 2 ) for 12h-24h to evaluate the effects of hypoxia and re-oxygenation on KB metabolism. Results: PA (100 μM) and LC (1 mM) induced higher KB production (mean ± SD in pmol/μg /24h, n=6) in astroglia (AA: 40.8 ± 1.3, BHB: 9.6 ± 1.4) than in neurons (AA: 0.3 ± 1.5, BHB: 2.2 ± 2.7), while CO 2 production from PA was less than 5% of the KB production in astroglia. KB production was augmented by AICAR (500 μM), a cell-permeable AMPK activator (AA: 66.8 ± 8.7, BHB: 12.7 ± 0.9) as well as hypoxia (AA: 59.4 ± 5.1, BHB: 30.0 ± 14.4) in astroglia. [1- 14 C]BHB oxidation (mean ± SD in pmol/μg/h, n=4) in neurons (2.9 ± 0.6) was about 1.5 times as high as that in astroglia (1.8 ± 0.1). [U- 14 C]lactate oxidation in astroglia (14.0 ± 4.6) was not affected by addition of BHB (13.3 ± 4.7) in astroglia, while that in neurons (21.5 ± 2.8) was reduced by 15% (18.1 ± 1.2, P <0.05). Conclusions: Astroglia responded to hypoxia by enhancing KB production in the presence of PA and LC, and KBs produced by astroglia might serve as a neuronal energy substrate for the TCA cycle in place of lactate, since pyruvate dehydrogenase is susceptible to ischemia. The activation of astroglial ketogenesis may reduce ischemic cell damage after stroke.

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>

scholarly journals Mitochondrial Mistranslation in Brain Provokes a Metabolic Response Which Mitigates the Age-Associated Decline in Mitochondrial Gene Expression

2021 ◽  
Vol 22 (5) ◽  
pp. 2746
Author(s):  
Dimitri Shcherbakov ◽  
Reda Juskeviciene ◽  
Adrián Cortés Sanchón ◽  
Margarita Brilkova ◽  
Hubert Rehrauer ◽  
...  
Keyword(s):  
Gene Expression ◽  
Metabolic Response ◽  
Mitochondrial Gene ◽  
Tca Cycle ◽  
Brain Mitochondria ◽  
Mitochondrial Gene Expression ◽  
Rna Seq ◽  
The Tca Cycle ◽  
Neurological Phenotype

Mitochondrial misreading, conferred by mutation V338Y in mitoribosomal protein Mrps5, in-vivo is associated with a subtle neurological phenotype. Brain mitochondria of homozygous knock-in mutant Mrps5V338Y/V338Y mice show decreased oxygen consumption and reduced ATP levels. Using a combination of unbiased RNA-Seq with untargeted metabolomics, we here demonstrate a concerted response, which alleviates the impaired functionality of OXPHOS complexes in Mrps5 mutant mice. This concerted response mitigates the age-associated decline in mitochondrial gene expression and compensates for impaired respiration by transcriptional upregulation of OXPHOS components together with anaplerotic replenishment of the TCA cycle (pyruvate, 2-ketoglutarate).

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