bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2021–04–25
forty-two papers selected by
Christian Frezza, , University of Cambridge, MRC Cancer Unit
  1. Optic atrophy-associated TMEM126A is an assembly factor for the ND4-module of mitochondrial complex I.
  2. Mitochondrial protein import as a quality control sensor.
  3. Mitochondrial NADP(H) generation is essential for proline biosynthesis.
  4. Skeletal muscle heme oxygenase-1 activity regulates aerobic capacity.
  5. The adverse metabolic effects of branched-chain amino acids are mediated by isoleucine and valine.
  6. NDUFS3 depletion permits complex I maturation and reveals TMEM126A/OPA7 as an assembly factor binding the ND4-module intermediate.
  7. Enhanced triacylglycerol catabolism by Carboxylesterase 1 promotes aggressive colorectal carcinoma.
  8. Immunometabolic Endothelial Phenotypes: Integrating Inflammation and Glucose Metabolism.
  9. Architecture of the mycobacterial succinate dehydrogenase with a membrane-embedded Rieske FeS cluster.
  10. Interplay Between Thiamine and p53/p21 Axes Affects Antiproliferative Action of Cisplatin in Lung Adenocarcinoma Cells by Changing Metabolism of 2-Oxoglutarate/Glutamate.
  11. The emerging relationship between metabolism and DNA repair.
  12. Mechanistic connections between mitochondrial biology and regulated cell death.
  13. Autophagy promotes mitochondrial respiration by providing serine for one-carbon-metabolism.
  14. Macropinocytosis: the big drinker behind cancer cell self-consumption.
  15. Potassium ions promote hexokinase-II dependent glycolysis.
  16. EPHA2-dependent outcompetition of KRASG12D mutant cells by wild-type neighbors in the adult pancreas.
  17. The Metabolic Landscape of RAS-Driven Cancers from biology to therapy.
  18. Reciprocal regulation of cellular mechanics and metabolism.
  19. Arginine is an epigenetic regulator targeting TEAD4 to modulate OXPHOS in prostate cancer cells.
  20. Tryptophan metabolism in brain tumors - IDO and beyond.
  21. NKX3.1 localization to mitochondria suppresses prostate cancer initiation.
  22. Ferroptosis: Biochemistry and Biology in Cancers.
  23. Amino acids and RagD potentiate mTORC1 activation in CD8+ T cells to confer antitumor immunity.
  24. Tissue Nutrient Environments and Their Effect on Regulatory T Cell Biology.
  25. Contextual cues from cancer cells govern cancer-associated fibroblast heterogeneity.
  26. Glutathionylation chemistry promotes interleukin-1 beta-mediated glycolytic reprogramming and pro-inflammatory signaling in lung epithelial cells.
  27. A novel and highly effective mitochondrial uncoupling drug in T-cell leukemia.
  28. RRM2B Is Frequently Amplified Across Multiple Tumor Types: Implications for DNA Repair, Cellular Survival, and Cancer Therapy.
  29. Chemistry and Biology of Ferritin.
  30. Therapeutic Repurposing of Biguanides in Cancer.
  31. Epigenomic landscape of human colorectal cancer unveils an aberrant core of pan-cancer enhancers orchestrated by YAP/TAZ.
  32. Interleukin-33 regulates metabolic reprogramming of the retinal pigment epithelium in response to immune stressors.
  33. Dimethyl fumarate induces ferroptosis and impairs NF-κB/STAT3 signaling in DLBCL.
  34. Tissue metabolic profiling reveals major metabolic alteration in colorectal cancer.
  35. Defective apoptotic cell contractility provokes sterile inflammation leading to liver damage and tumour suppression.
  36. Single-cell visualization and quantification of trace metals in Chlamydomonas lysosome-related organelles.
  37. Caloric restriction creates a metabolic pattern of chronological aging delay that in budding yeast differs from the metabolic design established by two other geroprotectors.
  38. The landscape of metabolic pathway dependencies in cancer cell lines.
  39. MitopatHs: a new logically-framed tool for visualizing multiple mitochondrial pathways.
  40. PBRM1 Deficiency Confers Synthetic Lethality to DNA Repair Inhibitors in Cancer.
  41. KRAS mutant rectal cancer cells interact with surrounding fibroblasts to deplete the extracellular matrix.
  42. A metabolic CRISPR-Cas9 screen in Chinese hamster ovary cells identifies glutamine-sensitive genes.
  1. Proc Natl Acad Sci U S A. 2021 Apr 27. pii: e2019665118. [Epub ahead of print]118(17):
    Optic atrophy-associated TMEM126A is an assembly factor for the ND4-module of mitochondrial complex I.
    Luke E Formosa, Boris Reljic, Alice J Sharpe, Daniella H Hock, Linden Muellner-Wong, David A Stroud, Michael T Ryan.
      Mitochondrial disease is a debilitating condition with a diverse genetic etiology. Here, we report that TMEM126A, a protein that is mutated in patients with autosomal-recessive optic atrophy, participates directly in the assembly of mitochondrial complex I. Using a combination of genome editing, interaction studies, and quantitative proteomics, we find that loss of TMEM126A results in an isolated complex I deficiency and that TMEM126A interacts with a number of complex I subunits and assembly factors. Pulse-labeling interaction studies reveal that TMEM126A associates with the newly synthesized mitochondrial DNA (mtDNA)-encoded ND4 subunit of complex I. Our findings indicate that TMEM126A is involved in the assembly of the ND4 distal membrane module of complex I. In addition, we find that the function of TMEM126A is distinct from its paralogue TMEM126B, which acts in assembly of the ND2-module of complex I.
    Keywords:  complex I; membrane protein; mitochondria; optic atrophy; oxidative phosphorylation
    DOI:  https://doi.org/10.1073/pnas.2019665118
  2. Biol Cell. 2021 Apr 18.
    Mitochondrial protein import as a quality control sensor.
    Sebabrata Maity, Oishee Chakrabarti.
      Mitochondria are organelles involved in various functions related to cellular metabolism and homeostasis. Though mitochondria contain own genome, their nuclear counterparts encode most of the different mitochondrial proteins. These are synthesized as precursors in the cytosol and have to be delivered into the mitochondria. These organelles hence have elaborate machineries for the import of precursor proteins from cytosol. The protein import machineries present in both mitochondrial membrane and aqueous compartments show great variability in pre-protein recognition, translocation and sorting across or into it. Mitochondrial protein import machineries also interact transiently with other protein complexes of the respiratory chain or those involved in the maintenance of membrane architecture. Hence mitochondrial protein translocation is an indispensable part of the regulatory network that maintains protein biogenesis, bioenergetics, membrane dynamics and quality control of the organelle. Various stress conditions and diseases that are associated with mitochondrial import defects lead to changes in cellular transcriptomic and proteomic profiles. Dysfunction in mitochondrial protein import also causes over-accumulation of precursor proteins and their aggregation in the cytosol. Multiple pathways may be activated for buffering these harmful consequences. Here we present a comprehensive picture of import machinery and its role in cellular quality control in response to defective mitochondrial import. We also discuss the pathological consequences of dysfunctional mitochondrial protein import in neurodegeneration and cancer. This article is protected by copyright. All rights reserved.
    Keywords:  Intracellular compartmentalization; Mitochondria; Protein degradation/proteases
    DOI:  https://doi.org/10.1111/boc.202100002
  3. Science. 2021 Apr 22. pii: eabd5491. [Epub ahead of print]
    Mitochondrial NADP(H) generation is essential for proline biosynthesis.
    Jiajun Zhu, Simon Schwörer, Mirela Berisa, Yeon Ju Kyung, Keun Woo Ryu, Junmei Yi, Xuejun Jiang, Justin R Cross, Craig B Thompson.
      The coenzyme nicotinamide adenine dinucleotide phosphate (NADP+) and its reduced form (NADPH) regulate reductive metabolism in a subcellularly compartmentalized manner. Mitochondrial NADP(H) production depends on the phosphorylation of NAD(H) by NAD kinase 2 (NADK2). Deletion of NADK2 in human cell lines did not alter mitochondrial folate pathway activity, tricarboxylic acid cycle activity, or mitochondrial oxidative stress, but led to impaired cell proliferation in minimal medium. This growth defect was rescued by proline supplementation. NADK2-mediated mitochondrial NADP(H) generation was required for the reduction of glutamate and hence proline biosynthesis. Furthermore, mitochondrial NADP(H) availability determined the production of collagen proteins by cells of mesenchymal lineage. Thus, a primary function of the mitochondrial NADP(H) pool is to support proline biosynthesis for use in cytosolic protein synthesis.
    DOI:  https://doi.org/10.1126/science.abd5491
  4. Cell Rep. 2021 Apr 20. pii: S2211-1247(21)00332-6. [Epub ahead of print]35(3): 109018
    Skeletal muscle heme oxygenase-1 activity regulates aerobic capacity.
    Rodrigo W Alves de Souza, David Gallo, Ghee Rye Lee, Eri Katsuyama, Alexa Schaufler, Janick Weber, Eva Csizmadia, George C Tsokos, Lauren G Koch, Steven L Britton, Ulrik Wisløff, Patricia C Brum, Leo E Otterbein.
      Physical exercise has profound effects on quality of life and susceptibility to chronic disease; however, the regulation of skeletal muscle function at the molecular level after exercise remains unclear. We tested the hypothesis that the benefits of exercise on muscle function are linked partly to microtraumatic events that result in accumulation of circulating heme. Effective metabolism of heme is controlled by Heme Oxygenase-1 (HO-1, Hmox1), and we find that mouse skeletal muscle-specific HO-1 deletion (Tam-Cre-HSA-Hmox1fl/fl) shifts the proportion of muscle fibers from type IIA to type IIB concomitant with a disruption in mitochondrial content and function. In addition to a significant impairment in running performance and response to exercise training, Tam-Cre-HSA-Hmox1fl/fl mice show remarkable muscle atrophy compared to Hmox1fl/fl controls. Collectively, these data define a role for heme and HO-1 as central regulators in the physiologic response of skeletal muscle to exercise.
    Keywords:  DAMP; exercise training; heme; heme oxygenase-1; hemopexin; mitochondrial dysfunction; muscle atrophy; muscle microtrauma; satellite cells
    DOI:  https://doi.org/10.1016/j.celrep.2021.109018
  5. Cell Metab. 2021 Apr 16. pii: S1550-4131(21)00166-2. [Epub ahead of print]
    The adverse metabolic effects of branched-chain amino acids are mediated by isoleucine and valine.
    Deyang Yu, Nicole E Richardson, Cara L Green, Alexandra B Spicer, Michaela E Murphy, Victoria Flores, Cholsoon Jang, Ildiko Kasza, Maria Nikodemova, Matthew H Wakai, Jay L Tomasiewicz, Shany E Yang, Blake R Miller, Heidi H Pak, Jacqueline A Brinkman, Jennifer M Rojas, William J Quinn, Eunhae P Cheng, Elizabeth N Konon, Lexington R Haider, Megan Finke, Michelle Sonsalla, Caroline M Alexander, Joshua D Rabinowitz, Joseph A Baur, Kristen C Malecki, Dudley W Lamming.
      Low-protein diets promote metabolic health in rodents and humans, and the benefits of low-protein diets are recapitulated by specifically reducing dietary levels of the three branched-chain amino acids (BCAAs), leucine, isoleucine, and valine. Here, we demonstrate that each BCAA has distinct metabolic effects. A low isoleucine diet reprograms liver and adipose metabolism, increasing hepatic insulin sensitivity and ketogenesis and increasing energy expenditure, activating the FGF21-UCP1 axis. Reducing valine induces similar but more modest metabolic effects, whereas these effects are absent with low leucine. Reducing isoleucine or valine rapidly restores metabolic health to diet-induced obese mice. Finally, we demonstrate that variation in dietary isoleucine levels helps explain body mass index differences in humans. Our results reveal isoleucine as a key regulator of metabolic health and the adverse metabolic response to dietary BCAAs and suggest reducing dietary isoleucine as a new approach to treating and preventing obesity and diabetes.
    Keywords:  FGF21; GCN2; body mass index; branched-chain amino acids; diabetes; insulin resistance; isoleucine; mTORC1; obesity; valine
    DOI:  https://doi.org/10.1016/j.cmet.2021.03.025
  6. Cell Rep. 2021 Apr 20. pii: S2211-1247(21)00316-8. [Epub ahead of print]35(3): 109002
    NDUFS3 depletion permits complex I maturation and reveals TMEM126A/OPA7 as an assembly factor binding the ND4-module intermediate.
    Luigi D'Angelo, Elisa Astro, Monica De Luise, Ivana Kurelac, Nikkitha Umesh-Ganesh, Shujing Ding, Ian M Fearnley, Giuseppe Gasparre, Massimo Zeviani, Anna Maria Porcelli, Erika Fernandez-Vizarra, Luisa Iommarini.
      Complex I (CI) is the largest enzyme of the mitochondrial respiratory chain, and its defects are the main cause of mitochondrial disease. To understand the mechanisms regulating the extremely intricate biogenesis of this fundamental bioenergetic machine, we analyze the structural and functional consequences of the ablation of NDUFS3, a non-catalytic core subunit. We show that, in diverse mammalian cell types, a small amount of functional CI can still be detected in the complete absence of NDUFS3. In addition, we determine the dynamics of CI disassembly when the amount of NDUFS3 is gradually decreased. The process of degradation of the complex occurs in a hierarchical and modular fashion in which the ND4 module remains stable and bound to TMEM126A. We, thus, uncover the function of TMEM126A, the product of a disease gene causing recessive optic atrophy as a factor necessary for the correct assembly and function of CI.
    Keywords:  CI; CI modules; NDUFS3; SILAC; TMEM126A; assembly factor; optic atrophy type 7; respiratory complex I
    DOI:  https://doi.org/10.1016/j.celrep.2021.109002
  7. J Clin Invest. 2021 Apr 20. pii: 137845. [Epub ahead of print]
    Enhanced triacylglycerol catabolism by Carboxylesterase 1 promotes aggressive colorectal carcinoma.
    Daria Capece, Daniel D'Andrea, Federica Begalli, Laura Goracci, Laura Tornatore, James L Alexander, Alessandra Di Veroli, Shi-Chi Leow, Thamil S Vaiyapuri, James K Ellis, Daniela Verzella, Jason Bennett, Luca Savino, Yue Ma, James S McKenzie, Maria Luisa Doria, Sam E Mason, Kern Rei Chng, Hector C Keun, Gary Frost, Vinay Tergaonkar, Katarzyna Broniowska, Walter Stunkel, Zoltan Takats, James M Kinross, Gabriele Cruciani, Guido Franzoso.
      The ability to adapt to low-nutrient microenvironments is essential for tumor-cell survival and progression in solid cancers, such as colorectal carcinoma (CRC). Signaling by the NF-κB transcription-factor pathway associates with advanced disease stages and shorter survival in CRC patients. NF-κB has been shown to drive tumor-promoting inflammation, cancer-cell survival and intestinal epithelial cell (IEC) dedifferentiation in mouse models of CRC. However, whether NF-κB affects the metabolic adaptations that fuel aggressive disease in CRC patients is unknown. Here, we identified carboxylesterase 1 (CES1) as an essential NF-κB-regulated lipase linking obesity-associated inflammation with fat metabolism and adaptation to energy stress in aggressive CRC. CES1 promoted CRC-cell survival via cell-autonomous mechanisms that fuel fatty-acid oxidation (FAO) and prevent the toxic build-up of triacylglycerols. We found that elevated CES1 expression correlated with worse outcomes in overweight CRC patients. Accordingly, NF-κB drove CES1 expression in CRC consensus molecular subtype (CMS)4, associated with obesity, stemness and inflammation. CES1 was also upregulated by gene amplifications of its transcriptional regulator, HNF4A, in CMS2 tumors, reinforcing its clinical relevance as a driver of CRC. This subtype-based distribution and unfavourable prognostic correlation distinguished CES1 from other intracellular triacylglycerol lipases and suggest CES1 could provide a route to treat aggressive CRC.
    Keywords:  Colorectal cancer; Metabolism; NF-kappaB; Oncology
    DOI:  https://doi.org/10.1172/JCI137845
  8. Circ Res. 2021 Apr 23.
    Immunometabolic Endothelial Phenotypes: Integrating Inflammation and Glucose Metabolism.
    Wusheng Xiao, William M Oldham, Carnen Priolo, Arvind K Pandey, Joseph Loscalzo.
      Rationale: Specific mechanisms linking inflammation and metabolic re-programming, two hallmarks of many pathobiological processes, remain incompletely defined. Objective: To delineate the integrative regulatory actions governing inflammation and metabolism in endothelial cells (ECs). Methods and Results: Metabolomic profiling, glucose labeling and tracing, and Seahorse extracellular flux analyses revealed that the inflammatory mediators, tumor necrosis factor α (TNFα) and lipopolysaccharide (LPS), extensively reprogram cellular metabolism, and particularly enhance glycolysis, mitochondrial oxidative phosphorylation (OXPHOS), and the pentose phosphate pathway (PPP) in primary human arterial ECs. Mechanistically, the enhancement in glycolysis and PPP is mediated by activation of the nuclear factor-κB (NF-κB)-6-phosphofructo-2-kinase/fructose 2,6-bisphosphatase 3 (PFKFB3) axis and upregulation of glucose 6-phosphate dehydrogenase (G6PD), respectively; while enhanced OXPHOS was attributed to suppression of the forkhead box O1 (FOXO1)-pyruvate dehydrogenase kinase 4 (PDK4) axis. Restoration of the FOXO1-PDK4 axis attenuated the TNFα- or LPS-induced increase in OXPHOS but worsened inflammation in vitro, whereas enhancement of OXPHOS by pharmacological blockade of PDKs attenuated inflammation in mesenteric vessels of LPS-treated mice. Notably, suppression of G6PD expression or its activity potentiated the metabolic shift to glycolysis and/or endothelial inflammation, while inhibition of the NF-κB-PFKFB3 signaling, conversely, blunted the increased glycolysis and/or inflammation in in vitro and in vivo sepsis models. Conclusions: These results indicate that inflammatory mediators modulate the metabolic fates of glucose, and that stimulation of glycolysis promotes inflammation, whereas enhancement of OXPHOS and the PPP suppresses inflammation in the endothelium. Characterization of these immunometabolic phenotypes may have implications for the pathogenesis and treatment of many cardiovascular diseases.
    Keywords:  Glucose-6-phosphate dehydrogenase; metabolic reprogramming; phosphofructo-2-kinase/fructose-2,6,bisphosphatase 3; pyruvate dehydrogenase kinase 4
    DOI:  https://doi.org/10.1161/CIRCRESAHA.120.318805
  9. Proc Natl Acad Sci U S A. 2021 Apr 13. pii: e2022308118. [Epub ahead of print]118(15):
    Architecture of the mycobacterial succinate dehydrogenase with a membrane-embedded Rieske FeS cluster.
    Xiaoting Zhou, Yan Gao, Weiwei Wang, Xiaolin Yang, Xiuna Yang, Fengjiang Liu, Yanting Tang, Sin Man Lam, Guanghou Shui, Lu Yu, Changlin Tian, Luke W Guddat, Quan Wang, Zihe Rao, Hongri Gong.
      Complex II, also known as succinate dehydrogenase (SQR) or fumarate reductase (QFR), is an enzyme involved in both the Krebs cycle and oxidative phosphorylation. Mycobacterial Sdh1 has recently been identified as a new class of respiratory complex II (type F) but with an unknown electron transfer mechanism. Here, using cryoelectron microscopy, we have determined the structure of Mycobacterium smegmatis Sdh1 in the presence and absence of the substrate, ubiquinone-1, at 2.53-Å and 2.88-Å resolution, respectively. Sdh1 comprises three subunits, two that are water soluble, SdhA and SdhB, and one that is membrane spanning, SdhC. Within these subunits we identified a quinone-binding site and a rarely observed Rieske-type [2Fe-2S] cluster, the latter being embedded in the transmembrane region. A mutant, where two His ligands of the Rieske-type [2Fe-2S] were changed to alanine, abolished the quinone reduction activity of the Sdh1. Our structures allow the proposal of an electron transfer pathway that connects the substrate-binding and quinone-binding sites. Given the unique features of Sdh1 and its essential role in Mycobacteria, these structures will facilitate antituberculosis drug discovery efforts that specifically target this complex.
    Keywords:  Mycobacterium smegmatis; cryoelectron microscopy; electron transport chain; succinate dehydrogenase
    DOI:  https://doi.org/10.1073/pnas.2022308118
  10. Front Genet. 2021 ;12 658446
    Interplay Between Thiamine and p53/p21 Axes Affects Antiproliferative Action of Cisplatin in Lung Adenocarcinoma Cells by Changing Metabolism of 2-Oxoglutarate/Glutamate.
    Vasily A Aleshin, Xiaoshan Zhou, Shuba Krishnan, Anna Karlsson, Victoria I Bunik.
      Thiamine (vitamin B1) is often deficient in oncopatients, particularly those undergoing chemotherapy. However, interaction between the thiamine deficiency and anticancer action of drugs has not been characterized. A major natural thiamine derivative, thiamine diphosphate (ThDP), is a coenzyme of central metabolism, also known to affect transcriptional activity of the master metabolic regulator and genome guardian p53. A direct transcriptional target of p53, p21, regulates cell cycle dynamics and DNA damage response. Our work focuses on dependence of the action of the DNA damaging anticancer drug cisplatin on metabolic regulation through p53/p21 axes and cellular thiamine status in human lung adenocarcinoma cells A549. These cells are used as a model of a hardly curable cancer, known to develop chemoresistance to platinum drugs, such as cisplatin. Compared to wild type (A549WT), a stable line with a 60% knockdown of p21 (A549p21-) is less sensitive to antiproliferative action of cisplatin. In contrast, in the thiamine-deficient medium, cisplatin impairs the viability of A549p21- cells more than that of A549WT cells. Analysis of the associated metabolic changes in the cells indicates that (i) p21 knockdown restricts the production of 2-oxoglutarate via glutamate oxidation, stimulating that within the tricarboxylic acid (TCA) cycle; (ii) cellular cisplatin sensitivity is associated with a 4-fold upregulation of glutamic-oxaloacetic transaminase (GOT2) by cisplatin; (iii) cellular cisplatin resistance is associated with a 2-fold upregulation of p53 by cisplatin. Correlation analysis of the p53 expression and enzymatic activities upon variations in cellular thiamine/ThDP levels indicates that p21 knockdown substitutes positive correlation of the p53 expression with the activity of 2-oxoglutarate dehydrogenase complex (OGDHC) for that with the activity of glutamate dehydrogenase (GDH). The knockdown also changes correlations of the levels of OGDHC, GDH and GOT2 with those of the malate and isocitrate dehydrogenases. Thus, a p53/p21-dependent change in partitioning of the glutamate conversion to 2-oxoglutarate through GOT2 or GDH, linked to NAD(P)-dependent metabolism of 2-oxoglutarate in affiliated pathways, adapts A549 cells to thiamine deficiency or cisplatin treatment. Cellular thiamine deficiency may interfere with antiproliferative action of cisplatin due to their common modulation of the p53/p21-dependent metabolic switch between the glutamate oxidation and transamination.
    Keywords:  A549 adenocarcinoma cells; TCA cycle; cisplatin; glutamate metabolism; p21; p53; thiamine deficiency
    DOI:  https://doi.org/10.3389/fgene.2021.658446
  11. Cell Cycle. 2021 Apr 20. 1-17
    The emerging relationship between metabolism and DNA repair.
    Danilo Cucchi, Amy Gibson, Sarah A Martin.
      The DNA damage response (DDR) consists of multiple specialized pathways that recognize different insults sustained by DNA and repairs them where possible to avoid the accumulation of mutations. While loss of activity of genes in the DDR has been extensively associated with cancer predisposition and progression, in recent years it has become evident that there is a relationship between the DDR and cellular metabolism. The activity of the metabolic pathways can influence the DDR by regulating the availability of substrates required for the repair process and the function of its players. Additionally, proteins of the DDR can regulate the metabolic flux through the major pathways such as glycolysis, tricarboxylic acid cycle (TCA) and pentose phosphate pathway (PPP) and the production of reactive oxygen species (ROS). This newly discovered connection bears great importance in the biology of cancer and represents a new therapeutic opportunity. Here we describe the nature of the relationship between DDR and metabolism and its potential application in the treatment of cancer. Keywords: DNA repair, metabolism, mitochondria.
    Keywords:  DNA repair; metabolism; mitochondria
    DOI:  https://doi.org/10.1080/15384101.2021.1912889
  12. Dev Cell. 2021 Apr 16. pii: S1534-5807(21)00308-7. [Epub ahead of print]
    Mechanistic connections between mitochondrial biology and regulated cell death.
    Jerry Edward Chipuk, Jarvier N Mohammed, Jesse D Gelles, Yiyang Chen.
      The ancient, dynamic, and multifaceted functions of the mitochondrial network are essential for organismal homeostasis and contribute to numerous human diseases. As central hubs for metabolism, ion transport, and multiple macromolecular synthesis pathways, mitochondria establish and control extensive signaling networks to ensure cellular survival. In this review, we explore how these same mitochondrial functions also participate in the control of regulated cell death (RCD). We discuss the complementary essential mitochondrial functions as compartments that participate in the production and presentation of key molecules and platforms that actively enable, initiate, and execute RCD.
    Keywords:  cell biology; mitochondrial function; programed cell death; regulated cell death; signal transduction; stress signaling
    DOI:  https://doi.org/10.1016/j.devcel.2021.03.033
  13. Autophagy. 2021 Apr 18. 1-4
    Autophagy promotes mitochondrial respiration by providing serine for one-carbon-metabolism.
    Rajesh Kumar, Andreas S Reichert.
      Whether macroautophagy/autophagy is physiologically relevant to regulate mitochondrial function for a rapid and dynamic adaptation of yeast cells to respiratory growth was not fully understood until recently. May et al. (2020. Nat Commun) report that bulk autophagy provides serine as a one-carbon (1C) metabolite that controls respiratory growth onset by initiating mitochondrial initiator tRNAMet modification and mitochondrial translation linking autophagy mechanistically to mitochondrial function. We discuss the mechanistic interplay between autophagy, one-carbon-metabolism, and mitochondrial function and the possible implications in neurodegeneration, aging, and carcinogenesis.
    Keywords:  Autophagy; mitochondrial respiration; mitochondrial translation; one-carbon metabolism; respiratory growth
    DOI:  https://doi.org/10.1080/15548627.2021.1909408
  14. Autophagy. 2021 Apr 20.
    Macropinocytosis: the big drinker behind cancer cell self-consumption.
    Hua Su, Fei Yang, Beicheng Sun, Michael Karin.
      Poorly vascularized tumors embedded within a thick desmoplastic stroma, like pancreatic ductal adenocarcinoma (PDAC), are nutritionally stressed. Such tumors are also hypoxic and rely on a number of adaptive responses, including macroautophagy/autophagy and macropinocytosis (MP), to support their bioenergetic needs. Whereas autophagy enables starved cells to recycle intracellular macromolecules via lysosomal degradation and use the liberated amino acids (AA) to fuel their metabolism, MP allows cells to take up extracellular proteins via fluid-phase endocytosis and use them as an energy source. However, how any MP-enabled organism, including the prototypical cancer cell, coordinately regulates and balances autophagy and MP is not fully understood. We recently found that inhibition of autophagy results in upregulation of MP, which enables cancer cells to overcome autophagy deficiency and continue to support their bioenergetic demands. The NFE2L2/NRF2-driven induction of MP-related genes (MRGs) is responsible for the upregulation of MP in autophagy inhibited, hypoxic, and oxidatively stressed-exposed cancer cells. Concurrent autophagy and MP blockade effectively cuts off the cancer cell's nutrient and supplies, leading to rapid tumor regression. These findings suggest MP to be an important target in cancer treatment and that shutting off the energy spigot is a promising therapeutic strategy.
    Keywords:  NRF2; PDAC; autophagy; cancer; macropinocytosis; metabolism
    DOI:  https://doi.org/10.1080/15548627.2021.1919969
  15. iScience. 2021 Apr 23. 24(4): 102346
    Potassium ions promote hexokinase-II dependent glycolysis.
    Helmut Bischof, Sandra Burgstaller, Anna Springer, Lucas Matt, Thomas Rauter, Olaf A Bachkönig, Tony Schmidt, Klaus Groschner, Rainer Schindl, Tobias Madl, Nikolaus Plesnila, Robert Lukowski, Wolfgang F Graier, Roland Malli.
      High expression levels of mitochondria-associated hexokinase-II (HKII) represent a hallmark of metabolically highly active cells such as fast proliferating cancer cells. Typically, the enzyme provides a crucial metabolic switch towards aerobic glycolysis. By imaging metabolic activities on the single-cell level with genetically encoded fluorescent biosensors, we here demonstrate that HKII activity requires intracellular K+. The K+ dependency of glycolysis in cells expressing HKII was confirmed in cell populations using extracellular flux analysis and nuclear magnetic resonance-based metabolomics. Reductions of intracellular K+ by gramicidin acutely disrupted HKII-dependent glycolysis and triggered energy stress pathways, while K+ re-addition promptly restored glycolysis-dependent adenosine-5'-triphosphate generation. Moreover, expression and activation of KV1.3, a voltage-gated K+ channel, lowered cellular K+ content and the glycolytic activity of HEK293 cells. Our findings unveil K+ as an essential cofactor of HKII and provide a mechanistic link between activities of distinct K+ channels and cell metabolism.
    Keywords:  Biochemical Mechanism; Biochemistry; Molecular Physiology
    DOI:  https://doi.org/10.1016/j.isci.2021.102346
  16. Curr Biol. 2021 Apr 19. pii: S0960-9822(21)00467-X. [Epub ahead of print]
    EPHA2-dependent outcompetition of KRASG12D mutant cells by wild-type neighbors in the adult pancreas.
    William Hill, Andreas Zaragkoulias, Beatriz Salvador-Barbero, Geraint J Parfitt, Markella Alatsatianos, Ana Padilha, Sean Porazinski, Thomas E Woolley, Jennifer P Morton, Owen J Sansom, Catherine Hogan.
      As we age, our tissues are repeatedly challenged by mutational insult, yet cancer occurrence is a relatively rare event. Cells carrying cancer-causing genetic mutations compete with normal neighbors for space and survival in tissues. However, the mechanisms underlying mutant-normal competition in adult tissues and the relevance of this process to cancer remain incompletely understood. Here, we investigate how the adult pancreas maintains tissue health in vivo following sporadic expression of oncogenic Kras (KrasG12D), the key driver mutation in human pancreatic cancer. We find that when present in tissues in low numbers, KrasG12D mutant cells are outcompeted and cleared from exocrine and endocrine compartments in vivo. Using quantitative 3D tissue imaging, we show that before being cleared, KrasG12D cells lose cell volume, pack into round clusters, and E-cadherin-based cell-cell adhesions decrease at boundaries with normal neighbors. We identify EphA2 receptor as an essential signal in the clearance of KrasG12D cells from exocrine and endocrine tissues in vivo. In the absence of functional EphA2, KrasG12D cells do not alter cell volume or shape, E-cadherin-based cell-cell adhesions increase and KrasG12D cells are retained in tissues. The retention of KRasG12D cells leads to the early appearance of premalignant pancreatic intraepithelial neoplasia (PanINs) in tissues. Our data show that adult pancreas tissues remodel to clear KrasG12D cells and maintain tissue health. This study provides evidence to support a conserved functional role of EphA2 in Ras-driven cell competition in epithelial tissues and suggests that EphA2 is a novel tumor suppressor in pancreatic cancer.
    Keywords:  E-cadherin; EphA2; PanINs; cell competition; early tumorigenesis; epithelial tissue; homeostasis; oncogenic KRAS; pancreas; pancreatic cancer
    DOI:  https://doi.org/10.1016/j.cub.2021.03.094
  17. Nat Cancer. 2021 Mar;2(3): 271-283
    The Metabolic Landscape of RAS-Driven Cancers from biology to therapy.
    Suman Mukhopadhyay, Matthew G Vander Heiden, Frank McCormick.
      Our understanding of how the RAS protein family, and in particular mutant KRAS promote metabolic dysregulation in cancer cells has advanced significantly over the last decade. In this Review, we discuss the metabolic reprogramming mediated by oncogenic RAS in cancer, and elucidating the underlying mechanisms could translate to novel therapeutic opportunities to target metabolic vulnerabilities in RAS-driven cancers.
    Keywords:  KRAS; autophagy; cancer therapeutics; chemoresistance; ferroptosis; glutaminolysis; glycolysis; macropinocytosis; metabolism
    DOI:  https://doi.org/10.1038/s43018-021-00184-x
  18. Nat Metab. 2021 Apr;3(4): 456-468
    Reciprocal regulation of cellular mechanics and metabolism.
    Tom M J Evers, Liam J Holt, Simon Alberti, Alireza Mashaghi.
      Metabolism and mechanics are intrinsically intertwined. External forces, sensed through the cytoskeleton or distortion of the cell and organelles, induce metabolic changes in the cell. The resulting changes in metabolism, in turn, feed back to regulate every level of cell biology, including the mechanical properties of cells and tissues. Here we examine the links between metabolism and mechanics, highlighting signalling pathways involved in the regulation and response to cellular mechanosensing. We consider how forces and metabolism regulate one another through nanoscale molecular sensors, micrometre-scale cytoskeletal networks, organelles and dynamic biomolecular condensates. Understanding this cross-talk will create diagnostic and therapeutic opportunities for metabolic disorders such as cancer, cardiovascular pathologies and obesity.
    DOI:  https://doi.org/10.1038/s42255-021-00384-w
  19. Nat Commun. 2021 Apr 23. 12(1): 2398
    Arginine is an epigenetic regulator targeting TEAD4 to modulate OXPHOS in prostate cancer cells.
    Chia-Lin Chen, Sheng-Chieh Hsu, Tan-Ya Chung, Cheng-Ying Chu, Hung-Jung Wang, Pei-Wen Hsiao, Shauh-Der Yeh, David K Ann, Yun Yen, Hsing-Jien Kung.
      Arginine plays diverse roles in cellular physiology. As a semi-essential amino acid, arginine deprivation has been used to target cancers with arginine synthesis deficiency. Arginine-deprived cancer cells exhibit mitochondrial dysfunction, transcriptional reprogramming and eventual cell death. In this study, we show in prostate cancer cells that arginine acts as an epigenetic regulator to modulate histone acetylation, leading to global upregulation of nuclear-encoded oxidative phosphorylation (OXPHOS) genes. TEAD4 is retained in the nucleus by arginine, enhancing its recruitment to the promoter/enhancer regions of OXPHOS genes and mediating coordinated upregulation in a YAP1-independent but mTOR-dependent manner. Arginine also activates the expression of lysine acetyl-transferases and increases overall levels of acetylated histones and acetyl-CoA, facilitating TEAD4 recruitment. Silencing of TEAD4 suppresses OXPHOS functions and prostate cancer cell growth in vitro and in vivo. Given the strong correlation of TEAD4 expression and prostate carcinogenesis, targeting TEAD4 may be beneficially used to enhance arginine-deprivation therapy and prostate cancer therapy.
    DOI:  https://doi.org/10.1038/s41467-021-22652-9
  20. Curr Opin Immunol. 2021 Apr 01. pii: S0952-7915(21)00025-X. [Epub ahead of print]70 57-66
    Tryptophan metabolism in brain tumors - IDO and beyond.
    Michael Platten, Mirco Friedrich, Derek A Wainwright, Verena Panitz, Christiane A Opitz.
      Metabolism of the essential amino acid tryptophan is a key metabolic pathway that restricts antitumor immunity and is a drug development target for cancer immunotherapy. Tryptophan metabolism is active in brain tumors including gliomas and promotes a malignant phenotype and contributes to the immunosuppressive tumor microenvironment. In recent years, improved understanding of the regulation and downstream function of tryptophan metabolism has been significantly expanded beyond the initial in vitro observation that the enzyme indoleamine-2,3-dioxygenase 1 (IDO1) promotes the depletion of intracellular tryptophan. Here, we revisit the specific roles of tryptophan metabolites in regulating brain functioning and neuronal integrity as well as in the context of brain tumors. This review summarizes recent developments in identifying key regulators, as well as the cellular and molecular effects of tryptophan metabolism with a particular focus on potential therapeutic targets in glioma.
    DOI:  https://doi.org/10.1016/j.coi.2021.03.005
  21. Cancer Discov. 2021 Apr 23. pii: candisc.1765.2020. [Epub ahead of print]
    NKX3.1 localization to mitochondria suppresses prostate cancer initiation.
    Alexandros Papachristodoulou, Antonio Rodriguez-Calero, Sukanya Panja, Elizabeth Margolskee, Renu K Virk, Teresa A Milner, Luis Pina Martina, Jaime Y Kim, Matteo Di Bernardo, Alanna B Williams, Elvis A Maliza, Joseph M Caputo, Christopher Haas, Vinson Wang, Guarionex Joel De Castro, Sven Wenske, Hanina Hibshoosh, James M McKiernan, Michael M Shen, Mark A Rubin, Antonina Mitrofanova, Aditya Dutta, Cory Abate-Shen.
      Mitochondria provide the front-line of defense against the tumor-promoting effects of oxidative stress. Here we show that the prostate-specific homeoprotein, NKX3.1, suppresses prostate cancer initiation by protecting mitochondria from oxidative stress. Integrating analyses of genetically-engineered mouse models, human prostate cancer cells, and human prostate cancer organotypic cultures, we find that, in response to oxidative stress, NKX3.1 is imported to mitochondria via the chaperone protein, HSPA9, where it regulates transcription of mitochondrial-encoded electron transport chain (ETC) genes, thereby restoring oxidative phosphorylation and preventing cancer initiation. Germline polymorphisms of NKX3.1 associated with increased cancer risk fail to protect from oxidative stress or suppress tumorigenicity. Low expression levels of NKX3.1 combined with low expression of mitochondrial ETC genes are associated with adverse clinical outcome, whereas high levels of mitochondrial NKX3.1 protein are associated with favorable outcome. This work reveals an extranuclear role for NKX3.1 in suppression of prostate cancer by protecting mitochondrial function.
    DOI:  https://doi.org/10.1158/2159-8290.CD-20-1765
  22. Front Oncol. 2021 ;11 579286
    Ferroptosis: Biochemistry and Biology in Cancers.
    Zhiyuan Shi, Lei Zhang, Jianzhong Zheng, Huimin Sun, Chen Shao.
      The challenge of eradicating cancer is that cancer cells possess diverse mechanisms to protect themselves from clinical strategies. Recently, ferroptosis has been shown to exhibit appreciable anti-tumor activity that could be harnessed for cancer therapy in the future. Ferroptosis is an iron-dependent form of regulated cell death that is characterized by the oxidization of polyunsaturated fatty acids (PUFAs) and accumulation of lipid peroxides. Ferroptosis has been closely correlated with numerous biological processes, such as amino acid metabolism, glutathione metabolism, iron metabolism, and lipid metabolism, as well as key regulators including GPX4, FSP1, NRF2, and p53. Although ferroptosis could be involved in killing various cancer cells, multiple aspects of this phenomenon remain unresolved. In this review, we summarize the biochemistry and biology of ferroptosis in diverse cancers and discuss the potential mechanisms of ferroptosis, which might pave the way for guiding cancer therapeutics.
    Keywords:  amino acid metabolism; cancers; ferroptosis; iron metabolism; lipid metabolism
    DOI:  https://doi.org/10.3389/fonc.2021.579286
  23. J Immunother Cancer. 2021 Apr;pii: e002137. [Epub ahead of print]9(4):
    Amino acids and RagD potentiate mTORC1 activation in CD8+ T cells to confer antitumor immunity.
    Yiwen Zhang, Hongrong Hu, Weiwei Liu, Shu-Mei Yan, Yuzhuang Li, Likai Tan, Yingshi Chen, Jun Liu, Zhilin Peng, Yaochang Yuan, Wenjing Huang, Fei Yu, Xin He, Bo Li, Hui Zhang.
       BACKGROUND: In the tumor microenvironment, tumor cells are able to suppress antitumor immunity by competing for essential nutrients, including amino acids. However, whether amino acid depletion modulates the activity of CD8+ tumor-infiltrating lymphocytes (TILs) is unclear.
    METHOD: In this study, we evaluated the roles of amino acids and the Rag complex in regulating mammalian target of rapamycin complex 1 (mTORC1) signaling in CD8+ TILs.
    RESULTS: We discovered that the Rag complex, particularly RagD, was crucial for CD8+ T-cell antitumor immunity. RagD expression was positively correlated with the antitumor response of CD8+ TILs in both murine syngeneic tumor xenografts and clinical human colon cancer samples. On RagD deficiency, CD8+ T cells were rendered more dysfunctional, as demonstrated by attenuation of mTORC1 signaling and reductions in proliferation and cytokine secretion. Amino acids maintained RagD-mediated mTORC1 translocation to the lysosome, thereby achieving maximal mTORC1 activity in CD8+ T cells. Moreover, the limited T-cell access to leucine (LEU), overshadowed by tumor cell amino acid consumption, led to impaired RagD-dependent mTORC1 activity. Finally, combined with antiprogrammed cell death protein 1 antibody, LEU supplementation improved T-cell immunity in MC38 tumor-bearing mice in vivo.
    CONCLUSION: Our results revealed that robust signaling of amino acids by RagD and downstream mTORC1 signaling were crucial for T-cell receptor-initiated antitumor immunity. The characterization the role of RagD and LEU in nutrient mTORC1 signaling in TILs might suggest potential therapeutic strategies based on the manipulation of RagD and its upstream pathway.
    Keywords:  CD8-positive T-lymphocytes; lymphocyte activation; lymphocytes; metabolic networks and pathways; tumor microenvironment; tumor-infiltrating
    DOI:  https://doi.org/10.1136/jitc-2020-002137
  24. Front Immunol. 2021 ;12 637960
    Tissue Nutrient Environments and Their Effect on Regulatory T Cell Biology.
    Julianna Blagih, Marc Hennequart, Fabio Zani.
      Regulatory T cells (Tregs) are essential for mitigating inflammation. Tregs are found in nearly every tissue and play either beneficial or harmful roles in the host. The availability of various nutrients can either enhance or impair Treg function. Mitochondrial oxidative metabolism plays a major role in supporting Treg differentiation and fitness. While Tregs rely heavily on oxidation of fatty acids to support mitochondrial activity, they have found ways to adapt to different tissue types, such as tumors, to survive in competitive environments. In addition, metabolic by-products from commensal organisms in the gut also have a profound impact on Treg differentiation. In this review, we will focus on the core metabolic pathways engaged in Tregs, especially in the context of tissue nutrient environments, and how they can affect Treg function, stability and differentiation.
    Keywords:  metabolic adaptation; metabolism; nutrients; regulatory T cells; tissues
    DOI:  https://doi.org/10.3389/fimmu.2021.637960
  25. Cell Rep. 2021 Apr 20. pii: S2211-1247(21)00323-5. [Epub ahead of print]35(3): 109009
    Contextual cues from cancer cells govern cancer-associated fibroblast heterogeneity.
    Neus Bota-Rabassedas, Priyam Banerjee, Yichi Niu, Wenjian Cao, Jiayi Luo, Yuanxin Xi, Xiaochao Tan, Kuanwei Sheng, Young-Ho Ahn, Sieun Lee, Edwin Roger Parra, Jaime Rodriguez-Canales, Jacob Albritton, Michael Weiger, Xin Liu, Hou-Fu Guo, Jiang Yu, B Leticia Rodriguez, Joshua J A Firestone, Barbara Mino, Chad J Creighton, Luisa M Solis, Pamela Villalobos, Maria Gabriela Raso, Daniel W Sazer, Don L Gibbons, William K Russell, Gregory D Longmore, Ignacio I Wistuba, Jing Wang, Harold A Chapman, Jordan S Miller, Chenghang Zong, Jonathan M Kurie.
      Cancer cells function as primary architects of the tumor microenvironment. However, the molecular features of cancer cells that govern stromal cell phenotypes remain unclear. Here, we show that cancer-associated fibroblast (CAF) heterogeneity is driven by lung adenocarcinoma (LUAD) cells at either end of the epithelial-to-mesenchymal transition (EMT) spectrum. LUAD cells that have high expression of the EMT-activating transcription factor ZEB1 reprogram CAFs through a ZEB1-dependent secretory program and direct CAFs to the tips of invasive projections through a ZEB1-driven CAF repulsion process. The EMT, in turn, sensitizes LUAD cells to pro-metastatic signals from CAFs. Thus, CAFs respond to contextual cues from LUAD cells to promote metastasis.
    Keywords:  EMT; cancer-associated fibroblast; invasion; lung cancer; metastasis; microRNA; secretion; single-cell RNA sequencing; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.celrep.2021.109009
  26. FASEB J. 2021 May;35(5): e21525
    Glutathionylation chemistry promotes interleukin-1 beta-mediated glycolytic reprogramming and pro-inflammatory signaling in lung epithelial cells.
    Reem Aboushousha, Evan Elko, Shi B Chia, Allison M Manuel, Cheryl van de Wetering, Jos van der Velden, Maximilian MacPherson, Cuixia Erickson, Julie A Reisz, Angelo D'Alessandro, Emiel F M Wouters, Niki L Reynaert, Ying-Wai Lam, Vikas Anathy, Albert van der Vliet, David J Seward, Yvonne M W Janssen-Heininger.
      Glycolysis is a well-known process by which metabolically active cells, such as tumor or immune cells meet their high metabolic demands. Previously, our laboratory has demonstrated that in airway epithelial cells, the pleiotropic cytokine, interleukin-1 beta (IL1B) induces glycolysis and that this contributes to allergic airway inflammation and remodeling. Activation of glycolysis is known to increase NADPH reducing equivalents generated from the pentose phosphate pathway, linking metabolic reprogramming with redox homeostasis. In addition, numerous glycolytic enzymes are known to be redox regulated. However, whether and how redox chemistry regulates metabolic reprogramming more generally remains unclear. In this study, we employed a multi-omics approach in primary mouse airway basal cells to evaluate the role of protein redox biochemistry, specifically protein glutathionylation, in mediating metabolic reprogramming. Our findings demonstrate that IL1B induces glutathionylation of multiple proteins involved in metabolic regulation, notably in the glycolysis pathway. Cells lacking Glutaredoxin-1 (Glrx), the enzyme responsible for reversing glutathionylation, show modulation of multiple metabolic pathways including an enhanced IL1B-induced glycolytic response. This was accompanied by increased secretion of thymic stromal lymphopoietin (TSLP), a cytokine important in asthma pathogenesis. Targeted inhibition of glycolysis prevented TSLP release, confirming the functional relevance of enhanced glycolysis in cells stimulated with IL1B. Collectively, data herein point to an intriguing link between glutathionylation chemistry and glycolytic reprogramming in epithelial cells and suggest that glutathionylation chemistry may represent a therapeutic target in pulmonary pathologies with perturbations in the glycolysis pathway.
    Keywords:  asthma; glutathionylation; glycolysis; inflammation
    DOI:  https://doi.org/10.1096/fj.202002687RR
  27. Blood. 2021 Apr 19. pii: blood.2020008955. [Epub ahead of print]
    A novel and highly effective mitochondrial uncoupling drug in T-cell leukemia.
    Victoria da Silva-Diz, Bin Cao, Olga Lancho, Eric Chiles, Amer Alasadi, Maya Aleksandrova, Shirley Luo, Amartya Singh, Hanlin Tao, David John Augeri, Sonia Minuzzo, Stefano Indraccolo, Hossein Khiabanian, Xiaoyang Su, Shengkan Jin, Daniel Herranz.
      T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy. Despite recent advances in treatments with intensified chemotherapy regimens, relapse rates and associated morbidities remain high. In this context, metabolic dependencies have emerged as a druggable opportunity for the treatment of leukemia. Here, we tested the antileukemic effects of MB1-47, a newly developed mitochondrial uncoupling compound. MB1-47 treatment in T-ALL cells robustly inhibited cell proliferation via both cytostatic and cytotoxic effects as a result of compromised mitochondrial energy and metabolite depletion, which severely impaired nucleotide biosynthesis. Mechanistically, acute treatment with MB1-47 in primary leukemias promoted AMPK activation and downregulation of mTOR signaling, stalling anabolic pathways that support leukemic cell survival. Indeed, MB1-47 treatment in mice harboring either murine NOTCH1-induced primary leukemias or human T-ALL PDXs led to potent antileukemic effects with a significant extension in survival without overlapping toxicities. Overall, our findings demonstrate a critical role for mitochondrial oxidative phosphorylation in T-ALL and uncover MB1-47-driven mitochondrial uncoupling as a novel therapeutic strategy for the treatment of this disease.
    DOI:  https://doi.org/10.1182/blood.2020008955
  28. Front Genet. 2021 ;12 628758
    RRM2B Is Frequently Amplified Across Multiple Tumor Types: Implications for DNA Repair, Cellular Survival, and Cancer Therapy.
    Waleed Iqbal, Elena V Demidova, Samantha Serrao, Taha ValizadehAslani, Gail Rosen, Sanjeevani Arora.
      RRM2B plays a crucial role in DNA replication, repair and oxidative stress. While germline RRM2B mutations have been implicated in mitochondrial disorders, its relevance to cancer has not been established. Here, using TCGA studies, we investigated RRM2B alterations in cancer. We found that RRM2B is highly amplified in multiple tumor types, particularly in MYC-amplified tumors, and is associated with increased RRM2B mRNA expression. We also observed that the chromosomal region 8q22.3-8q24, is amplified in multiple tumors, and includes RRM2B, MYC along with several other cancer-associated genes. An analysis of genes within this 8q-amplicon showed that cancers that have both RRM2B-amplified along with MYC have a distinct pattern of amplification compared to cancers that are unaltered or those that have amplifications in RRM2B or MYC only. Investigation of curated biological interactions revealed that gene products of the amplified 8q22.3-8q24 region have important roles in DNA repair, DNA damage response, oxygen sensing, and apoptosis pathways and interact functionally. Notably, RRM2B-amplified cancers are characterized by mutation signatures of defective DNA repair and oxidative stress, and at least RRM2B-amplified breast cancers are associated with poor clinical outcome. These data suggest alterations in RR2MB and possibly the interacting 8q-proteins could have a profound effect on regulatory pathways such as DNA repair and cellular survival, highlighting therapeutic opportunities in these cancers.
    Keywords:  8q-amplicon; MYC; RRM2B; cancer; chromosome 8
    DOI:  https://doi.org/10.3389/fgene.2021.628758
  29. Metallomics. 2021 Apr 21. pii: mfab021. [Epub ahead of print]
    Chemistry and Biology of Ferritin.
    Marina Plays, Sebastian Müller, Raphaël Rodriguez.
      Iron is an essential element required by cells and has been described as a key player in ferroptosis. Ferritin operates as a fundamental iron storage protein in cells forming multimeric assemblies with crystalline iron cores. We discuss the latest findings on ferritin structure and activity and its link to cell metabolism and ferroptosis. The chemistry of iron, including its oxidations states, is important for its biological functions, its reactivity and the biology of ferritin. Ferritin can be localized in different cellular compartments and secreted by cells with a variety of functions depending on its spatial context. Here, we discuss how cellular ferritin localization is tightly linked to its function in a tissue-specific manner, and how impairment of iron homeostasis is implicated in diseases including cancer and COVID-19. Ferritin is a potential biomarker and we discuss latest research where it has been employed for imaging purposes and drug delivery.
    DOI:  https://doi.org/10.1093/mtomcs/mfab021
  30. Trends Cancer. 2021 Apr 14. pii: S2405-8033(21)00064-9. [Epub ahead of print]
    Therapeutic Repurposing of Biguanides in Cancer.
    Hongyun Zhao, Kenneth D Swanson, Bin Zheng.
      Biguanides are a class of antidiabetic drugs that includes phenformin and metformin; however, the former was withdrawn from approval in many countries due to its toxicity. Findings from retrospective epidemiological studies in diabetic populations and preclinical laboratory models have demonstrated that biguanides possess antitumor activities that suggest their repurposing for cancer prevention and treatment. However, a better understanding of how these biguanides behave as antitumor agents is needed to guide their improved applications in cancer therapy, spurring increased interest in their pharmacology. Here, we present evidence for proposed mechanisms of action related to their antitumor activity, including their effects on central carbon metabolism in cancer cells and immune-modulating activity, and then review progress on biguanide repurposing in cancer therapeutics and the possible re-evaluation of phenformin as a cancer therapeutic agent.
    Keywords:  AMPK; cancer cell metabolism; cancer immunotherapy; immunometabolism; metformin; phenformin
    DOI:  https://doi.org/10.1016/j.trecan.2021.03.001
  31. Nat Commun. 2021 Apr 20. 12(1): 2340
    Epigenomic landscape of human colorectal cancer unveils an aberrant core of pan-cancer enhancers orchestrated by YAP/TAZ.
    Giulia Della Chiara, Federica Gervasoni, Michaela Fakiola, Chiara Godano, Claudia D'Oria, Luca Azzolin, Raoul Jean Pierre Bonnal, Giulia Moreni, Lorenzo Drufuca, Grazisa Rossetti, Valeria Ranzani, Ramona Bason, Marco De Simone, Francesco Panariello, Ivan Ferrari, Tanya Fabbris, Francesca Zanconato, Mattia Forcato, Oriana Romano, Jimmy Caroli, Paola Gruarin, Maria Lucia Sarnicola, Michelangelo Cordenonsi, Alberto Bardelli, Nicola Zucchini, Andrea Pisani Ceretti, Nicolò Maria Mariani, Andrea Cassingena, Andrea Sartore-Bianchi, Giuseppe Testa, Luca Gianotti, Enrico Opocher, Federica Pisati, Claudio Tripodo, Giuseppe Macino, Salvatore Siena, Silvio Bicciato, Stefano Piccolo, Massimiliano Pagani.
      Cancer is characterized by pervasive epigenetic alterations with enhancer dysfunction orchestrating the aberrant cancer transcriptional programs and transcriptional dependencies. Here, we epigenetically characterize human colorectal cancer (CRC) using de novo chromatin state discovery on a library of different patient-derived organoids. By exploring this resource, we unveil a tumor-specific deregulated enhancerome that is cancer cell-intrinsic and independent of interpatient heterogeneity. We show that the transcriptional coactivators YAP/TAZ act as key regulators of the conserved CRC gained enhancers. The same YAP/TAZ-bound enhancers display active chromatin profiles across diverse human tumors, highlighting a pan-cancer epigenetic rewiring which at single-cell level distinguishes malignant from normal cell populations. YAP/TAZ inhibition in established tumor organoids causes extensive cell death unveiling their essential role in tumor maintenance. This work indicates a common layer of YAP/TAZ-fueled enhancer reprogramming that is key for the cancer cell state and can be exploited for the development of improved therapeutic avenues.
    DOI:  https://doi.org/10.1038/s41467-021-22544-y
  32. JCI Insight. 2021 Apr 22. pii: 129429. [Epub ahead of print]6(8):
    Interleukin-33 regulates metabolic reprogramming of the retinal pigment epithelium in response to immune stressors.
    Louis M Scott, Emma E Vincent, Natalie Hudson, Chris Neal, Nicholas Jones, Ed Lavelle, Matthew Campbell, Andrew P Halestrap, Andrew D Dick, Sofia Theodoropoulou.
      It remains unresolved how retinal pigment epithelial cell metabolism is regulated following immune activation to maintain retinal homeostasis and retinal function. We exposed retinal pigment epithelium (RPE) to several stress signals, particularly Toll-like receptor stimulation, and uncovered an ability of RPE to adapt their metabolic preference on aerobic glycolysis or oxidative glucose metabolism in response to different immune stimuli. We have identified interleukin-33 (IL-33) as a key metabolic checkpoint that antagonizes the Warburg effect to ensure the functional stability of the RPE. The identification of IL-33 as a key regulator of mitochondrial metabolism suggests roles for the cytokine that go beyond its extracellular "alarmin" activities. IL-33 exerts control over mitochondrial respiration in RPE by facilitating oxidative pyruvate catabolism. We have also revealed that in the absence of IL-33, mitochondrial function declined and resultant bioenergetic switching was aligned with altered mitochondrial morphology. Our data not only shed new light on the molecular pathway of activation of mitochondrial respiration in RPE in response to immune stressors but also uncover a potentially novel role of nuclear intrinsic IL-33 as a metabolic checkpoint regulator.
    Keywords:  Glucose metabolism; Metabolism; Mitochondria; Ophthalmology; Retinopathy
    DOI:  https://doi.org/10.1172/jci.insight.129429
  33. Blood. 2021 Apr 19. pii: blood.2020009404. [Epub ahead of print]
    Dimethyl fumarate induces ferroptosis and impairs NF-κB/STAT3 signaling in DLBCL.
    Anja Schmitt, Wendan Xu, Philip Bucher, Melanie Grimm, Martina Konantz, Heike Horn, Myroslav Zapukhlyak, Philipp Berning, Marc Brändle, Mohamed-Ali Jarboui, Caroline Schönfeld, Karsten Boldt, Andreas Rosenwald, German Ott, Michael Grau, Pavel Klener, Petra Vockova, Claudia Lengerke, Georg Lenz, Klaus Schulze-Osthoff, Stephan Hailfinger.
      Despite the development of novel targeted drugs, the molecular heterogeneity of diffuse large B-cell lymphoma (DLBCL) still poses a major therapeutic challenge. DLBCL can be classified into at least two major subtypes, i.e. germinal center B-cell-like (GCB) and the aggressive activated B-cell-like (ABC) DLBCL, each characterized by specific gene expression profiles and mutation patterns. Here we demonstrate a broad anti-tumor effect of dimethyl fumarate (DMF) on both DLBCL subtypes, which is mediated by the induction of ferroptosis, a form of cell death driven by the peroxidation of phospholipids. Due to high expression of arachidonate 5-lipoxygenase in concert with low glutathione and glutathione peroxidase 4 levels, DMF induces lipid peroxidation and thus ferroptosis particularly in GCB DLBCL. In ABC DLBCL cells, which are addicted to NF-κB and STAT3 survival signaling, DMF treatment efficiently inhibits the activity of the IKK complex and JAK kinases. Interestingly, the BCL-2 specific BH3 mimetic ABT-199 and an inhibitor of ferroptosis suppressor protein 1 synergize with DMF in inducing cell death in DLBCL. Collectively, our findings identify the clinically approved drug DMF as a promising novel therapeutic option in the treatment of both GCB and ABC DLBCL.
    DOI:  https://doi.org/10.1182/blood.2020009404
  34. Mol Omics. 2021 Apr 20.
    Tissue metabolic profiling reveals major metabolic alteration in colorectal cancer.
    Yao Shen, Mao Sun, Jun Zhu, Mengying Wei, Huichen Li, Pan Zhao, Jiajia Wang, Ruikai Li, Lianlian Tian, Yanyan Tao, Peng Shen, Jian Zhang.
      Metabolic reprogramming is a hallmark of cancer, which is still far from being fully understood in colorectal cancer. In order to characterize the metabolic changes in colorectal cancer, we performed metabolomics analysis of paired colon tissues from colorectal cancer patients by using a liquid chromatography-mass spectrometry (LC-MS)-based method. Bioinformation analysis was used to define important metabolites and metabolic pathways, as well as the prognosis significance and expression levels of the key molecules. The results indicated that the metabolite phenotype in cancerous colon tissues was obviously different from their normal counterpart, and we identified a series of important metabolic changes in colorectal cancer, including decreased trends of glucose, citrate, serotonin, 5-hydroxytryptophol and 5-hydroxyindoleacetate, as well as increased trends of glutamate, glutathione, creatine, proline, lactate, fructose 1,6-bisphosphate, succinate, tryptophan, kynurenine and long chain acyl-carnitines. These metabolites are mainly implicated in energy metabolism, amino acid metabolism, glutathione metabolism and fatty acid metabolism. In addition, we found that the expression levels of several key molecules in these pathways were closely correlated with the prognosis of colorectal cancer patients. This study characterizes the metabolic profile in colorectal cancer tissues and provides more insightful understanding of the metabolic reprogramming of colorectal cancer.
    DOI:  https://doi.org/10.1039/d1mo00022e
  35. Elife. 2021 Apr 19. pii: e61983. [Epub ahead of print]10
    Defective apoptotic cell contractility provokes sterile inflammation leading to liver damage and tumour suppression.
    Linda Julian, Gregory Naylor, Grant R Wickman, Nicola Rath, Giovanni Costino, David Stevenson, Sheila Bryson, June Munro, Lynn McGarry, Margaret Mullin, Alistair Rice, Armando Del Río Hernández, Michael F Olson.
      Apoptosis is characterized by profound morphological changes, but their physiological purpose is unknown. To characterize the role of apoptotic cell contraction, ROCK1 was rendered caspase non-cleavable (ROCK1nc) by mutating Aspartate 1113, which revealed that ROCK1 cleavage was necessary for forceful contraction and membrane blebbing. When homozygous ROCK1nc mice were treated with the liver-selective apoptotic stimulus of diethylnitrosamine, ROCK1nc mice had more profound liver damage with greater neutrophil infiltration than wild-type mice. Inhibition of the damage associated molecular pattern protein HMGB1 or signalling by its cognate receptor TLR4 lowered neutrophil infiltration and reduced liver damage. ROCK1nc mice also developed fewer diethylnitrosamine-induced hepatocellular carcinoma (HCC) tumours, while HMGB1 inhibition increased HCC tumour numbers. Thus, ROCK1 activation and consequent cell contraction are required to limit sterile inflammation and damage amplification following tissue-scale cell death. Additionally, these findings reveal a previously unappreciated role for acute sterile inflammation as an efficient tumour suppressive mechanism.
    Keywords:  cancer biology; cell biology; mouse
    DOI:  https://doi.org/10.7554/eLife.61983
  36. Proc Natl Acad Sci U S A. 2021 Apr 20. pii: e2026811118. [Epub ahead of print]118(16):
    Single-cell visualization and quantification of trace metals in Chlamydomonas lysosome-related organelles.
    Stefan Schmollinger, Si Chen, Daniela Strenkert, Colleen Hui, Martina Ralle, Sabeeha S Merchant.
      The acidocalcisome is an acidic organelle in the cytosol of eukaryotes, defined by its low pH and high calcium and polyphosphate content. It is visualized as an electron-dense object by transmission electron microscopy (TEM) or described with mass spectrometry (MS)-based imaging techniques or multimodal X-ray fluorescence microscopy (XFM) based on its unique elemental composition. Compared with MS-based imaging techniques, XFM offers the additional advantage of absolute quantification of trace metal content, since sectioning of the cell is not required and metabolic states can be preserved rapidly by either vitrification or chemical fixation. We employed XFM in Chlamydomonas reinhardtii to determine single-cell and organelle trace metal quotas within algal cells in situations of trace metal overaccumulation (Fe and Cu). We found up to 70% of the cellular Cu and 80% of Fe sequestered in acidocalcisomes in these conditions and identified two distinct populations of acidocalcisomes, defined by their unique trace elemental makeup. We utilized the vtc1 mutant, defective in polyphosphate synthesis and failing to accumulate Ca, to show that Fe sequestration is not dependent on either. Finally, quantitation of the Fe and Cu contents of individual cells and compartments via XFM, over a range of cellular metal quotas created by nutritional and genetic perturbations, indicated excellent correlation with bulk data from corresponding cell cultures, establishing a framework to distinguish the nutritional status of single cells.
    Keywords:  heavy metal detoxification; trace metal sequestration; vacuole VTC XRF
    DOI:  https://doi.org/10.1073/pnas.2026811118
  37. Oncotarget. 2021 Mar 30. 12(7): 608-625
    Caloric restriction creates a metabolic pattern of chronological aging delay that in budding yeast differs from the metabolic design established by two other geroprotectors.
    Karamat Mohammad, Vladimir I Titorenko.
      Caloric restriction and the tor1Δ mutation are robust geroprotectors in yeast and other eukaryotes. Lithocholic acid is a potent geroprotector in Saccharomyces cerevisiae. Here, we used liquid chromatography coupled with tandem mass spectrometry method of non-targeted metabolomics to compare the effects of these three geroprotectors on the intracellular metabolome of chronologically aging budding yeast. Yeast cells were cultured in a nutrient-rich medium. Our metabolomic analysis identified and quantitated 193 structurally and functionally diverse water-soluble metabolites implicated in the major pathways of cellular metabolism. We show that the three different geroprotectors create distinct metabolic profiles throughout the entire chronological lifespan of S. cerevisiae. We demonstrate that caloric restriction generates a unique metabolic pattern. Unlike the tor1Δ mutation or lithocholic acid, it slows down the metabolic pathway for sulfur amino acid biosynthesis from aspartate, sulfate and 5-methyltetrahydrofolate. Consequently, caloric restriction significantly lowers the intracellular concentrations of methionine, S-adenosylmethionine and cysteine. We also noticed that the low-calorie diet, but not the tor1Δ mutation or lithocholic acid, decreases intracellular ATP, increases the ADP:ATP and AMP:ATP ratios, and rises intracellular ADP during chronological aging. We propose a model of how the specific remodeling of cellular metabolism by caloric restriction contributes to yeast chronological aging delay.
    Keywords:  caloric restriction; cellular aging; geroprotectors; metabolism; methionine
    DOI:  https://doi.org/10.18632/oncotarget.27926
  38. PLoS Comput Biol. 2021 Apr 19. 17(4): e1008942
    The landscape of metabolic pathway dependencies in cancer cell lines.
    James H Joly, Brandon T L Chew, Nicholas A Graham.
      The metabolic reprogramming of cancer cells creates metabolic vulnerabilities that can be therapeutically targeted. However, our understanding of metabolic dependencies and the pathway crosstalk that creates these vulnerabilities in cancer cells remains incomplete. Here, by integrating gene expression data with genetic loss-of-function and pharmacological screening data from hundreds of cancer cell lines, we identified metabolic vulnerabilities at the level of pathways rather than individual genes. This approach revealed that metabolic pathway dependencies are highly context-specific such that cancer cells are vulnerable to inhibition of one metabolic pathway only when activity of another metabolic pathway is altered. Notably, we also found that the no single metabolic pathway was universally essential, suggesting that cancer cells are not invariably dependent on any metabolic pathway. In addition, we confirmed that cell culture medium is a major confounding factor for the analysis of metabolic pathway vulnerabilities. Nevertheless, we found robust associations between metabolic pathway activity and sensitivity to clinically approved drugs that were independent of cell culture medium. Lastly, we used parallel integration of pharmacological and genetic dependency data to confidently identify metabolic pathway vulnerabilities. Taken together, this study serves as a comprehensive characterization of the landscape of metabolic pathway vulnerabilities in cancer cell lines.
    DOI:  https://doi.org/10.1371/journal.pcbi.1008942
  39. iScience. 2021 Apr 23. 24(4): 102324
    MitopatHs: a new logically-framed tool for visualizing multiple mitochondrial pathways.
    Saverio Marchi, Marco Zanella, Paolo Pinton, Silvia Crafa, Giovanni Boniolo.
      Mitochondria are key organelles inside the cell that house a wide range of molecular pathways involved in energy metabolism, ions homeostasis, and cell death. Several databases characterize the different mitochondrial aspects and thus support basic and clinical research. Here we present MitopatHs, a web-based data set that allows navigating among the biochemical signaling pathways (PatHs) of human (H) mitochondria (Mito). MitopatHs is designed to visualize and comprehend virtually all types of pathways in two complementary ways: a logical view, where the sequence of biochemical reactions is presented as logical deductions, and an intuitive graphical visualization, which enables the examination and the analysis of each step of the pathway. MitopatHs is a manually curated, open access and collaborative tool, whose goal is to enable the visualization and comprehension of complicated molecular routes in an easy and fast way.
    Keywords:  Cell Biology; Molecular Network; Software
    DOI:  https://doi.org/10.1016/j.isci.2021.102324
  40. Cancer Res. 2021 Apr 22.
    PBRM1 Deficiency Confers Synthetic Lethality to DNA Repair Inhibitors in Cancer.
    Roman M Chabanon, Daphné Morel, Thomas Eychenne, Léo Colmet-Daage, Ilirjana Bajrami, Nicolas Dorvault, Marlène Garrido, Cornelia Meisenberg, Andrew Lamb, Carine Ngo, Suzanna R Hopkins, Theodoros I Roumeliotis, Samuel Jouny, Clémence Hénon, Asuka Kawai-Kawachi, Clémence Astier, Asha Konde, Elaine Del Nery, Christophe Massard, Stephen J Pettitt, Raphaël Margueron, Jyoti S Choudhary, Geneviève Almouzni, Jean-Charles Soria, Eric Deutsch, Jessica A Downs, Christopher J Lord, Sophie Postel-Vinay.
      Inactivation of Polybromo 1 (PBRM1), a specific subunit of the PBAF chromatin remodeling complex, occurs frequently in cancer, including 40% of clear cell renal cell carcinomas (ccRCC). To identify novel therapeutic approaches to targeting PBRM1-defective cancers, we used a series of orthogonal functional genomic screens that identified PARP and ATR inhibitors as being synthetic lethal with PBRM1 deficiency. The PBRM1/PARP inhibitor synthetic lethality was recapitulated using several clinical PARP inhibitors in a series of in vitro model systems and in vivo in a xenograft model of ccRCC. In the absence of exogenous DNA damage, PBRM1-defective cells exhibited elevated levels of replication stress, micronuclei, and R-loops. PARP inhibitor exposure exacerbated these phenotypes. Quantitative mass spectrometry revealed that multiple R-loop processing factors were downregulated in PBRM1-defective tumor cells. Exogenous expression of the R-loop resolution enzyme RNase H1 reversed the sensitivity of PBRM1-deficient cells to PARP inhibitors, suggesting that excessive levels of R-loops could be a cause of this synthetic lethality. PARP and ATR inhibitors also induced cyclic GMP-AMP synthase/stimulator of interferon genes (cGAS/STING) innate immune signaling in PBRM1-defective tumor cells. Overall, these findings provide the preclinical basis for using PARP inhibitors in PBRM1-defective cancers. SIGNIFICANCE: This study demonstrates that PARP and ATR inhibitors are synthetic lethal with the loss of PBRM1, a PBAF-specific subunit, thus providing the rationale for assessing these inhibitors in patients with PBRM1-defective cancer. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/00/0/000/F1.large.jpg.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-21-0628
  41. Mol Oncol. 2021 Apr 04.
    KRAS mutant rectal cancer cells interact with surrounding fibroblasts to deplete the extracellular matrix.
    Jin K Kim, Michael R Marco, Seo-Hyun Choi, Xuan Qu, Chin-Tung Chen, Moshe Elkabets, Lauren Fairchild, Oliver Chow, Francisco M Barriga, Lukas E Dow, Kevin O'Rourke, Bryan Szeglin, Dmitry Yarilin, Sho Fujisawa, Katia Manova-Todorova, Philip B Paty, Jinru Shia, Christina Leslie, J Joshua Smith, Scott Lowe, Raphael Pelossof, Francisco Sanchez-Vega, Julio Garcia-Aguilar.
      Somatic mutations in the KRAS oncogene are associated with poor outcomes in locally advanced rectal cancer but the underlying biologic mechanisms are not fully understood. We profiled mRNA in 76 locally advanced rectal adenocarcinomas from patients that were enrolled in a prospective clinical trial and investigated differences in gene expression between KRAS-mutant (KRAS-mt) and KRAS-wild-type (KRAS-wt) patients. We found that KRAS-mt tumors display lower expression of genes related to the tumor stroma and remodeling of the extracellular matrix. We validated our findings using samples from The Cancer Genome Atlas (TCGA) data and also by performing immunohistochemistry (IHC) and immunofluorescence (IF) in orthogonal cohorts. Using in vitro and in vivo models, we show that oncogenic KRAS signaling within the epithelial cancer cells modulates the activity of the surrounding fibroblasts in the tumor microenvironment.
    Keywords:  KRAS; cancer-associated-fibroblast; extracellular matrix; rectal cancer; tumor response; tumor stroma
    DOI:  https://doi.org/10.1002/1878-0261.12960
  42. Metab Eng. 2021 Apr 01. pii: S1096-7176(21)00053-7. [Epub ahead of print]
    A metabolic CRISPR-Cas9 screen in Chinese hamster ovary cells identifies glutamine-sensitive genes.
    Karen Julie la Cour Karottki, Hooman Hefzi, Songyuan Li, Lasse Ebdrup Pedersen, Philipp N Spahn, Chintan Joshi, David Ruckerbauer, Juan A Hernandez Bort, Alex Thomas, Jae Seong Lee, Nicole Borth, Gyun Min Lee, Helene Faustrup Kildegaard, Nathan E Lewis.
      Media and feed optimization have fueled many-fold improvements in mammalian biopharmaceutical production, but genome editing offers an emerging avenue for further enhancing cell metabolism and bioproduction. However, the complexity of metabolism, involving thousands of genes, makes it unclear which engineering strategies will result in desired traits. Here we present a comprehensive pooled CRISPR screen for CHO cell metabolism, including ∼16,000 gRNAs against ∼2500 metabolic enzymes and regulators. Using this screen, we identified a glutamine response network in CHO cells. Glutamine is particularly important since it is often over-fed to drive increased TCA cycle flux, but toxic ammonia may accumulate. With the screen we found one orphan glutamine-responsive gene with no clear connection to our network. Knockout of this novel and poorly characterized lipase, Abhd11, substantially increased growth in glutamine-free media by altering the regulation of the TCA cycle. Thus, the screen provides an invaluable targeted platform to comprehensively study genes involved in any metabolic trait, and elucidate novel regulators of metabolism.
    Keywords:  CHO; CRISPR pooled Screen; Glutamine; Metabolism
    DOI:  https://doi.org/10.1016/j.ymben.2021.03.017
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