bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2021–11–07
29 papers selected by
Christian Frezza, , University of Cambridge, MRC Cancer Unit
  1. Analysis of Leukemia Cell Metabolism through Stable Isotope Tracing in Mice.
  2. ND3 Cys39 in complex I is exposed during mitochondrial respiration.
  3. Constitutive activation of the PI3K-Akt-mTORC1 pathway sustains the m.3243 A > G mtDNA mutation.
  4. Implications of mitochondrial DNA mutations in human induced pluripotent stem cells.
  5. Loss of FBXW7 correlates with increased IDH1 expression in glioma and enhances IDH1-mutant cancer cell sensitivity to radiation.
  6. Regulatory T cell differentiation is controlled by αKG-induced alterations in mitochondrial metabolism and lipid homeostasis.
  7. The glutaminase inhibitor telaglenastat enhances the antitumor activity of signal transduction inhibitors everolimus and cabozantinib in models of renal cell carcinoma.
  8. Newcastle disease virus degrades SIRT3 via PINK1-PRKN-dependent mitophagy to reprogram energy metabolism in infected cells.
  9. The existence of a nonclassical TCA cycle in the nucleus that wires the metabolic-epigenetic circuitry.
  10. Subcellular Specialization of Mitochondrial Form and Function in Skeletal Muscle Cells.
  11. Extracellular Matrix Signals as Drivers of Mitochondrial Bioenergetics and Metabolic Plasticity of Cancer Cells During Metastasis.
  12. The dominant-negative mitochondrial calcium uniporter subunit MCUb drives macrophage polarization during skeletal muscle regeneration.
  13. A mediator of metabolic signals influences puberty and growth.
  14. Microbiota-derived acetate enables the metabolic fitness of the brain innate immune system during health and disease.
  15. Insulin and the last gasp of failing adipocytes.
  16. Cul4A-DDB1-mediated monoubiquitination of phosphoglycerate dehydrogenase promotes colorectal cancer metastasis via increased S-adenosylmethionine.
  17. WAVE complex regulation by force.
  18. Spatial mapping reveals human adipocyte subpopulations with distinct sensitivities to insulin.
  19. The context-specific role of germline pathogenicity in tumorigenesis.
  20. Microeconomics of Metabolism: The Warburg Effect as Giffen Behaviour.
  21. Metabolic Reprogramming in Kidney Diseases: Evidence and Therapeutic Opportunities.
  22. Mitochondrial Drp1 recognizes and induces excessive mPTP opening after hypoxia through BAX-PiC and LRRK2-HK2.
  23. Targeting glioblastoma signaling and metabolism with a re-purposed brain-penetrant drug.
  24. Synonymous mutations reveal genome-wide levels of positive selection in healthy tissues.
  25. Mitochondrial respiration contributes to the interferon gamma response in antigen presenting cells.
  26. A gene toolbox for monitoring autophagy transcription.
  27. The transcriptional corepressor CtBP2 serves as a metabolite sensor orchestrating hepatic glucose and lipid homeostasis.
  28. RNA promotes the formation of spatial compartments in the nucleus.
  29. The metabolic adaptation evoked by arginine enhances the effect of radiation in brain metastases.
  1. Bio Protoc. 2021 Oct 05. 11(19): e4171
    Analysis of Leukemia Cell Metabolism through Stable Isotope Tracing in Mice.
    Nick van Gastel, Jessica B Spinelli, Marcia C Haigis, David T Scadden.
      Once thought to be a mere consequence of the state of a cell, intermediary metabolism is now recognized as a key regulator of mammalian cell fate and function. In addition, cell metabolism is often disturbed in malignancies such as cancer, and targeting metabolic pathways can provide new therapeutic options. Cell metabolism is mostly studied in cell cultures in vitro, using techniques such as metabolomics, stable isotope tracing, and biochemical assays. Increasing evidence however shows that the metabolic profile of cells is highly dependent on the microenvironment, and metabolic vulnerabilities identified in vitro do not always translate to in vivo settings. Here, we provide a detailed protocol on how to perform in vivo stable isotope tracing in leukemia cells in mice, focusing on glutamine metabolism in acute myeloid leukemia (AML) cells. This method allows studying the metabolic profile of leukemia cells in their native bone marrow niche.
    Keywords:  Cancer biology; Cell metabolism; Glutamine; Leukemia; Metabolic tracing; Mouse models
    DOI:  https://doi.org/10.21769/BioProtoc.4171
  2. Cell Chem Biol. 2021 Nov 02. pii: S2451-9456(21)00444-X. [Epub ahead of print]
    ND3 Cys39 in complex I is exposed during mitochondrial respiration.
    Nils Burger, Andrew M James, John F Mulvey, Kurt Hoogewijs, Shujing Ding, Ian M Fearnley, Marta Loureiro-López, Abigail A I Norman, Sabine Arndt, Amin Mottahedin, Olga Sauchanka, Richard C Hartley, Thomas Krieg, Michael P Murphy.
      Mammalian complex I can adopt catalytically active (A-) or deactive (D-) states. A defining feature of the reversible transition between these two defined states is thought to be exposure of the ND3 subunit Cys39 residue in the D-state and its occlusion in the A-state. As the catalytic A/D transition is important in health and disease, we set out to quantify it by measuring Cys39 exposure using isotopic labeling and mass spectrometry, in parallel with complex I NADH/CoQ oxidoreductase activity. To our surprise, we found significant Cys39 exposure during NADH/CoQ oxidoreductase activity. Furthermore, this activity was unaffected if Cys39 alkylation occurred during complex I-linked respiration. In contrast, alkylation of catalytically inactive complex I irreversibly blocked the reactivation of NADH/CoQ oxidoreductase activity by NADH. Thus, Cys39 of ND3 is exposed in complex I during mitochondrial respiration, with significant implications for our understanding of the A/D transition and the mechanism of complex I.
    Keywords:  Cys39; NADH:ubiquinone oxidoreductase; active/deactive transition; complex I; ischemia-reperfusion (IR) injury; mitochondria; redox regulation; reverse electron transport (RET)
    DOI:  https://doi.org/10.1016/j.chembiol.2021.10.010
  3. Nat Commun. 2021 Nov 04. 12(1): 6409
    Constitutive activation of the PI3K-Akt-mTORC1 pathway sustains the m.3243 A > G mtDNA mutation.
    Chih-Yao Chung, Kritarth Singh, Vassilios N Kotiadis, Gabriel E Valdebenito, Jee Hwan Ahn, Emilie Topley, Joycelyn Tan, William D Andrews, Benoit Bilanges, Robert D S Pitceathly, Gyorgy Szabadkai, Mariia Yuneva, Michael R Duchen.
      Mutations of the mitochondrial genome (mtDNA) cause a range of profoundly debilitating clinical conditions for which treatment options are very limited. Most mtDNA diseases show heteroplasmy - tissues express both wild-type and mutant mtDNA. While the level of heteroplasmy broadly correlates with disease severity, the relationships between specific mtDNA mutations, heteroplasmy, disease phenotype and severity are poorly understood. We have carried out extensive bioenergetic, metabolomic and RNAseq studies on heteroplasmic patient-derived cells carrying the most prevalent disease related mtDNA mutation, the m.3243 A > G. These studies reveal that the mutation promotes changes in metabolites which are associated with the upregulation of the PI3K-Akt-mTORC1 axis in patient-derived cells and tissues. Remarkably, pharmacological inhibition of PI3K, Akt, or mTORC1 reduced mtDNA mutant load and partially rescued cellular bioenergetic function. The PI3K-Akt-mTORC1 axis thus represents a potential therapeutic target that may benefit people suffering from the consequences of the m.3243 A > G mutation.
    DOI:  https://doi.org/10.1038/s41467-021-26746-2
  4. Nat Rev Genet. 2021 Nov 02.
    Implications of mitochondrial DNA mutations in human induced pluripotent stem cells.
    Valerio Carelli, Michio Hirano, José Antonio Enríquez, Patrick F Chinnery.
      
    DOI:  https://doi.org/10.1038/s41576-021-00430-z
  5. Cancer Res. 2021 Nov 04. pii: canres.0384.2021. [Epub ahead of print]
    Loss of FBXW7 correlates with increased IDH1 expression in glioma and enhances IDH1-mutant cancer cell sensitivity to radiation.
    Zhuo Yang, Nan Hu, Weiwei Wang, Weihua Hu, Shaolong Zhou, Jianxiang Shi, Minghe Li, Zhou Jing, Chao Chen, Xuyang Zhang, Ruyi Yang, Xudong Fu, Xinjun Wang.
      F-box and WD repeat domain containing 7 (FBXW7) is a substrate receptor of the ubiquitin ligase SKP1-Cullin1-F-box complex and a potent tumor suppressor that prevents unregulated cell growth and tumorigenesis. However, little is known about FBXW7-mediated control of cell metabolism and related functions in cancer therapy. Here, we report that FBXW7 expression inversely correlates with the expression levels of the key metabolic enzyme isocitrate dehydrogenase 1 (IDH1) in glioma patients and public glioma datasets. Deletion of FBXW7 significantly increased both wild type (WT) and mutant IDH1 expression, which was mediated by blocking degradation of sterol regulatory element binding protein 1 (SREBP1). The upregulation of neomorphic mutant IDH1 by FBXW7 deletion stimulated production of the oncometabolite 2-hydroxyglutarate (2-HG) at the expense of increasing pentose phosphate pathway (PPP) activity and NADPH consumption, limiting the buffering ability against radiation-induced oxidative stress. Additionally, FBXW7 knockout and IDH1 mutations induced non-homologous end joining (NHEJ) and homologous recombination (HR) defects, respectively. In vitro and in vivo, loss of FBXW7 dramatically enhanced the efficacy of radiation treatment in IDH1 mutant cancer cells. Taken together, this work identifies FBXW7 deficiency as a potential biomarker representing both DNA repair and metabolic vulnerabilities that sensitizes IDH1 mutant cancers to radiotherapy.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-21-0384
  6. Cell Rep. 2021 Nov 02. pii: S2211-1247(21)01384-X. [Epub ahead of print]37(5): 109911
    Regulatory T cell differentiation is controlled by αKG-induced alterations in mitochondrial metabolism and lipid homeostasis.
    Maria I Matias, Carmen S Yong, Amir Foroushani, Chloe Goldsmith, Cédric Mongellaz, Erdinc Sezgin, Kandice R Levental, Ali Talebi, Julie Perrault, Anais Rivière, Jonas Dehairs, Océane Delos, Justine Bertand-Michel, Jean-Charles Portais, Madeline Wong, Julien C Marie, Ameeta Kelekar, Sandrina Kinet, Valérie S Zimmermann, Ilya Levental, Laurent Yvan-Charvet, Johannes V Swinnen, Stefan A Muljo, Hector Hernandez-Vargas, Saverio Tardito, Naomi Taylor, Valérie Dardalhon.
      Suppressive regulatory T cell (Treg) differentiation is controlled by diverse immunometabolic signaling pathways and intracellular metabolites. Here we show that cell-permeable α-ketoglutarate (αKG) alters the DNA methylation profile of naive CD4 T cells activated under Treg polarizing conditions, markedly attenuating FoxP3+ Treg differentiation and increasing inflammatory cytokines. Adoptive transfer of these T cells into tumor-bearing mice results in enhanced tumor infiltration, decreased FoxP3 expression, and delayed tumor growth. Mechanistically, αKG leads to an energetic state that is reprogrammed toward a mitochondrial metabolism, with increased oxidative phosphorylation and expression of mitochondrial complex enzymes. Furthermore, carbons from ectopic αKG are directly utilized in the generation of fatty acids, associated with lipidome remodeling and increased triacylglyceride stores. Notably, inhibition of either mitochondrial complex II or DGAT2-mediated triacylglyceride synthesis restores Treg differentiation and decreases the αKG-induced inflammatory phenotype. Thus, we identify a crosstalk between αKG, mitochondrial metabolism and triacylglyceride synthesis that controls Treg fate.
    Keywords:  CAR T cells; DNA methylation; T cell differentiation; TCA cycle; Th1; Treg; lipidome; mitochondrial metabolism; triacylglyceride synthesis; α-ketoglutarate
    DOI:  https://doi.org/10.1016/j.celrep.2021.109911
  7. PLoS One. 2021 ;16(11): e0259241
    The glutaminase inhibitor telaglenastat enhances the antitumor activity of signal transduction inhibitors everolimus and cabozantinib in models of renal cell carcinoma.
    Ethan Emberley, Alison Pan, Jason Chen, Rosalyn Dang, Matt Gross, Tony Huang, Weiqun Li, Andrew MacKinnon, Devansh Singh, Natalija Sotirovska, Susanne M Steggerda, Tracy Wang, Francesco Parlati.
      Dysregulated metabolism is a hallmark of cancer that manifests through alterations in bioenergetic and biosynthetic pathways to enable tumor cell proliferation and survival. Tumor cells exhibit high rates of glycolysis, a phenomenon known as the Warburg effect, and an increase in glutamine consumption to support the tricarboxylic acid (TCA) cycle. Renal cell carcinoma (RCC) tumors express high levels of glutaminase (GLS), the enzyme required for the first step in metabolic conversion of glutamine to glutamate and the entry of glutamine into the TCA cycle. We found that RCC cells are highly dependent on glutamine for proliferation, and this dependence strongly correlated with sensitivity to telaglenstat (CB-839), an investigational, first-in-class, selective, orally bioavailable GLS inhibitor. Metabolic profiling of RCC cell lines treated with telaglenastat revealed a decrease in glutamine consumption, which was concomitant with a decrease in the production of glutamate and other glutamine-derived metabolites, consistent with GLS inhibition. Treatment of RCC cells with signal transduction inhibitors everolimus (mTOR inhibitor) or cabozantinib (VEGFR/MET/AXL inhibitor) in combination with telaglenastat resulted in decreased consumption of both glucose and glutamine and synergistic anti-proliferative effects. Treatment of mice bearing Caki-1 RCC xenograft tumors with cabozantinib plus telaglenastat resulted in reduced tumor growth compared to either agent alone. Enhanced anti-tumor activity was also observed with the combination of everolimus plus telaglenastat. Collectively, our results demonstrate potent, synergistic, anti-tumor activity of telaglenastat plus signal transduction inhibitors cabozantinib or everolimus via a mechanism involving dual inhibition of glucose and glutamine consumption.
    DOI:  https://doi.org/10.1371/journal.pone.0259241
  8. Autophagy. 2021 Oct 31. 1-19
    Newcastle disease virus degrades SIRT3 via PINK1-PRKN-dependent mitophagy to reprogram energy metabolism in infected cells.
    Yabin Gong, Ning Tang, Panrao Liu, Yingjie Sun, Shanxin Lu, Weiwei Liu, Lei Tan, Cuiping Song, Xusheng Qiu, Ying Liao, Shengqing Yu, Xiufan Liu, Shu-Hai Lin, Chan Ding.
      Lacking a self-contained metabolism network, viruses have evolved multiple mechanisms for rewiring the metabolic system of their host to hijack the host's metabolic resources for replication. Newcastle disease virus (NDV) is a paramyxovirus, as an oncolytic virus currently being developed for cancer treatment. However, how NDV alters cellular metabolism is still far from fully understood. In this study, we show that NDV infection reprograms cell metabolism by increasing glucose utilization in the glycolytic pathway. Mechanistically, NDV induces mitochondrial damage, elevated mitochondrial reactive oxygen species (mROS) and ETC dysfunction. Infection of cells depletes nucleotide triphosphate levels, resulting in elevated AMP:ATP ratios, AMP-activated protein kinase (AMPK) phosphorylation, and MTOR crosstalk mediated autophagy. In a time-dependent manner, NDV shifts the balance of mitochondrial dynamics from fusion to fission. Subsequently, PINK1-PRKN-dependent mitophagy was activated, forming a ubiquitin chain with MFN2 (mitofusin 2), and molecular receptor SQSTM1/p62 recognized damaged mitochondria. We also found that NDV infection induces NAD+-dependent deacetylase SIRT3 loss via mitophagy to engender HIF1A stabilization, leading to the switch from oxidative phosphorylation (OXPHOS) to aerobic glycolysis. Overall, these studies support a model that NDV modulates host cell metabolism through PINK1-PRKN-dependent mitophagy for degrading SIRT3.Abbreviations: AMPK: AMP-activated protein kinase; CCCP: carbonyl cyanide 3-chlorophenylhydrazone; ECAR: extracellular acidification rate; hpi: hours post infection LC-MS: liquid chromatography-mass spectrometry; mito-QC: mCherry-GFP-FIS1[mt101-152]; MFN2: mitofusin 2; MMP: mitochondrial membrane potential; mROS: mitochondrial reactive oxygen species; MOI: multiplicity of infection; 2-NBDG: 2-(N-(7-nitrobenz-2-oxa-1, 3-diazol-4-yl) amino)-2-deoxyglucose; NDV: newcastle disease virus; OCR: oxygen consumption rate; siRNA: small interfering RNA; SIRT3: sirtuin 3; TCA: tricarboxylic acid; TCID50: tissue culture infective doses.
    Keywords:  Cellular metabolism; SIRT3; glycolysis; mitochondrial fission; mitophagy; newcastle disease virus
    DOI:  https://doi.org/10.1080/15548627.2021.1990515
  9. Signal Transduct Target Ther. 2021 Nov 03. 6(1): 375
    The existence of a nonclassical TCA cycle in the nucleus that wires the metabolic-epigenetic circuitry.
    Xujun Liu, Wenzhe Si, Lin He, Jianguo Yang, Yani Peng, Jie Ren, Xiaoping Liu, Tong Jin, Huajing Yu, Zihan Zhang, Xiao Cheng, Wenting Zhang, Lu Xia, Yunchao Huang, Yue Wang, Shumeng Liu, Lin Shan, Yu Zhang, Xiaohan Yang, Haixia Li, Jing Liang, Luyang Sun, Yongfeng Shang.
      The scope and variety of the metabolic intermediates from the mitochondrial tricarboxylic acid (TCA) cycle that are engaged in epigenetic regulation of the chromatin function in the nucleus raise an outstanding question about how timely and precise supply/consumption of these metabolites is achieved in the nucleus. We report here the identification of a nonclassical TCA cycle in the nucleus (nTCA cycle). We found that all the TCA cycle-associated enzymes including citrate synthase (CS), aconitase 2 (ACO2), isocitrate dehydrogenase 3 (IDH3), oxoglutarate dehydrogenase (OGDH), succinyl-CoA synthetase (SCS), fumarate hydratase (FH), and malate dehydrogenase 2 (MDH2), except for succinate dehydrogenase (SDH), a component of electron transport chain for generating ATP, exist in the nucleus. We showed that these nuclear enzymes catalyze an incomplete TCA cycle similar to that found in cyanobacteria. We propose that the nTCA cycle is implemented mainly to generate/consume metabolic intermediates, not for energy production. We demonstrated that the nTCA cycle is intrinsically linked to chromatin dynamics and transcription regulation. Together, our study uncovers the existence of a nonclassical TCA cycle in the nucleus that links the metabolic pathway to epigenetic regulation.
    DOI:  https://doi.org/10.1038/s41392-021-00774-2
  10. Front Cell Dev Biol. 2021 ;9 757305
    Subcellular Specialization of Mitochondrial Form and Function in Skeletal Muscle Cells.
    T Bradley Willingham, Peter T Ajayi, Brian Glancy.
      Across different cell types and within single cells, mitochondria are heterogeneous in form and function. In skeletal muscle cells, morphologically and functionally distinct subpopulations of mitochondria have been identified, but the mechanisms by which the subcellular specialization of mitochondria contributes to energy homeostasis in working muscles remains unclear. Here, we discuss the current data regarding mitochondrial heterogeneity in skeletal muscle cells and highlight potential new lines of inquiry that have emerged due to advancements in cellular imaging technologies.
    Keywords:  bioenergetics; intermyofibrillar mitochondria; mitochondrial connectivity; mitochondrial respiration; organelle interactions; paranuclear mitochondria; paravascular mitochondria; subsarcolemmal mitochondria
    DOI:  https://doi.org/10.3389/fcell.2021.757305
  11. Front Cell Dev Biol. 2021 ;9 751301
    Extracellular Matrix Signals as Drivers of Mitochondrial Bioenergetics and Metabolic Plasticity of Cancer Cells During Metastasis.
    Félix A Urra, Sebastián Fuentes-Retamal, Charlotte Palominos, Yarcely A Rodríguez-Lucart, Camila López-Torres, Ramiro Araya-Maturana.
      The role of metabolism in tumor growth and chemoresistance has received considerable attention, however, the contribution of mitochondrial bioenergetics in migration, invasion, and metastasis is recently being understood. Migrating cancer cells adapt their energy needs to fluctuating changes in the microenvironment, exhibiting high metabolic plasticity. This occurs due to dynamic changes in the contributions of metabolic pathways to promote localized ATP production in lamellipodia and control signaling mediated by mitochondrial reactive oxygen species. Recent evidence has shown that metabolic shifts toward a mitochondrial metabolism based on the reductive carboxylation, glutaminolysis, and phosphocreatine-creatine kinase pathways promote resistance to anoikis, migration, and invasion in cancer cells. The PGC1a-driven metabolic adaptations with increased electron transport chain activity and superoxide levels are essential for metastasis in several cancer models. Notably, these metabolic changes can be determined by the composition and density of the extracellular matrix (ECM). ECM stiffness, integrins, and small Rho GTPases promote mitochondrial fragmentation, mitochondrial localization in focal adhesion complexes, and metabolic plasticity, supporting enhanced migration and metastasis. Here, we discuss the role of ECM in regulating mitochondrial metabolism during migration and metastasis, highlighting the therapeutic potential of compounds affecting mitochondrial function and selectively block cancer cell migration.
    Keywords:  ECM stiffness; OXPHOS (oxidative phosphorylation); TCA cycle; integrin; metabolic shift; migrastatics; migrating cancer cells
    DOI:  https://doi.org/10.3389/fcell.2021.751301
  12. Sci Signal. 2021 Nov 02. 14(707): eabf3838
    The dominant-negative mitochondrial calcium uniporter subunit MCUb drives macrophage polarization during skeletal muscle regeneration.
    Simona Feno, Fabio Munari, Denis Vecellio Reane, Rosanna Gissi, Dieu-Huong Hoang, Alessandra Castegna, Bénédicte Chazaud, Antonella Viola, Rosario Rizzuto, Anna Raffaello.
      [Figure: see text].
    DOI:  https://doi.org/10.1126/scisignal.abf3838
  13. Nature. 2021 Nov 03.
    A mediator of metabolic signals influences puberty and growth.
    Alejandro Lomniczi.
      
    Keywords:  Genetics; Metabolism; Physiology
    DOI:  https://doi.org/10.1038/d41586-021-02954-0
  14. Cell Metab. 2021 Nov 02. pii: S1550-4131(21)00488-5. [Epub ahead of print]33(11): 2260-2276.e7
    Microbiota-derived acetate enables the metabolic fitness of the brain innate immune system during health and disease.
    Daniel Erny, Nikolaos Dokalis, Charlotte Mezö, Angela Castoldi, Omar Mossad, Ori Staszewski, Maximilian Frosch, Matteo Villa, Vidmante Fuchs, Arun Mayer, Jana Neuber, Janika Sosat, Stefan Tholen, Oliver Schilling, Andreas Vlachos, Thomas Blank, Mercedes Gomez de Agüero, Andrew J Macpherson, Edward J Pearce, Marco Prinz.
      As tissue macrophages of the central nervous system (CNS), microglia constitute the pivotal immune cells of this organ. Microglial features are strongly dependent on environmental cues such as commensal microbiota. Gut bacteria are known to continuously modulate microglia maturation and function by the production of short-chain fatty acids (SCFAs). However, the precise mechanism of this crosstalk is unknown. Here we determined that the immature phenotype of microglia from germ-free (GF) mice is epigenetically imprinted by H3K4me3 and H3K9ac on metabolic genes associated with substantial functional alterations including increased mitochondrial mass and specific respiratory chain dysfunctions. We identified acetate as the essential microbiome-derived SCFA driving microglia maturation and regulating the homeostatic metabolic state, and further showed that it is able to modulate microglial phagocytosis and disease progression during neurodegeneration. These findings indicate that acetate is an essential bacteria-derived molecule driving metabolic pathways and functions of microglia during health and perturbation.
    Keywords:  Alzheimer’s disease; SCFA; acetate; germ-free; metabolism; microbiota; microglia; mitochondria; respiratory chain
    DOI:  https://doi.org/10.1016/j.cmet.2021.10.010
  15. Nat Metab. 2021 Nov 03.
    Insulin and the last gasp of failing adipocytes.
    Sergio Rodriguez-Cuenca, Antonio Vidal-Puig.
      
    DOI:  https://doi.org/10.1038/s42255-021-00492-7
  16. J Clin Invest. 2021 Nov 01. pii: e146187. [Epub ahead of print]131(21):
    Cul4A-DDB1-mediated monoubiquitination of phosphoglycerate dehydrogenase promotes colorectal cancer metastasis via increased S-adenosylmethionine.
    Yajuan Zhang, Hua Yu, Jie Zhang, Hong Gao, Siyao Wang, Shuxian Li, Ping Wei, Ji Liang, Guanzhen Yu, Xiongjun Wang, Xinxiang Li, Dawei Li, Weiwei Yang.
      Although serine metabolism plays a crucial role in the proliferation and survival of tumor cells, how it supports tumor cell migration remains poorly understood. Phosphoglycerate dehydrogenase (PHGDH) catalyzes the oxidation of 3-phosphoglycerate to 3-phosphonooxypyruvate, the first committed step in de novo serine biosynthesis. Here we show that PHGDH was monoubiquitinated by cullin 4A-based E3 ligase complex at lysine 146 in colorectal cancer (CRC) cells, which enhanced PHGDH activity by recruiting a chaperone protein, DnaJ homolog subfamily A member 1, to promote its tetrameric formation, thereby increasing the levels of serine, glycine, and S-adenosylmethionine (SAM). Increased levels of SAM upregulated the expression of cell adhesion genes (laminin subunit gamma 2 and cysteine rich angiogenic inducer 61) by initiating SET domain containing 1A-mediated trimethylation of histone H3K4, thereby promoting tumor cell migration and CRC metastasis. Intriguingly, SAM levels in tumors or blood samples correlated with the metastatic recurrence of patients with CRC. Our finding not only reveals a potentially new role and mechanism of SAM-promoted tumor metastasis but also demonstrates a regulatory mechanism of PHGDH activity by monoubiquitination.
    Keywords:  Amino acid metabolism; Cell migration/adhesion; Colorectal cancer; Metabolism; Oncology
    DOI:  https://doi.org/10.1172/JCI146187
  17. Nat Cell Biol. 2021 Nov 04.
    WAVE complex regulation by force.
    Laura M Machesky, Robert H Insall.
      
    DOI:  https://doi.org/10.1038/s41556-021-00790-y
  18. Cell Metab. 2021 Nov 02. pii: S1550-4131(21)00490-3. [Epub ahead of print]33(11): 2301
    Spatial mapping reveals human adipocyte subpopulations with distinct sensitivities to insulin.
    Jesper Bäckdahl, Lovisa Franzén, Lucas Massier, Qian Li, Jutta Jalkanen, Hui Gao, Alma Andersson, Nayanika Bhalla, Anders Thorell, Mikael Rydén, Patrik L Ståhl, Niklas Mejhert.
      
    DOI:  https://doi.org/10.1016/j.cmet.2021.10.012
  19. Nat Genet. 2021 Nov;53(11): 1577-1585
    The context-specific role of germline pathogenicity in tumorigenesis.
    Preethi Srinivasan, Chaitanya Bandlamudi, Philip Jonsson, Yelena Kemel, Shweta S Chavan, Allison L Richards, Alexander V Penson, Craig M Bielski, Christopher Fong, Aijazuddin Syed, Gowtham Jayakumaran, Meera Prasad, Jason Hwee, Selcuk Onur Sumer, Ino de Bruijn, Xiang Li, JianJiong Gao, Nikolaus Schultz, Roy Cambria, Jesse Galle, Semanti Mukherjee, Joseph Vijai, Karen A Cadoo, Maria I Carlo, Michael F Walsh, Diana Mandelker, Ozge Ceyhan-Birsoy, Jinru Shia, Ahmet Zehir, Marc Ladanyi, David M Hyman, Liying Zhang, Kenneth Offit, Mark E Robson, David B Solit, Zsofia K Stadler, Michael F Berger, Barry S Taylor.
      Human cancers arise from environmental, heritable and somatic factors, but how these mechanisms interact in tumorigenesis is poorly understood. Studying 17,152 prospectively sequenced patients with cancer, we identified pathogenic germline variants in cancer predisposition genes, and assessed their zygosity and co-occurring somatic alterations in the concomitant tumors. Two major routes to tumorigenesis were apparent. In carriers of pathogenic germline variants in high-penetrance genes (5.1% overall), lineage-dependent patterns of biallelic inactivation led to tumors exhibiting mechanism-specific somatic phenotypes and fewer additional somatic oncogenic drivers. Nevertheless, 27% of cancers in these patients, and most tumors in patients with pathogenic germline variants in lower-penetrance genes, lacked particular hallmarks of tumorigenesis associated with the germline allele. The dependence of tumors on pathogenic germline variants is variable and often dictated by both penetrance and lineage, a finding with implications for clinical management.
    DOI:  https://doi.org/10.1038/s41588-021-00949-1
  20. Bull Math Biol. 2021 Oct 31. 83(12): 120
    Microeconomics of Metabolism: The Warburg Effect as Giffen Behaviour.
    Jumpei F Yamagishi, Tetsuhiro S Hatakeyama.
      Metabolic behaviours of proliferating cells are often explained as a consequence of rational optimization of cellular growth rate, whereas microeconomics formulates consumption behaviours as optimization problems. Here, we pushed beyond the analogy to precisely map metabolism onto the theory of consumer choice. We thereby revealed the correspondence between long-standing mysteries in both fields: the Warburg effect, a seemingly wasteful but ubiquitous strategy where cells favour aerobic glycolysis over more energetically efficient oxidative phosphorylation, and Giffen behaviour, the unexpected consumer behaviour where a good is demanded more as its price rises. We identified the minimal, universal requirements for the Warburg effect: a trade-off between oxidative phosphorylation and aerobic glycolysis and complementarity, i.e. impossibility of substitution for different metabolites. Thus, various hypotheses for the Warburg effect are integrated into an identical optimization problem with the same universal structure. Besides, the correspondence between the Warburg effect and Giffen behaviour implies that oxidative phosphorylation is counter-intuitively stimulated when its efficiency is decreased by metabolic perturbations such as drug administration or mitochondrial dysfunction; the concept of Giffen behaviour bridges the Warburg effect and the reverse Warburg effect. This highlights that the application of microeconomics to metabolism can offer new predictions and paradigms for both biology and economics.
    Keywords:  Metabolic systems; Overflow metabolism; Reverse Warburg effect; Theory of consumer choice
    DOI:  https://doi.org/10.1007/s11538-021-00952-x
  21. Int J Nephrol. 2021 ;2021 5497346
    Metabolic Reprogramming in Kidney Diseases: Evidence and Therapeutic Opportunities.
    Yin Li, Zixin Sha, Hui Peng.
      Metabolic reprogramming originally referred to the ability of cancer cells to metabolically adapt to changes in environmental conditions to meet both energy consumption and proliferation requirements. According to recent studies, renal cells are also capable of reprogramming their metabolism after kidney injury, and these cells undergo different kinds of metabolic reprogramming in different kidney diseases. Metabolic reprogramming also plays a role in the progression and prognosis of kidney diseases. Therefore, metabolic reprogramming is not only a prominent feature but also an important contributor to the pathophysiology of kidney diseases. Here, we briefly review kidney diseases and metabolic reprogramming and discuss new ways to treat kidney diseases.
    DOI:  https://doi.org/10.1155/2021/5497346
  22. Cell Death Dis. 2021 Nov 05. 12(11): 1050
    Mitochondrial Drp1 recognizes and induces excessive mPTP opening after hypoxia through BAX-PiC and LRRK2-HK2.
    Chenyang Duan, Lei Kuang, Chen Hong, Xinming Xiang, Jiancang Liu, Qinghui Li, Xiaoyong Peng, Yuanqun Zhou, Hongchen Wang, Liangming Liu, Tao Li.
      Mitochondrial mass imbalance is one of the key causes of cardiovascular dysfunction after hypoxia. The activation of dynamin-related protein 1 (Drp1), as well as its mitochondrial translocation, play important roles in the changes of both mitochondrial morphology and mitochondrial functions after hypoxia. However, in addition to mediating mitochondrial fission, whether Drp1 has other regulatory roles in mitochondrial homeostasis after mitochondrial translocation is unknown. In this study, we performed a series of interaction and colocalization assays and found that, after mitochondrial translocation, Drp1 may promote the excessive opening of the mitochondrial permeability transition pore (mPTP) after hypoxia. Firstly, mitochondrial Drp1 maximumly recognizes mPTP channels by binding Bcl-2-associated X protein (BAX) and a phosphate carrier protein (PiC) in the mPTP. Then, leucine-rich repeat serine/threonine-protein kinase 2 (LRRK2) is recruited, whose kinase activity is inhibited by direct binding with mitochondrial Drp1 after hypoxia. Subsequently, the mPTP-related protein hexokinase 2 (HK2) is inactivated at Thr-473 and dissociates from the mitochondrial membrane, ultimately causing structural disruption and overopening of mPTP, which aggravates mitochondrial and cellular dysfunction after hypoxia. Thus, our study interprets the dual direct regulation of mitochondrial Drp1 on mitochondrial morphology and functions after hypoxia and proposes a new mitochondrial fission-independent mechanism for the role of Drp1 after its translocation in hypoxic injury.
    DOI:  https://doi.org/10.1038/s41419-021-04343-x
  23. Cell Rep. 2021 Nov 02. pii: S2211-1247(21)01434-0. [Epub ahead of print]37(5): 109957
    Targeting glioblastoma signaling and metabolism with a re-purposed brain-penetrant drug.
    Junfeng Bi, Atif Khan, Jun Tang, Aaron M Armando, Sihan Wu, Wei Zhang, Ryan C Gimple, Alex Reed, Hui Jing, Tomoyuki Koga, Ivy Tsz-Lo Wong, Yuchao Gu, Shunichiro Miki, Huijun Yang, Briana Prager, Ellis J Curtis, Derek A Wainwright, Frank B Furnari, Jeremy N Rich, Timothy F Cloughesy, Harley I Kornblum, Oswald Quehenberger, Andrey Rzhetsky, Benjamin F Cravatt, Paul S Mischel.
      The highly lethal brain cancer glioblastoma (GBM) poses a daunting challenge because the blood-brain barrier renders potentially druggable amplified or mutated oncoproteins relatively inaccessible. Here, we identify sphingomyelin phosphodiesterase 1 (SMPD1), an enzyme that regulates the conversion of sphingomyelin to ceramide, as an actionable drug target in GBM. We show that the highly brain-penetrant antidepressant fluoxetine potently inhibits SMPD1 activity, killing GBMs, through inhibition of epidermal growth factor receptor (EGFR) signaling and via activation of lysosomal stress. Combining fluoxetine with temozolomide, a standard of care for GBM, causes massive increases in GBM cell death and complete tumor regression in mice. Incorporation of real-world evidence from electronic medical records from insurance databases reveals significantly increased survival in GBM patients treated with fluoxetine, which was not seen in patients treated with other selective serotonin reuptake inhibitor (SSRI) antidepressants. These results nominate the repurposing of fluoxetine as a potentially safe and promising therapy for patients with GBM and suggest prospective randomized clinical trials.
    Keywords:  EGFR signaling; Membrane lipids; SMPD1; combination therapy; electronic medical records; fluoxetine; glioblastoma; real-world evidence; sphingolipid metabolism
    DOI:  https://doi.org/10.1016/j.celrep.2021.109957
  24. Nat Genet. 2021 Nov;53(11): 1597-1605
    Synonymous mutations reveal genome-wide levels of positive selection in healthy tissues.
    Gladys Y P Poon, Caroline J Watson, Daniel S Fisher, Jamie R Blundell.
      Genetic alterations under positive selection in healthy tissues have implications for cancer risk. However, total levels of positive selection across the genome remain unknown. Passenger mutations are influenced by all driver mutations, regardless of type or location in the genome. Therefore, the total number of passengers can be used to estimate the total number of drivers-including unidentified drivers outside of cancer genes that are traditionally missed. Here we analyze the variant allele frequency spectrum of synonymous mutations from healthy blood and esophagus to quantify levels of missing positive selection. In blood, we find that only 30% of passengers can be explained by single-nucleotide variants in driver genes, suggesting high levels of positive selection for mutations elsewhere in the genome. In contrast, more than half of all passengers in the esophagus can be explained by just the two driver genes NOTCH1 and TP53, suggesting little positive selection elsewhere.
    DOI:  https://doi.org/10.1038/s41588-021-00957-1
  25. Elife. 2021 Nov 02. pii: e65109. [Epub ahead of print]10
    Mitochondrial respiration contributes to the interferon gamma response in antigen presenting cells.
    Michael C Kiritsy, Katelyn McCann, Daniel Mott, Stephen M Holland, Samuel M Behar, Christopher M Sassetti, Andrew J Olive.
      The immunological synapse allows antigen presenting cells (APC) to convey a wide array of functionally distinct signals to T cells, which ultimately shape the immune response. The relative effect of stimulatory and inhibitory signals is influenced by the activation state of the APC, which is determined by an interplay between signal transduction and metabolic pathways. While pathways downstream of toll-like receptors rely on glycolytic metabolism for the proper expression of inflammatory mediators, little is known about the metabolic dependencies of other critical signals such as interferon gamma (IFNg). Using CRISPR-Cas9, we performed a series of genome-wide knockout screens in murine macrophages to identify the regulators of IFNg-inducible T cell stimulatory or inhibitory proteins MHCII, CD40, and PD-L1. Our multi-screen approach enabled us to identify novel pathways that control these functionally distinct markers. Further integration of these screening data implicated complex I of the mitochondrial respiratory chain in the expression of all three markers, and by extension the IFNg signaling pathway. We report that the IFNg response requires mitochondrial respiration, and APCs are unable to activate T cells upon genetic or chemical inhibition of complex I. These findings suggest a dichotomous metabolic dependency between IFNg and toll-like receptor signaling, implicating mitochondrial function as a fulcrum of innate immunity.
    Keywords:  human; immunology; inflammation; mouse
    DOI:  https://doi.org/10.7554/eLife.65109
  26. Cell Death Dis. 2021 Nov 02. 12(11): 1044
    A gene toolbox for monitoring autophagy transcription.
    Matteo Bordi, Rossella De Cegli, Beatrice Testa, Ralph A Nixon, Andrea Ballabio, Francesco Cecconi.
      Autophagy is a highly dynamic and multi-step process, regulated by many functional protein units. Here, we have built up a comprehensive and up-to-date annotated gene list for the autophagy pathway, by combining previously published gene lists and the most recent publications in the field. We identified 604 genes and created main categories: MTOR and upstream pathways, autophagy core, autophagy transcription factors, mitophagy, docking and fusion, lysosome and lysosome-related genes. We then classified such genes in sub-groups, based on their functions or on their sub-cellular localization. Moreover, we have curated two shorter sub-lists to predict the extent of autophagy activation and/or lysosomal biogenesis; we next validated the "induction list" by Real-time PCR in cell lines during fasting or MTOR inhibition, identifying ATG14, ATG7, NBR1, ULK1, ULK2, and WDR45, as minimal transcriptional targets. We also demonstrated that our list of autophagy genes can be particularly useful during an effective RNA-sequencing analysis. Thus, we propose our lists as a useful toolbox for performing an informative and functionally-prognostic gene scan of autophagy steps.
    DOI:  https://doi.org/10.1038/s41419-021-04121-9
  27. Nat Commun. 2021 Nov 02. 12(1): 6315
    The transcriptional corepressor CtBP2 serves as a metabolite sensor orchestrating hepatic glucose and lipid homeostasis.
    Motohiro Sekiya, Kenta Kainoh, Takehito Sugasawa, Ryunosuke Yoshino, Takatsugu Hirokawa, Hiroaki Tokiwa, Shogo Nakano, Satoru Nagatoishi, Kouhei Tsumoto, Yoshinori Takeuchi, Takafumi Miyamoto, Takashi Matsuzaka, Hitoshi Shimano.
      Biological systems to sense and respond to metabolic perturbations are critical for the maintenance of cellular homeostasis. Here we describe a hepatic system in this context orchestrated by the transcriptional corepressor C-terminal binding protein 2 (CtBP2) that harbors metabolite-sensing capabilities. The repressor activity of CtBP2 is reciprocally regulated by NADH and acyl-CoAs. CtBP2 represses Forkhead box O1 (FoxO1)-mediated hepatic gluconeogenesis directly as well as Sterol Regulatory Element-Binding Protein 1 (SREBP1)-mediated lipogenesis indirectly. The activity of CtBP2 is markedly defective in obese liver reflecting the metabolic perturbations. Thus, liver-specific CtBP2 deletion promotes hepatic gluconeogenesis and accelerates the progression of steatohepatitis. Conversely, activation of CtBP2 ameliorates diabetes and hepatic steatosis in obesity. The structure-function relationships revealed in this study identify a critical structural domain called Rossmann fold, a metabolite-sensing pocket, that is susceptible to metabolic liabilities and potentially targetable for developing therapeutic approaches.
    DOI:  https://doi.org/10.1038/s41467-021-26638-5
  28. Cell. 2021 Nov 03. pii: S0092-8674(21)01230-7. [Epub ahead of print]
    RNA promotes the formation of spatial compartments in the nucleus.
    Sofia A Quinodoz, Joanna W Jachowicz, Prashant Bhat, Noah Ollikainen, Abhik K Banerjee, Isabel N Goronzy, Mario R Blanco, Peter Chovanec, Amy Chow, Yolanda Markaki, Jasmine Thai, Kathrin Plath, Mitchell Guttman.
      RNA, DNA, and protein molecules are highly organized within three-dimensional (3D) structures in the nucleus. Although RNA has been proposed to play a role in nuclear organization, exploring this has been challenging because existing methods cannot measure higher-order RNA and DNA contacts within 3D structures. To address this, we developed RNA & DNA SPRITE (RD-SPRITE) to comprehensively map the spatial organization of RNA and DNA. These maps reveal higher-order RNA-chromatin structures associated with three major classes of nuclear function: RNA processing, heterochromatin assembly, and gene regulation. These data demonstrate that hundreds of ncRNAs form high-concentration territories throughout the nucleus, that specific RNAs are required to recruit various regulators into these territories, and that these RNAs can shape long-range DNA contacts, heterochromatin assembly, and gene expression. These results demonstrate a mechanism where RNAs form high-concentration territories, bind to diffusible regulators, and guide them into compartments to regulate essential nuclear functions.
    Keywords:  RNA processing; cajal bodies; chromocenters; histone locus bodies; lncRNAs; ncRNAs; nuclear bodies; nuclear structure
    DOI:  https://doi.org/10.1016/j.cell.2021.10.014
  29. Sci Adv. 2021 Nov 05. 7(45): eabg1964
    The metabolic adaptation evoked by arginine enhances the effect of radiation in brain metastases.
    Rossella Marullo, Monica Castro, Shira Yomtoubian, M Nieves Calvo-Vidal, Maria Victoria Revuelta, Jan Krumsiek, Andrew Cho, Pablo Cresta Morgado, ShaoNing Yang, Vanina Medina, Berta M Roth, Marcelo Bonomi, Kayvan R Keshari, Vivek Mittal, Alfredo Navigante, Leandro Cerchietti.
      [Figure: see text].
    DOI:  https://doi.org/10.1126/sciadv.abg1964
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