bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2022–09–11
forty-six papers selected by
Christian Frezza, Universität zu Köln
  1. A brown fat-selective mechanism of mitochondrial calcium import?
  2. Methionine metabolism controls the B cell EBV epigenome and viral latency.
  3. Metabolic flux between organs measured by arteriovenous metabolite gradients.
  4. PRDM16 stability and metabolically healthy adipose tissue.
  5. Bidirectional lysosome transport: a balancing act between ARL8 effectors.
  6. Targeting Myocardial Mitochondria-STING-Polyamine Axis Prevents Cardiac Hypertrophy in Chronic Kidney Disease.
  7. Branched-chain amino acids in cardiovascular disease.
  8. The microbiome-derived metabolite TMAO drives immune activation and boosts responses to immune checkpoint blockade in pancreatic cancer.
  9. cAMP/PKA Signaling Modulates Mitochondrial Supercomplex Organization.
  10. STAT6 in mitochondrial outer membrane impairs mitochondrial fusion by inhibiting MFN2 dimerization.
  11. Alternative pathways driven by STING: From innate immunity to lipid metabolism.
  12. Hyperactivation of mTOR and AKT in a cardiac hypertrophy animal model of Friedreich ataxia.
  13. O-GlcNAcylation enhances CPS1 catalytic efficiency for ammonia and promotes ureagenesis.
  14. Role of released mitochondrial DNA in acute lung injury.
  15. Dietary lipids inhibit mitochondria transfer to macrophages to divert adipocyte-derived mitochondria into the blood.
  16. Walking the high wire: How neurons maintain stability in the crossline of neurodegeneration.
  17. Small leucine zipper protein functions as a modulator for metabolic reprogramming of colorectal cancer cells by inducing nutrient stress-mediated autophagy.
  18. Connexins and Glucose Metabolism in Cancer.
  19. Circadian cardiac NAD+ metabolism, from transcriptional regulation to healthy aging.
  20. Quantification of cytosolic DNA species by immunofluorescence microscopy and automated image analysis.
  21. Spatially resolved characterization of tissue metabolic compartments in fasted and high-fat diet livers.
  22. Non-conventional mitochondrial permeability transition: Its regulation by mitochondrial dynamics.
  23. Diet and Exercise in Cancer Metabolism.
  24. DarT-mediated mtDNA damage induces dynamic reorganization and selective segregation of mitochondria.
  25. Metabolite Exchange between Mammalian Organs Quantified in Pigs.
  26. Methionine restriction forces Epstein-Barr virus out of latency.
  27. Mitochondrial respiratory complexes: Significance in human mitochondrial disorders and cancers.
  28. Ku proteins promote DNA binding and condensation of cyclic GMP-AMP synthase.
  29. Mitochondrial protein synthesis and the bioenergetic cost of neurodevelopment.
  30. An exercise-induced metabolic shield in distant organs blocks cancer progression and metastatic dissemination.
  31. In situ mass spectrometry imaging reveals heterogeneous glycogen stores in human normal and cancerous tissues.
  32. Increased glucose metabolism in TAMs fuels O-GlcNAcylation of lysosomal Cathepsin B to promote cancer metastasis and chemoresistance.
  33. The lysosomal proteome of senescent cells contributes to the senescence secretome.
  34. Spermidine-mediated hypusination of translation factor EIF5A improves mitochondrial fatty acid oxidation and prevents non-alcoholic steatohepatitis progression.
  35. A phosphoinositide signalling pathway mediates rapid lysosomal repair.
  36. Activation of mitochondrial TRAP1 stimulates mitochondria-lysosome crosstalk and correction of lysosomal dysfunction.
  37. Metabolic and Cellular Compartments of Acetyl-CoA in the Healthy and Diseased Brain.
  38. The nucleolus is the site for inflammatory RNA decay during infection.
  39. Multimodal single cell sequencing implicates chromatin accessibility and genetic background in diabetic kidney disease progression.
  40. Lysosome Inhibition Reduces Basal and Nutrient-Induced Fat Accumulation in Caenorhabditis elegans.
  41. The mutational signatures of formalin fixation on the human genome.
  42. Circadian Control of Glial Cell Homeodynamics.
  43. Life through the lens of metabolism.
  44. Lysosomal enzyme trafficking factor LYSET enables nutritional usage of extracellular proteins.
  45. Pronounced sequence specificity of the TET enzyme catalytic domain guides its cellular function.
  46. Genomic Landscapes and Hallmarks of Mutant RAS in Human Cancers.
  1. Cell Metab. 2022 Sep 06. pii: S1550-4131(22)00354-0. [Epub ahead of print]34(9): 1231-1233
    A brown fat-selective mechanism of mitochondrial calcium import?
    Janane F Rahbani, Lawrence Kazak.
      In this issue of Cell Metabolism, Xue et al. propose that the mitochondrial calcium uniporter (MCU) binds uncoupling protein 1 (UCP1) via the MCU regulator (EMRE) to form a protein complex that the authors term the "thermoporter." Through gain- and loss-of-function experiments, the authors infer that the thermoporter promotes calcium influx into the mitochondrial matrix to enhance NADH production, which supports thermogenesis in brown adipose tissue (BAT).
    DOI:  https://doi.org/10.1016/j.cmet.2022.08.011
  2. Cell Metab. 2022 Sep 06. pii: S1550-4131(22)00351-5. [Epub ahead of print]34(9): 1280-1297.e9
    Methionine metabolism controls the B cell EBV epigenome and viral latency.
    Rui Guo, Jin Hua Liang, Yuchen Zhang, Michael Lutchenkov, Zhixuan Li, Yin Wang, Vicenta Trujillo-Alonso, Rishi Puri, Lisa Giulino-Roth, Benjamin E Gewurz.
      Epstein-Barr virus (EBV) subverts host epigenetic pathways to switch between viral latency programs, colonize the B cell compartment, and reactivate. Within memory B cells, the reservoir for lifelong infection, EBV genomic DNA and histone methylation marks restrict gene expression. But this epigenetic strategy also enables EBV-infected tumors, including Burkitt lymphomas, to evade immune detection. Little is known about host cell metabolic pathways that support EBV epigenome landscapes. We therefore used amino acid restriction, metabolomic, and CRISPR approaches to identify that an abundant methionine supply and interconnecting methionine and folate cycles maintain Burkitt EBV gene silencing. Methionine restriction, or methionine cycle perturbation, hypomethylated EBV genomes and de-repressed latent membrane protein and lytic gene expression. Methionine metabolism also shaped EBV latency gene regulation required for B cell immortalization. Dietary methionine restriction altered murine Burkitt xenograft metabolomes and de-repressed EBV immunogens in vivo. These results highlight epigenetic/immunometabolism crosstalk supporting the EBV B cell life cycle and suggest therapeutic approaches.
    Keywords:  dietary amino acid restriction; folate metabolism; gamma-herpesvirus; immunometabolism; lytic reactivation; methionine cycle; methionine metabolism; one-carbon metabolism; tumor virus; viral latency
    DOI:  https://doi.org/10.1016/j.cmet.2022.08.008
  3. Exp Mol Med. 2022 Sep 08.
    Metabolic flux between organs measured by arteriovenous metabolite gradients.
    Hosung Bae, Katie Lam, Cholsoon Jang.
      Mammalian organs convert dietary nutrients into circulating metabolites and share them to maintain whole-body metabolic homeostasis. While the concentrations of circulating metabolites have been frequently measured in a variety of pathophysiological conditions, the exchange flux of circulating metabolites between organs is not easily measurable due to technical difficulties. Isotope tracing is useful for measuring such fluxes for a metabolite of interest, but the shuffling of isotopic atoms between metabolites requires mathematical modeling. Arteriovenous metabolite gradient measurements can complement isotope tracing to infer organ-specific net fluxes of many metabolites simultaneously. Here, we review the historical development of arteriovenous measurements and discuss their advantages and limitations with key example studies that have revealed metabolite exchange flux between organs in diverse pathophysiological contexts.
    DOI:  https://doi.org/10.1038/s12276-022-00803-2
  4. Nat Metab. 2022 Sep 05.
    PRDM16 stability and metabolically healthy adipose tissue.
    Carla Horvath, Camilla Scheele.
      
    DOI:  https://doi.org/10.1038/s42255-022-00639-0
  5. Nat Commun. 2022 Sep 07. 13(1): 5261
    Bidirectional lysosome transport: a balancing act between ARL8 effectors.
    Agnieszka A Kendrick, Jenna R Christensen.
      
    DOI:  https://doi.org/10.1038/s41467-022-32965-y
  6. JACC Basic Transl Sci. 2022 Aug;7(8): 820-840
    Targeting Myocardial Mitochondria-STING-Polyamine Axis Prevents Cardiac Hypertrophy in Chronic Kidney Disease.
    Wenhao Han, Changhong Du, Yingguo Zhu, Li Ran, Yue Wang, Jiachuan Xiong, Yiding Wu, Qigang Lan, Yaqin Wang, Liting Wang, Junping Wang, Ke Yang, Jinghong Zhao.
      Chronic kidney disease (CKD) is well recognized as a distinct contributor to cardiac hypertrophy, while the underlying mechanism remains incompletely understood. Here, the authors show that myocardial mitochondrial oxidative damage is early and prominent in CKD and distinctively stimulates the STING-NFκB pathway by releasing mitochondrial DNA to drive cardiac hypertrophy. Furthermore, the authors reveal that ornithine decarboxylase (ODC1)-putrescine metabolic flux is transactivated by NFκB and is required for the STING-NFκB pathway to drive cardiac hypertrophy. Finally, genetic or pharmacologic inhibition of the myocardial mitochondria-STING-NFκB-ODC1 axis significantly prevents CKD-associated cardiac hypertrophy. Therefore, targeting the myocardial mitochoandria-STING-NFκB-ODC1 axis is a promising therapeutic strategy for cardiac hypertrophy in patients with CKD.
    Keywords:  ATP, adenosine triphosphate; CKD, chronic kidney disease; LV, left ventricular; MOMP, mitochondrial outer membrane permeabilization; MPTP, mitochondrial permeability transition pore; NRCM, primary neonatal rat cardiomyocyte; ODC1, ornithine decarboxylase; PUT, putrescine; ROS, reactive oxygen species; VDAC1, voltage-dependent anion channel 1; cGAS-STING pathway; cardiac hypertrophy; chronic kidney disease; mitochondria; mtDNA, mitochondrial DNA; polyamine metabolism; siRNA, small interfering RNA
    DOI:  https://doi.org/10.1016/j.jacbts.2022.03.006
  7. Nat Rev Cardiol. 2022 Sep 05.
    Branched-chain amino acids in cardiovascular disease.
    Robert W McGarrah, Phillip J White.
      Research conducted in the past 15 years has yielded crucial insights that are reshaping our understanding of the systems physiology of branched-chain amino acid (BCAA) metabolism and the molecular mechanisms underlying the close relationship between BCAA homeostasis and cardiovascular health. The rapidly evolving literature paints a complex picture, in which numerous tissue-specific and disease-specific modes of BCAA regulation initiate a diverse set of molecular mechanisms that connect changes in BCAA homeostasis to the pathogenesis of cardiovascular diseases, including myocardial infarction, ischaemia-reperfusion injury, atherosclerosis, hypertension and heart failure. In this Review, we outline the current understanding of the major factors regulating BCAA abundance and metabolic fate, highlight molecular mechanisms connecting impaired BCAA homeostasis to cardiovascular disease, discuss the epidemiological evidence connecting BCAAs with various cardiovascular disease states and identify current knowledge gaps requiring further investigation.
    DOI:  https://doi.org/10.1038/s41569-022-00760-3
  8. Sci Immunol. 2022 Sep 09. 7(75): eabn0704
    The microbiome-derived metabolite TMAO drives immune activation and boosts responses to immune checkpoint blockade in pancreatic cancer.
    Gauri Mirji, Alison Worth, Sajad Ahmad Bhat, Mohamed El Sayed, Toshitha Kannan, Aaron R Goldman, Hsin-Yao Tang, Qin Liu, Noam Auslander, Chi V Dang, Mohamed Abdel-Mohsen, Andrew Kossenkov, Ben Z Stanger, Rahul S Shinde.
      The composition of the gut microbiome can control innate and adaptive immunity and has emerged as a key regulator of tumor growth, especially in the context of immune checkpoint blockade (ICB) therapy. However, the underlying mechanisms for how the microbiome affects tumor growth remain unclear. Pancreatic ductal adenocarcinoma (PDAC) tends to be refractory to therapy, including ICB. Using a nontargeted, liquid chromatography-tandem mass spectrometry-based metabolomic screen, we identified the gut microbe-derived metabolite trimethylamine N-oxide (TMAO), which enhanced antitumor immunity to PDAC. Delivery of TMAO intraperitoneally or via a dietary choline supplement to orthotopic PDAC-bearing mice reduced tumor growth, associated with an immunostimulatory tumor-associated macrophage (TAM) phenotype, and activated effector T cell response in the tumor microenvironment. Mechanistically, TMAO potentiated the type I interferon (IFN) pathway and conferred antitumor effects in a type I IFN-dependent manner. Delivering TMAO-primed macrophages intravenously produced similar antitumor effects. Combining TMAO with ICB (anti-PD1 and/or anti-Tim3) in a mouse model of PDAC significantly reduced tumor burden and improved survival beyond TMAO or ICB alone. Last, the levels of bacteria containing CutC (an enzyme that generates trimethylamine, the TMAO precursor) correlated with long-term survival in patients with PDAC and improved response to anti-PD1 in patients with melanoma. Together, our study identifies the gut microbial metabolite TMAO as a driver of antitumor immunity and lays the groundwork for potential therapeutic strategies targeting TMAO.
    DOI:  https://doi.org/10.1126/sciimmunol.abn0704
  9. Int J Mol Sci. 2022 Aug 25. pii: 9655. [Epub ahead of print]23(17):
    cAMP/PKA Signaling Modulates Mitochondrial Supercomplex Organization.
    Anna Signorile, Consiglia Pacelli, Luigi Leonardo Palese, Arcangela Santeramo, Emilio Roca, Tiziana Cocco, Domenico De Rasmo.
      The oxidative phosphorylation (OXPHOS) system couples the transfer of electrons to oxygen with pumping of protons across the inner mitochondrial membrane, ensuring the ATP production. Evidence suggests that respiratory chain complexes may also assemble into supramolecular structures, called supercomplexes (SCs). The SCs appear to increase the efficiency/capacity of OXPHOS and reduce the reactive oxygen species (ROS) production, especially that which is produced by complex I. Studies suggest a mutual regulation between complex I and SCs, while SCs organization is important for complex I assembly/stability, complex I is involved in the supercomplex formation. Complex I is a pacemaker of the OXPHOS system, and it has been shown that the PKA-dependent phosphorylation of some of its subunits increases the activity of the complex, reducing the ROS production. In this work, using in ex vivo and in vitro models, we show that the activation of cAMP/PKA cascade resulted in an increase in SCs formation associated with an enhanced capacity of electron flux and ATP production rate. This is also associated with the phosphorylation of the NDUFS4 subunit of complex I. This aspect highlights the key role of complex I in cellular energy production.
    Keywords:  NDUFS4; cAMP/PKA; complex I; mitochondria; mitochondrial supercomplexes
    DOI:  https://doi.org/10.3390/ijms23179655
  10. iScience. 2022 Sep 16. 25(9): 104923
    STAT6 in mitochondrial outer membrane impairs mitochondrial fusion by inhibiting MFN2 dimerization.
    Hyunmi Kim, Soo Jung Park, Ilo Jou.
      Although it is reported that mitochondria-localized nuclear transcription factors (TFs) regulate mitochondrial processes such as apoptosis and mitochondrial transcription/respiration, the functions and mechanisms of mitochondrial dynamics regulated by mitochondria-localized nuclear TFs are yet to be fully characterized. Here, we identify STAT6 as a mitochondrial protein that is localized in the outer membrane of mitochondria (OMM). STAT6 in OMM inhibits mitochondrial fusion by blocking MFN2 dimerization. This implies that STAT6 has a critical role in mitochondrial dynamics. Moreover, mitochondrial accumulation of STAT6 in response to hypoxic conditions reveals that STAT6 is a regulator of mitochondrial processes including fusion/fission mechanisms.
    Keywords:  Biological sciences; Molecular biology; Molecular interaction; Natural sciences
    DOI:  https://doi.org/10.1016/j.isci.2022.104923
  11. Cytokine Growth Factor Rev. 2022 Sep 01. pii: S1359-6101(22)00071-5. [Epub ahead of print]
    Alternative pathways driven by STING: From innate immunity to lipid metabolism.
    Isabelle K Vila, Soumyabrata Guha, Joanna Kalucka, David Olagnier, Nadine Laguette.
      The Stimulator of Interferon Genes (STING) is a major adaptor protein that is central to the initiation of type I interferon responses and proinflammatory signalling. STING-dependent signalling is triggered by the presence of cytosolic nucleic acids that are generated following pathogen infection or cellular stress. Beyond this central role in controlling immune responses through the production of cytokines and chemokines, recent reports have uncovered inflammation-independent STING functions. Amongst these, a rapidly growing body of evidence demonstrates a key role of STING in controlling metabolic pathways at several levels. Since immunity and metabolic homeostasis are tightly interconnected, these findings deepen our understanding of the involvement of STING in human pathologies. Here, we discuss these findings and reflect on their impact on our current understanding of how nucleic acid immunity controls homeostasis and promotes pathological outcomes.
    Keywords:  Inflammation; Innate immunity; Lipid metabolism; Metabolism; STING
    DOI:  https://doi.org/10.1016/j.cytogfr.2022.08.006
  12. Heliyon. 2022 Aug;8(8): e10371
    Hyperactivation of mTOR and AKT in a cardiac hypertrophy animal model of Friedreich ataxia.
    Wing-Hang Tong, Hayden Ollivierre, Audrey Noguchi, Manik C Ghosh, Danielle A Springer, Tracey A Rouault.
      Cardiomyopathy is a primary cause of death in Friedreich ataxia (FRDA) patients with defective iron-sulfur cluster (ISC) biogenesis due to loss of functional frataxin and in rare patients with functional loss of other ISC biogenesis factors. The mechanistic target of rapamycin (mTOR) and AKT signaling cascades that coordinate eukaryotic cell growth and metabolism with environmental inputs, including nutrients and growth factors, are crucial regulators of cardiovascular growth and homeostasis. We observed increased phosphorylation of AKT and dysregulation of multiple downstream effectors of mTORC1, including S6K1, S6, ULK1 and 4EBP1, in a cardiac/skeletal muscle specific FRDA conditional knockout (cKO) mouse model and in human cell lines depleted of ISC biogenesis factors. Knockdown of several mitochondrial metabolic proteins that are downstream targets of ISC biogenesis, including lipoyl synthase and subunit B of succinate dehydrogenase, also resulted in activation of mTOR and AKT signaling, suggesting that mTOR and AKT hyperactivations are part of the metabolic stress response to ISC deficiencies. Administration of rapamycin, a specific inhibitor of mTOR signaling, enhanced the survival of the Fxn cKO mice, providing proof of concept for the potential of mTOR inhibition to ameliorate cardiac disease in patients with defective ISC biogenesis. However, AKT phosphorylation remained high in rapamycin-treated Fxn cKO hearts, suggesting that parallel mTOR and AKT inhibition might be necessary to further improve the lifespan and healthspan of ISC deficient individuals.
    Keywords:  AKT; Cardiac hypertrophy; FXN; Frataxin; Friedreich ataxia; ISCU; Iron-sulfur cluster biogenesis; Metabolic stress; mTOR
    DOI:  https://doi.org/10.1016/j.heliyon.2022.e10371
  13. Nat Commun. 2022 Sep 05. 13(1): 5212
    O-GlcNAcylation enhances CPS1 catalytic efficiency for ammonia and promotes ureagenesis.
    Leandro R Soria, Georgios Makris, Alfonso M D'Alessio, Angela De Angelis, Iolanda Boffa, Veronica M Pravata, Véronique Rüfenacht, Sergio Attanasio, Edoardo Nusco, Paola Arena, Andrew T Ferenbach, Debora Paris, Paola Cuomo, Andrea Motta, Matthew Nitzahn, Gerald S Lipshutz, Ainhoa Martínez-Pizarro, Eva Richard, Lourdes R Desviat, Johannes Häberle, Daan M F van Aalten, Nicola Brunetti-Pierri.
      Life-threatening hyperammonemia occurs in both inherited and acquired liver diseases affecting ureagenesis, the main pathway for detoxification of neurotoxic ammonia in mammals. Protein O-GlcNAcylation is a reversible and nutrient-sensitive post-translational modification using as substrate UDP-GlcNAc, the end-product of hexosamine biosynthesis pathway. Here we show that increased liver UDP-GlcNAc during hyperammonemia increases protein O-GlcNAcylation and enhances ureagenesis. Mechanistically, O-GlcNAcylation on specific threonine residues increased the catalytic efficiency for ammonia of carbamoyl phosphate synthetase 1 (CPS1), the rate-limiting enzyme in ureagenesis. Pharmacological inhibition of O-GlcNAcase, the enzyme removing O-GlcNAc from proteins, resulted in clinically relevant reductions of systemic ammonia in both genetic (hypomorphic mouse model of propionic acidemia) and acquired (thioacetamide-induced acute liver failure) mouse models of liver diseases. In conclusion, by fine-tuned control of ammonia entry into ureagenesis, hepatic O-GlcNAcylation of CPS1 increases ammonia detoxification and is a novel target for therapy of hyperammonemia in both genetic and acquired diseases.
    DOI:  https://doi.org/10.1038/s41467-022-32904-x
  14. Front Immunol. 2022 ;13 973089
    Role of released mitochondrial DNA in acute lung injury.
    Gangyu Long, Rui Gong, Qian Wang, Dingyu Zhang, Chaolin Huang.
      Acute lung injury(ALI)/acute respiratory distress syndrome(ARDS) is a form of acute-onset hypoxemic respiratory failure characterised by an acute, diffuse, inflammatory lung injury, and increased alveolar-capillary permeability, which is caused by a variety of pulmonary or nonpulmonary insults. Recently, aberrant mitochondria and mitochondrial DNA(mtDNA) level are associated with the development of ALI/ARDS, and plasma mtDNA level shows the potential to be a promising biomarker for clinical diagnosis and evaluation of lung injury severity. In mechanism, the mtDNA and its oxidised form, which are released from impaired mitochondria, play a crucial role in the inflammatory response and histopathological changes in the lung. In this review, we discuss mitochondrial outer membrane permeabilisation (MOMP), mitochondrial permeability transition pore(mPTP), extracellular vesicles (EVs), extracellular traps (ETs), and passive release as the principal mechanisms for the release of mitochondrial DNA into the cytoplasm and extracellular compartments respectively. Further, we explain how the released mtDNA and its oxidised form can induce inflammatory cytokine production and aggravate lung injury through the Toll-like receptor 9(TLR9) signalling, cytosolic cGAS-stimulator of interferon genes (STING) signalling (cGAS-STING) pathway, and inflammasomes activation. Additionally, we propose targeting mtDNA-mediated inflammatory pathways as a novel therapeutic approach for treating ALI/ARDS.
    Keywords:  ALI; ARDS; STING; TLR9; inflammasomes activation; mtDNA
    DOI:  https://doi.org/10.3389/fimmu.2022.973089
  15. Cell Metab. 2022 Aug 30. pii: S1550-4131(22)00353-9. [Epub ahead of print]
    Dietary lipids inhibit mitochondria transfer to macrophages to divert adipocyte-derived mitochondria into the blood.
    Nicholas Borcherding, Wentong Jia, Rocky Giwa, Rachael L Field, John R Moley, Benjamin J Kopecky, Mandy M Chan, Bin Q Yang, Jessica M Sabio, Emma C Walker, Omar Osorio, Andrea L Bredemeyer, Terri Pietka, Jennifer Alexander-Brett, Sharon Celeste Morley, Maxim N Artyomov, Nada A Abumrad, Joel Schilling, Kory Lavine, Clair Crewe, Jonathan R Brestoff.
      Adipocytes transfer mitochondria to macrophages in white and brown adipose tissues to maintain metabolic homeostasis. In obesity, adipocyte-to-macrophage mitochondria transfer is impaired, and instead, adipocytes release mitochondria into the blood to induce a protective antioxidant response in the heart. We found that adipocyte-to-macrophage mitochondria transfer in white adipose tissue is inhibited in murine obesity elicited by a lard-based high-fat diet, but not a hydrogenated-coconut-oil-based high-fat diet, aging, or a corn-starch diet. The long-chain fatty acids enriched in lard suppress mitochondria capture by macrophages, diverting adipocyte-derived mitochondria into the blood for delivery to other organs, such as the heart. The depletion of macrophages rapidly increased the number of adipocyte-derived mitochondria in the blood. These findings suggest that dietary lipids regulate mitochondria uptake by macrophages locally in white adipose tissue to determine whether adipocyte-derived mitochondria are released into systemic circulation to support the metabolic adaptation of distant organs in response to nutrient stress.
    Keywords:  CD36; EXT1; aging; beige fat; brown adipose tissue; cell-free mitochondria; fatty acids; heparan sulfate; horizontal mitochondria transfer; intercellular mitochondria transfer; lipids; macrophage; mitochondria; obesity; palmitate; white adipose tissue
    DOI:  https://doi.org/10.1016/j.cmet.2022.08.010
  16. Cell Metab. 2022 Sep 06. pii: S1550-4131(22)00356-4. [Epub ahead of print]34(9): 1227-1229
    Walking the high wire: How neurons maintain stability in the crossline of neurodegeneration.
    Matheus B Victor, Li-Huei Tsai.
      In this issue of Cell Metabolism, Traxler et al. report a metabolic switch in neurons that hinges on the critical balance of pyruvate kinase M (PKM) isoform ratios. Using directly induced neurons (iNs) derived from patients with Alzheimer's disease (AD), the work delineates the impact of an AD-specific switch from PKM1 to PKM2 onto neuronal resilience against neurodegeneration.
    DOI:  https://doi.org/10.1016/j.cmet.2022.08.013
  17. Cell Mol Life Sci. 2022 Sep 04. 79(9): 505
    Small leucine zipper protein functions as a modulator for metabolic reprogramming of colorectal cancer cells by inducing nutrient stress-mediated autophagy.
    Suhyun Kim, Minseok Oh, Minsoo Kang, Jesang Ko.
      In multiple cancers, autophagy promotes tumor development by recycling intracellular components into metabolic pathways. Autophagy-induced metabolic reprogramming and plasticity lead to cancer cell survival and resistance to anticancer therapy. We investigated the role of small leucine zipper protein (sLZIP) in autophagy and cell survival under nutrient-deficient conditions in colorectal cancer (CRC). sLZIP was induced by nutrient stress and increased the transcription of microtubule-associated protein 1A/1B-light chain 3 (LC3), by directly binding to its promoter. Under nutrient stress conditions, sLZIP activated autophagy and promoted the survival of CRC cells. sLZIP induced metabolic reprogramming of CRC cells, to activate glutaminolysis and the tricarboxylic acid cycle. sLZIP also enhanced the autophagic degradation of Keap1 and the nuclear accumulation of Nrf2, leading to NQO1 expression, for maintenance of redox homeostasis. sLZIP-knockout CRC cells exhibited impaired autophagy induction in the glycolytic inhibition state. Xenograft mice lacking sLZIP showed decreased tumor growth, by rendering CRC cells sensitive to glycolysis inhibition. The expression of sLZIP and LC3B was highly elevated in tumors of CRC patients compared to that in normal tissues, and correlated with the progression of CRC. These findings suggest that sLZIP drives autophagy and metabolic reprogramming to promote colorectal tumorigenesis.
    Keywords:  Autophagy; Colorectal cancer; Metabolic reprogramming; Transcriptional regulation
    DOI:  https://doi.org/10.1007/s00018-022-04535-4
  18. Int J Mol Sci. 2022 Sep 05. pii: 10172. [Epub ahead of print]23(17):
    Connexins and Glucose Metabolism in Cancer.
    Jennifer C Jones, Thomas M Bodenstine.
      Connexins are a family of transmembrane proteins that regulate diverse cellular functions. Originally characterized for their ability to mediate direct intercellular communication through the formation of highly regulated membrane channels, their functions have been extended to the exchange of molecules with the extracellular environment, and the ability to modulate numerous channel-independent effects on processes such as motility and survival. Notably, connexins have been implicated in cancer biology for their context-dependent roles that can both promote or suppress cancer cell function. Moreover, connexins are able to mediate many aspects of cellular metabolism including the intercellular coupling of nutrients and signaling molecules. During cancer progression, changes to substrate utilization occur to support energy production and biomass accumulation. This results in metabolic plasticity that promotes cell survival and proliferation, and can impact therapeutic resistance. Significant progress has been made in our understanding of connexin and cancer biology, however, delineating the roles these multi-faceted proteins play in metabolic adaptation of cancer cells is just beginning. Glucose represents a major carbon substrate for energy production, nucleotide synthesis, carbohydrate modifications and generation of biosynthetic intermediates. While cancer cells often exhibit a dependence on glycolytic metabolism for survival, cellular reprogramming of metabolic pathways is common when blood perfusion is limited in growing tumors. These metabolic changes drive aggressive phenotypes through the acquisition of functional traits. Connections between glucose metabolism and connexin function in cancer cells and the surrounding stroma are now apparent, however much remains to be discovered regarding these relationships. This review discusses the existing evidence in this area and highlights directions for continued investigation.
    Keywords:  connexin; gap junction; glucose; metabolism
    DOI:  https://doi.org/10.3390/ijms231710172
  19. Am J Physiol Cell Physiol. 2022 Sep 05.
    Circadian cardiac NAD+ metabolism, from transcriptional regulation to healthy aging.
    Bryce J Carpenter, Pieterjan Dierickx.
      Nicotinamide adenine dinucleotide (NAD+) is a critical redox factor and coenzyme with rhythmic availability, and reduced NAD+ levels are a common factor of many disease states, including risk factors associated with aging. Recent studies have expanded on the role of circadian rhythms and the core clock factors that maintain them in the regulation of NAD+ levels in the heart. This has revealed that NAD+ pools and their use are tightly linked to cardiac function, but also heart failure. The convergence of these fields, namely, clock regulation, heart disease, and NAD+ metabolism present a complex network ripe with potential scientific and clinical discoveries, given the growing number of animal models, recently developed technology, and opportunity for safe and accessible precursor supplementation. This review seeks to briefly present known information on circadian rhythms in the heart, connect that research to our understanding of cardiac NAD+ metabolism, and finally discuss potential future experiments to better understand interventional opportunities in cardiovascular health regarding these subjects.
    Keywords:  Cardiovascular Health; Circadian Rhythms; NAD+ Metabolism
    DOI:  https://doi.org/10.1152/ajpcell.00239.2022
  20. Methods Cell Biol. 2022 ;pii: S0091-679X(22)00063-2. [Epub ahead of print]172 115-134
    Quantification of cytosolic DNA species by immunofluorescence microscopy and automated image analysis.
    Ai Sato, Norma Bloy, Claudia Galassi, Carlos Jiménez-Cortegana, Vanessa Klapp, Artur Aretz, Emma Guilbaud, Takahiro Yamazaki, Giulia Petroni, Lorenzo Galluzzi, Aitziber Buqué.
      When employed according to specific doses and fractionation schedules, radiation therapy (RT) elicits potent tumor-targeting immune responses that rely on the secretion of type I interferon (IFN) by irradiated cancer cells. Most often, this is initiated by the ability of RT to promote the cytosolic accumulation of double-stranded DNA (dsDNA) molecules, which are detected by cyclic GMP-AMP synthase (CGAS) to engage the stimulator of interferon response cGAMP interactor 1 (STING1)-dependent transactivation of type I IFN-coding genes via interferon regulatory factor 3 (IRF3). Here, we describe a simple protocol for the quantification of cytosolic dsDNA species by immunofluorescence microscopy coupled to automated image analysis, as enabled by precise sample processing conditions that permeabilize plasma-but not nuclear or inner mitochondrial-membranes. As compared to subcellular fractionation-based techniques, this approach is compatible with assessments in individual cells aimed at gauging inter-cellular heterogeneity, as well as subcellular tests including co-localization studies.
    Keywords:  CGAS; Cancer immunotherapy; FIJI; Type I interferon; mtDNA
    DOI:  https://doi.org/10.1016/bs.mcb.2022.05.004
  21. PLoS One. 2022 ;17(9): e0261803
    Spatially resolved characterization of tissue metabolic compartments in fasted and high-fat diet livers.
    Sylwia A Stopka, Jiska van der Reest, Walid M Abdelmoula, Daniela F Ruiz, Shakchhi Joshi, Alison E Ringel, Marcia C Haigis, Nathalie Y R Agar.
      Cells adapt their metabolism to physiological stimuli, and metabolic heterogeneity exists between cell types, within tissues, and subcellular compartments. The liver plays an essential role in maintaining whole-body metabolic homeostasis and is structurally defined by metabolic zones. These zones are well-understood on the transcriptomic level, but have not been comprehensively characterized on the metabolomic level. Mass spectrometry imaging (MSI) can be used to map hundreds of metabolites directly from a tissue section, offering an important advance to investigate metabolic heterogeneity in tissues compared to extraction-based metabolomics methods that analyze tissue metabolite profiles in bulk. We established a workflow for the preparation of tissue specimens for matrix-assisted laser desorption/ionization (MALDI) MSI that can be implemented to achieve broad coverage of central carbon, nucleotide, and lipid metabolism pathways. Herein, we used this approach to visualize the effect of nutrient stress and excess on liver metabolism. Our data revealed a highly organized metabolic tissue compartmentalization in livers, which becomes disrupted under high fat diet. Fasting caused changes in the abundance of several metabolites, including increased levels of fatty acids and TCA intermediates while fatty livers had higher levels of purine and pentose phosphate-related metabolites, which generate reducing equivalents to counteract oxidative stress. This spatially conserved approach allowed the visualization of liver metabolic compartmentalization at 30 μm pixel resolution and can be applied more broadly to yield new insights into metabolic heterogeneity in vivo.
    DOI:  https://doi.org/10.1371/journal.pone.0261803
  22. Biochim Biophys Acta Bioenerg. 2022 Sep 02. pii: S0005-2728(22)00384-X. [Epub ahead of print] 148914
    Non-conventional mitochondrial permeability transition: Its regulation by mitochondrial dynamics.
    Yisang Yoon, Hakjoo Lee, Marilen Federico, Shey-Shing Sheu.
      Mitochondrial permeability transition (MPT) is a phenomenon that the inner mitochondrial membrane (IMM) loses its selective permeability, leading to mitochondrial dysfunction and cell injury. Electrophysiological evidence indicates the presence of a mega-channel commonly called permeability transition pore (PTP) whose opening is responsible for MPT. However, the molecular identity of the PTP is still under intensive investigations and debates, although cyclophilin D that is inhibited by cyclosporine A (CsA) is the established regulatory component of the PTP. PTP can also open transiently and functions as a rapid mitochondrial Ca2+ releasing mechanism. Mitochondrial fission and fusion, the main components of mitochondrial dynamics, control the number and size of mitochondria, and have been shown to play a role in regulating MPT directly or indirectly. Studies by us and others have indicated the potential existence of a form of transient MPT that is insensitive to CsA. This "non-conventional" MPT is regulated by mitochondrial dynamics and may serve a protective role possibly by decreasing the susceptibility for a frequent or sustained PTP opening; hence, it may have a therapeutic value in many disease conditions involving MPT.
    Keywords:  Mitochondrial dynamics; Mitochondrial permeability transition; Non-conventional mitochondrial permeability transition; Permeability transition pore
    DOI:  https://doi.org/10.1016/j.bbabio.2022.148914
  23. Cancer Discov. 2022 Sep 05. OF1-OF9
    Diet and Exercise in Cancer Metabolism.
    Jason W Locasale.
      Diet and exercise are modifiable lifestyle factors known to have a major influence on metabolism. Clinical practice addresses diseases of altered metabolism such as diabetes or hypertension by altering these factors. Despite enormous public interest, there are limited defined diet and exercise regimens for patients with cancer. Nevertheless, the molecular basis of cancer has converged over the past 15 years on an essential role for altered metabolism in cancer. However, our understanding of the molecular mechanisms that underlie the impact of diet and exercise on cancer metabolism is in its very early stages. In this perspective, I propose conceptual frameworks for understanding the consequences of diet and exercise on cancer cell metabolism and tumor biology and also highlight recent developments. By advancing our mechanistic understanding, I will discuss actionable ways that such interventions could eventually reach the mainstay of both medical oncology and cancer control and prevention.
    DOI:  https://doi.org/10.1158/2159-8290.CD-22-0096
  24. J Cell Biol. 2022 Oct 03. pii: e202205104. [Epub ahead of print]221(10):
    DarT-mediated mtDNA damage induces dynamic reorganization and selective segregation of mitochondria.
    Nitish Dua, Akshaya Seshadri, Anjana Badrinarayanan.
      Mitochondria are dynamic organelles that play essential roles in cell growth and survival. Processes of fission and fusion are critical for the distribution, segregation, and maintenance of mitochondria and their genomes (mtDNA). While recent work has revealed the significance of mitochondrial organization for mtDNA maintenance, the impact of mtDNA perturbations on mitochondrial dynamics remains less understood. Here, we develop a tool to induce mitochondria-specific DNA damage using a mitochondrial-targeted base modifying bacterial toxin, DarT. Following damage, we observe dynamic reorganization of mitochondrial networks, likely driven by mitochondrial dysfunction. Changes in the organization are associated with the loss of mtDNA, independent of mitophagy. Unexpectedly, perturbation to exonuclease function of mtDNA replicative polymerase, Mip1, results in rapid loss of mtDNA. Our data suggest that, under damage, partitioning of defective mtDNA and organelle are de-coupled, with emphasis on mitochondrial segregation independent of its DNA. Together, our work underscores the importance of genome maintenance on mitochondrial function, which can act as a modulator of organelle organization and segregation.
    DOI:  https://doi.org/10.1083/jcb.202205104
  25. Cell Metab. 2022 Sep 06. pii: S1550-4131(22)00349-7. [Epub ahead of print]34(9): 1410
    Metabolite Exchange between Mammalian Organs Quantified in Pigs.
    Cholsoon Jang, Sheng Hui, Xianfeng Zeng, Alexis J Cowan, Lin Wang, Li Chen, Raphael J Morscher, Jorge Reyes, Christian Frezza, Ho Young Hwang, Akito Imai, Yoshiaki Saito, Keitaro Okamoto, Christine Vaspoli, Loewe Kasprenski, Gerald A Zsido, Joseph H Gorman, Robert C Gorman, Joshua D Rabinowitz.
      
    DOI:  https://doi.org/10.1016/j.cmet.2022.08.006
  26. Cell Metab. 2022 Sep 06. pii: S1550-4131(22)00352-7. [Epub ahead of print]34(9): 1229-1231
    Methionine restriction forces Epstein-Barr virus out of latency.
    Sriraksha Bharadwaj Kashyap, Racheal Mulondo, Peter J Mullen.
      EBV gene expression is repressed during viral latency to prevent an immune response, but it is not known how metabolism contributes to this silencing. In this issue of Cell Metabolism, Guo et al. describe how methionine restriction reactivates the expression of EBV genes, offering new therapeutic approaches against EBV-driven diseases.
    DOI:  https://doi.org/10.1016/j.cmet.2022.08.009
  27. J Cell Physiol. 2022 Sep 08.
    Mitochondrial respiratory complexes: Significance in human mitochondrial disorders and cancers.
    Kunwar Somesh Vikramdeo, Sarabjeet Kour Sudan, Ajay P Singh, Seema Singh, Santanu Dasgupta.
      Mitochondria are pivotal organelles that govern cellular energy production through the oxidative phosphorylation system utilizing five respiratory complexes. In addition, mitochondria also contribute to various critical signaling pathways including apoptosis, damage-associated molecular patterns, calcium homeostasis, lipid, and amino acid biosynthesis. Among these diverse functions, the energy generation program oversee by mitochondria represents an immaculate orchestration and functional coordination between the mitochondria and nuclear encoded molecules. Perturbation in this program through respiratory complexes' alteration results in the manifestation of various mitochondrial disorders and malignancy, which is alarmingly becoming evident in the recent literature. Considering the clinical relevance and importance of this emerging medical problem, this review sheds light on the timing and nature of molecular alterations in various respiratory complexes and their functional consequences observed in various mitochondrial disorders and human cancers. Finally, we discussed how this wealth of information could be exploited and tailored to develop respiratory complex targeted personalized therapeutics and biomarkers for better management of various incurable human mitochondrial disorders and cancers.
    Keywords:  ATP; cancer; genetic disorders; mitochondria; oxidative phosphorylation (OXPHOS); respiratory complexes
    DOI:  https://doi.org/10.1002/jcp.30869
  28. Cell Rep. 2022 Sep 06. pii: S2211-1247(22)01134-2. [Epub ahead of print]40(10): 111310
    Ku proteins promote DNA binding and condensation of cyclic GMP-AMP synthase.
    Xinyue Tao, Jiali Song, Ying Song, Yao Zhang, Jing Yang, Pengfei Zhang, Dechong Zhang, Dahua Chen, Qinmiao Sun.
      Cyclic GMP-AMP synthase (cGAS) is a cytosolic DNA sensor that plays a critical role in regulating antiviral signaling. cGAS binds to DNA and catalyzes the synthesis of cyclic GMP-AMP (cGAMP), which is essential for downstream signal transduction. The antiviral response is a rapid biological process; however, cGAS itself has relatively low DNA binding affinity, implying that formation of the cGAS-DNA complex requires an additional factor(s) that promotes cGAS-DNA binding, allowing efficient antiviral signal transduction. Here, we report that the Ku proteins (Ku80 and Ku70) directly interact with cGAS and positively regulate cGAS-mediated antiviral signaling. Mechanistically, we find that the interaction of the Ku proteins with cGAS significantly increases the DNA-binding affinity of cGAS and promotes cGAS condensation in the cytosol, thereby enhancing cGAS catalytic activity. Our results show that the Ku proteins are critical partners of cGAS in sensing DNA virus infection and ensuring efficient innate immune signal transduction.
    Keywords:  CP: Immunology; CP: Molecular biology; Ku70; Ku80; antiviral signaling; cGAS; innate immunity
    DOI:  https://doi.org/10.1016/j.celrep.2022.111310
  29. iScience. 2022 Sep 16. 25(9): 104920
    Mitochondrial protein synthesis and the bioenergetic cost of neurodevelopment.
    Pernille Bülow, Anupam Patgiri, Victor Faundez.
      The human brain consumes five orders of magnitude more energy than the sun by unit of mass and time. This staggering bioenergetic cost serves mostly synaptic transmission and actin cytoskeleton dynamics. The peak of both brain bioenergetic demands and the age of onset for neurodevelopmental disorders is approximately 5 years of age. This correlation suggests that defects in the machinery that provides cellular energy would be causative and/or consequence of neurodevelopmental disorders. We explore this hypothesis from the perspective of the machinery required for the synthesis of the electron transport chain, an ATP-producing and NADH-consuming enzymatic cascade. The electron transport chain is constituted by nuclear- and mitochondrial-genome-encoded subunits. These subunits are synthesized by the 80S and the 55S ribosomes, which are segregated to the cytoplasm and the mitochondrial matrix, correspondingly. Mitochondrial protein synthesis by the 55S ribosome is the rate-limiting step in the synthesis of electron transport chain components, suggesting that mitochondrial protein synthesis is a bottleneck for tissues with high bionergetic demands. We discuss genetic defects in the human nuclear and mitochondrial genomes that affect these protein synthesis machineries and cause a phenotypic spectrum spanning autism spectrum disorders to neurodegeneration during neurodevelopment. We propose that dysregulated mitochondrial protein synthesis is a chief, yet understudied, causative mechanism of neurodevelopmental and behavioral disorders.
    Keywords:  Biological Sciences; Cell Biology; Neuroscience
    DOI:  https://doi.org/10.1016/j.isci.2022.104920
  30. Cancer Res. 2022 Sep 09. pii: CAN-22-0237. [Epub ahead of print]
    An exercise-induced metabolic shield in distant organs blocks cancer progression and metastatic dissemination.
    Danna Sheinboim, Shivang Parikh, Paulee Manich, Irit Markus, Sapir Dahan, Roma Parikh, Elisa Stubbs, Gali Cohen, Valentina Zemser-Werner, Rachel E Bell, Sara Arciniegas Ruiz, Ruth Percik, Ronen Brenner, Stav Leibou, Hananya Vaknine, Gali Arad, Yariv Gerber, Lital Keinan Boker, Tal Shimony, Lior Bikovski, Nir Goldstein, Keren Constantini, Sapir Labes, Shimonov Mordechai, Hila Doron, Ariel Ionescu, Tamar Ziv, Eran Nizri, Guy Choshen, Hagit Eldar-Finkelman, Yuval Tabach, Aharon Helman, Shamgar Ben-Eliyahu, Neta Erez, Eran Perlson, Tamar Geiger, Danny Ben-Zvi, Mehdi Khaled, Yftach Gepner, Carmit Levy.
      Exercise prevents cancer incidence and recurrence, yet the underlying mechanism behind this relationship remains mostly unknown. Here we report that exercise induces metabolic reprogramming of internal organs that increases nutrient demand and protects against metastatic colonization by limiting nutrient availability to the tumor, generating an exercise-induced metabolic shield. Proteomic and ex vivo metabolic capacity analyses of murine internal organs revealed that exercise induces catabolic processes, glucose uptake, mitochondrial activity, and GLUT expression. Proteomic analysis of routinely active human subject plasma demonstrated increased carbohydrate utilization following exercise. Epidemiological data from a 20-year prospective study of a large human cohort of initially cancer-free participants revealed that exercise prior to cancer initiation had a modest impact on cancer incidence in low metastatic stages but significantly reduced the likelihood of highly metastatic cancer. In three models of melanoma in mice, exercise prior to cancer injection significantly protected against metastases in distant organs. The protective effects of exercise were dependent on mTOR activity, and inhibition of the mTOR pathway with rapamycin treatment ex vivo reversed the exercise-induced metabolic shield. Under limited glucose conditions, active stroma consumed significantly more glucose at the expense of the tumor. Collectively, these data suggest a clash between the metabolic plasticity of cancer and exercise-induced metabolic reprogramming of the stroma, raising an opportunity to block metastasis by challenging the metabolic needs of the tumor.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-22-0237
  31. EMBO Mol Med. 2022 Sep 05. e16029
    In situ mass spectrometry imaging reveals heterogeneous glycogen stores in human normal and cancerous tissues.
    Lyndsay E A Young, Lindsey R Conroy, Harrison A Clarke, Tara R Hawkinson, Kayli E Bolton, William C Sanders, Josephine E Chang, Madison B Webb, Warren J Alilain, Craig W Vander Kooi, Richard R Drake, Douglas A Andres, Tom C Badgett, Lars M Wagner, Derek B Allison, Ramon C Sun, Matthew S Gentry.
      Glycogen dysregulation is a hallmark of aging, and aberrant glycogen drives metabolic reprogramming and pathogenesis in multiple diseases. However, glycogen heterogeneity in healthy and diseased tissues remains largely unknown. Herein, we describe a method to define spatial glycogen architecture in mouse and human tissues using matrix-assisted laser desorption/ionization mass spectrometry imaging. This assay provides robust and sensitive spatial glycogen quantification and architecture characterization in the brain, liver, kidney, testis, lung, bladder, and even the bone. Armed with this tool, we interrogated glycogen spatial distribution and architecture in different types of human cancers. We demonstrate that glycogen stores and architecture are heterogeneous among diseases. Additionally, we observe unique hyperphosphorylated glycogen accumulation in Ewing sarcoma, a pediatric bone cancer. Using preclinical models, we correct glycogen hyperphosphorylation in Ewing sarcoma through genetic and pharmacological interventions that ablate in vivo tumor growth, demonstrating the clinical therapeutic potential of targeting glycogen in Ewing sarcoma.
    Keywords:  Ewing sarcoma; MALDI imaging; glycogen; glycogen storage disease; spatial metabolism
    DOI:  https://doi.org/10.15252/emmm.202216029
  32. Cancer Cell. 2022 Aug 30. pii: S1535-6108(22)00376-2. [Epub ahead of print]
    Increased glucose metabolism in TAMs fuels O-GlcNAcylation of lysosomal Cathepsin B to promote cancer metastasis and chemoresistance.
    Qingzhu Shi, Qicong Shen, Yanfang Liu, Yang Shi, Wenwen Huang, Xi Wang, Zhiqing Li, Yangyang Chai, Hao Wang, Xiangjia Hu, Nan Li, Qian Zhang, Xuetao Cao.
      How glucose metabolism remodels pro-tumor functions of tumor-associated macrophages (TAMs) needs further investigation. Here we show that M2-like TAMs bear the highest individual capacity to take up intratumoral glucose. Their increased glucose uptake fuels hexosamine biosynthetic pathway-dependent O-GlcNAcylation to promote cancer metastasis and chemoresistance. Glucose metabolism promotes O-GlcNAcylation of the lysosome-encapsulated protease Cathepsin B at serine 210, mediated by lysosome-localized O-GlcNAc transferase (OGT), elevating mature Cathepsin B in macrophages and its secretion in the tumor microenvironment (TME). Loss of OGT in macrophages reduces O-GlcNAcylation and mature Cathepsin B in the TME and disrupts cancer metastasis and chemoresistance. Human TAMs with high OGT are positively correlated with Cathepsin B expression, and both levels predict chemotherapy response and prognosis of individuals with cancer. Our study reports the biological and potential clinical significance of glucose metabolism in tumor-promoting TAMs and reveals insights into the underlying mechanisms.
    Keywords:  O-GlcNAc transferase; O-GlcNAcylation; cathepsin B; glucose metabolism; lysosome; metastasis; tumor-associated macrophages
    DOI:  https://doi.org/10.1016/j.ccell.2022.08.012
  33. Aging Cell. 2022 Sep 10. e13707
    The lysosomal proteome of senescent cells contributes to the senescence secretome.
    Miguel Rovira, Rebecca Sereda, David Pladevall-Morera, Valentina Ramponi, Ines Marin, Mate Maus, Julio Madrigal-Matute, Antonio Díaz, Fernando García, Javier Muñoz, Ana María Cuervo, Manuel Serrano.
      Senescent cells accumulate in tissues over time, favoring the onset and progression of multiple age-related diseases. Senescent cells present a remarkable increase in lysosomal mass and elevated autophagic activity. Here, we report that two main autophagic pathways macroautophagy (MA) and chaperone-mediated autophagy (CMA) are constitutively upregulated in senescent cells. Proteomic analyses of the subpopulations of lysosomes preferentially engaged in each of these types of autophagy revealed profound quantitative and qualitative changes in senescent cells, affecting both lysosomal resident proteins and cargo proteins delivered to lysosomes for degradation. These studies have led us to identify resident lysosomal proteins that are highly augmented in senescent cells and can be used as novel markers of senescence, such as arylsulfatase ARSA. The abundant secretome of senescent cells, known as SASP, is considered their main pathological mediator; however, little is known about the mechanisms of SASP secretion. Some secretory cells, including melanocytes, use the small GTPase RAB27A to perform lysosomal secretion. We found that this process is exacerbated in the case of senescent melanoma cells, as revealed by the exposure of lysosomal membrane integral proteins LAMP1 and LAMP2 in their plasma membrane. Interestingly, a subset of SASP components, including cytokines CCL2, CCL3, CXCL12, cathepsin CTSD, or the protease inhibitor SERPINE1, are secreted in a RAB27A-dependent manner in senescent melanoma cells. Finally, proteins previously identified as plasma biomarkers of aging are highly enriched in the lysosomes of senescent cells, including CTSD. We conclude that the lysosomal proteome of senescent cells is profoundly reconfigured, and that some senescent cells can be highly active in lysosomal exocytosis.
    Keywords:  SASP; aging; autophagy; cellular senescence; exocytosis; lysosome
    DOI:  https://doi.org/10.1111/acel.13707
  34. Nat Commun. 2022 Sep 03. 13(1): 5202
    Spermidine-mediated hypusination of translation factor EIF5A improves mitochondrial fatty acid oxidation and prevents non-alcoholic steatohepatitis progression.
    Jin Zhou, Jeremy Pang, Madhulika Tripathi, Jia Pei Ho, Anissa Anindya Widjaja, Shamini Guna Shekeran, Stuart Alexander Cook, Ayako Suzuki, Anna Mae Diehl, Enrico Petretto, Brijesh Kumar Singh, Paul Michael Yen.
      Spermidine is a natural polyamine that has health benefits and extends life span in several species. Deoxyhypusine synthase (DHPS) and deoxyhypusine hydroxylase (DOHH) are key enzymes that utilize spermidine to catalyze the post-translational hypusination of the translation factor EIF5A (EIF5AH). Here, we have found that hepatic DOHH mRNA expression is decreased in patients and mice with non-alcoholic steatohepatitis (NASH), and hepatic cells treated with fatty acids. The mouse and cell culture models of NASH have concomitant decreases in Eif5aH and mitochondrial protein synthesis which leads to lower mitochondrial activity and fatty acid β-oxidation. Spermidine treatment restores EIF5AH, partially restores protein synthesis and mitochondrial function in NASH, and prevents NASH progression in vivo. Thus, the disrupted DHPS-DOHH-EIF5AH pathway during NASH represents a therapeutic target to increase hepatic protein synthesis and mitochondrial fatty acid oxidation (FAO) and prevent NASH progression.
    DOI:  https://doi.org/10.1038/s41467-022-32788-x
  35. Nature. 2022 Sep 07.
    A phosphoinositide signalling pathway mediates rapid lysosomal repair.
    Jay Xiaojun Tan, Toren Finkel.
      Lysosomal dysfunction has been increasingly linked to disease and normal ageing1,2. Lysosomal membrane permeabilization (LMP), a hallmark of lysosome-related diseases, can be triggered by diverse cellular stressors3. Given the damaging contents of lysosomes, LMP must be rapidly resolved, although the underlying mechanisms are poorly understood. Here, using an unbiased proteomic approach, we show that LMP stimulates a phosphoinositide-initiated membrane tethering and lipid transport (PITT) pathway for rapid lysosomal repair. Upon LMP, phosphatidylinositol-4 kinase type 2α (PI4K2A) accumulates rapidly on damaged lysosomes, generating high levels of the lipid messenger phosphatidylinositol-4-phosphate. Lysosomal phosphatidylinositol-4-phosphate in turn recruits multiple oxysterol-binding protein (OSBP)-related protein (ORP) family members, including ORP9, ORP10, ORP11 and OSBP, to orchestrate extensive new membrane contact sites between damaged lysosomes and the endoplasmic reticulum. The ORPs subsequently catalyse robust endoplasmic reticulum-to-lysosome transfer of phosphatidylserine and cholesterol to support rapid lysosomal repair. Finally, the lipid transfer protein ATG2 is also recruited to damaged lysosomes where its activity is potently stimulated by phosphatidylserine. Independent of macroautophagy, ATG2 mediates rapid membrane repair through direct lysosomal lipid transfer. Together, our findings identify that the PITT pathway maintains lysosomal membrane integrity, with important implications for numerous age-related diseases characterized by impaired lysosomal function.
    DOI:  https://doi.org/10.1038/s41586-022-05164-4
  36. iScience. 2022 Sep 16. 25(9): 104941
    Activation of mitochondrial TRAP1 stimulates mitochondria-lysosome crosstalk and correction of lysosomal dysfunction.
    Fannie W Chen, Joanna P Davies, Raul Calvo, Jagruti Chaudhari, Georgia Dolios, Mercedes K Taylor, Samarjit Patnaik, Jean Dehdashti, Rebecca Mull, Patricia Dranchack, Amy Wang, Xin Xu, Emma Hughes, Noel Southall, Marc Ferrer, Rong Wang, Juan J Marugan, Yiannis A Ioannou.
      Numerous studies have established the involvement of lysosomal and mitochondrial dysfunction in the pathogenesis of neurodegenerative disorders such as Alzheimer's and Parkinson diseases. Building on our previous studies of the neurodegenerative lysosomal lipidosis Niemann-Pick C1 (NPC1), we have unexpectedly discovered that activation of the mitochondrial chaperone tumor necrosis factor receptor-associated protein 1 (TRAP1) leads to the correction of the lysosomal storage phenotype in patient cells from multiple lysosomal storage disorders including NPC1. Using small compound activators specific for TRAP1, we find that activation of this chaperone leads to a generalized restoration of lysosomal and mitochondrial health. Mechanistically, we show that this process includes inhibition of oxidative phosphorylation and reduction of oxidative stress, which results in activation of AMPK and ultimately stimulates lysosome recycling. Thus, TRAP1 participates in lysosomal-mitochondrial crosstalk to maintain cellular homeostasis and could represent a potential therapeutic target for multiple disorders.
    Keywords:  Cell biology; Cellular neuroscience; Neuroscience
    DOI:  https://doi.org/10.1016/j.isci.2022.104941
  37. Int J Mol Sci. 2022 Sep 03. pii: 10073. [Epub ahead of print]23(17):
    Metabolic and Cellular Compartments of Acetyl-CoA in the Healthy and Diseased Brain.
    Agnieszka Jankowska-Kulawy, Joanna Klimaszewska-Łata, Sylwia Gul-Hinc, Anna Ronowska, Andrzej Szutowicz.
      The human brain is characterised by the most diverse morphological, metabolic and functional structure among all body tissues. This is due to the existence of diverse neurons secreting various neurotransmitters and mutually modulating their own activity through thousands of pre- and postsynaptic interconnections in each neuron. Astroglial, microglial and oligodendroglial cells and neurons reciprocally regulate the metabolism of key energy substrates, thereby exerting several neuroprotective, neurotoxic and regulatory effects on neuronal viability and neurotransmitter functions. Maintenance of the pool of mitochondrial acetyl-CoA derived from glycolytic glucose metabolism is a key factor for neuronal survival. Thus, acetyl-CoA is regarded as a direct energy precursor through the TCA cycle and respiratory chain, thereby affecting brain cell viability. It is also used for hundreds of acetylation reactions, including N-acetyl aspartate synthesis in neuronal mitochondria, acetylcholine synthesis in cholinergic neurons, as well as divergent acetylations of several proteins, peptides, histones and low-molecular-weight species in all cellular compartments. Therefore, acetyl-CoA should be considered as the central point of metabolism maintaining equilibrium between anabolic and catabolic pathways in the brain. This review presents data supporting this thesis.
    Keywords:  acetyl-CoA metabolism; aging; neurodegenerative diseases; thiamine deficiency; zinc dyshomeostasis
    DOI:  https://doi.org/10.3390/ijms231710073
  38. Nat Commun. 2022 Sep 03. 13(1): 5203
    The nucleolus is the site for inflammatory RNA decay during infection.
    Taeyun A Lee, Heonjong Han, Ahsan Polash, Seok Keun Cho, Ji Won Lee, Eun A Ra, Eunhye Lee, Areum Park, Sujin Kang, Junhee L Choi, Ji Hyun Kim, Ji Eun Lee, Kyung-Won Min, Seong Wook Yang, Markus Hafner, Insuk Lee, Je-Hyun Yoon, Sungwook Lee, Boyoun Park.
      Inflammatory cytokines are key signaling molecules that can promote an immune response, thus their RNA turnover must be tightly controlled during infection. Most studies investigate the RNA decay pathways in the cytosol or nucleoplasm but never focused on the nucleolus. Although this organelle has well-studied roles in ribosome biogenesis and cellular stress sensing, the mechanism of RNA decay within the nucleolus is not completely understood. Here, we report that the nucleolus is an essential site of inflammatory pre-mRNA instability during infection. RNA-sequencing analysis reveals that not only do inflammatory genes have higher intronic read densities compared with non-inflammatory genes, but their pre-mRNAs are highly enriched in nucleoli during infection. Notably, nucleolin (NCL) acts as a guide factor for recruiting cytosine or uracil (C/U)-rich sequence-containing inflammatory pre-mRNAs and the Rrp6-exosome complex to the nucleolus through a physical interaction, thereby enabling targeted RNA delivery to Rrp6-exosomes and subsequent degradation. Consequently, Ncl depletion causes aberrant hyperinflammation, resulting in a severe lethality in response to LPS. Importantly, the dynamics of NCL post-translational modifications determine its functional activity in phases of LPS. This process represents a nucleolus-dependent pathway for maintaining inflammatory gene expression integrity and immunological homeostasis during infection.
    DOI:  https://doi.org/10.1038/s41467-022-32856-2
  39. Nat Commun. 2022 Sep 06. 13(1): 5253
    Multimodal single cell sequencing implicates chromatin accessibility and genetic background in diabetic kidney disease progression.
    Parker C Wilson, Yoshiharu Muto, Haojia Wu, Anil Karihaloo, Sushrut S Waikar, Benjamin D Humphreys.
      The proximal tubule is a key regulator of kidney function and glucose metabolism. Diabetic kidney disease leads to proximal tubule injury and changes in chromatin accessibility that modify the activity of transcription factors involved in glucose metabolism and inflammation. Here we use single nucleus RNA and ATAC sequencing to show that diabetic kidney disease leads to reduced accessibility of glucocorticoid receptor binding sites and an injury-associated expression signature in the proximal tubule. We hypothesize that chromatin accessibility is regulated by genetic background and closely-intertwined with metabolic memory, which pre-programs the proximal tubule to respond differently to external stimuli. Glucocorticoid excess has long been known to increase risk for type 2 diabetes, which raises the possibility that glucocorticoid receptor inhibition may mitigate the adverse metabolic effects of diabetic kidney disease.
    DOI:  https://doi.org/10.1038/s41467-022-32972-z
  40. Mol Cells. 2022 Sep 30. 45(9): 649-659
    Lysosome Inhibition Reduces Basal and Nutrient-Induced Fat Accumulation in Caenorhabditis elegans.
    Rui Lu, Juan Chen, Fangbin Wang, Lu Wang, Jian Liu, Yan Lin.
      A long-term energy nutritional imbalance fundamentally causes the development of obesity and associated fat accumulation. Lysosomes, as nutrient-sensing and lipophagy centers, critically control cellular lipid catabolism in response to nutrient deprivation. However, whether lysosome activity is directly involved in nutrient-induced fat accumulation remains unclear. In this study, worm fat accumulation was induced by 1 mM glucose or 0.02 mM palmitic acid supplementation. Along with the elevation of fat accumulation, lysosomal number and acidification were also increased, suggesting that lysosome activity might be correlated with nutrient-induced fat deposition in Caenorhabditis elegans. Furthermore, treatments with the lysosomal inhibitors chloroquine and leupeptin significantly reduced basal and nutrient-induced fat accumulation in C. elegans. The knockdown of hlh-30, which is a critical gene in lysosomal biogenesis, also resulted in worm fat loss. Finally, the mutation of aak-2, daf-15, and rsks-1 showed that mTORC1 (mechanistic target of rapamycin complex-1) signaling mediated the effects of lysosomes on basal and nutrient-induced fat accumulation in C. elegans. Overall, this study reveals the previously undescribed role of lysosomes in overnutrition sensing, suggesting a new strategy for controlling body fat accumulation.
    Keywords:  Caenorhabditis elegans; fat accumulation; lysosome; nutrient
    DOI:  https://doi.org/10.14348/molcells.2022.0073
  41. Nat Commun. 2022 09 06. 13(1): 4487
    The mutational signatures of formalin fixation on the human genome.
    Qingli Guo, Eszter Lakatos, Ibrahim Al Bakir, Kit Curtius, Trevor A Graham, Ville Mustonen.
      Clinical archives of patient material near-exclusively consist of formalin-fixed and paraffin-embedded (FFPE) blocks. The ability to precisely characterise mutational signatures from FFPE-derived DNA has tremendous translational potential. However, sequencing of DNA derived from FFPE material is known to be riddled with artefacts. Here we derive genome-wide mutational signatures caused by formalin fixation. We show that the FFPE-signature is highly similar to signature 30 (the signature of Base Excision Repair deficiency due to NTHL1 mutations), and chemical repair of DNA lesions leads to a signature highly similar to signature 1 (clock-like signature due to spontaneous deamination of methylcytosine). We demonstrate that using uncorrected mutational catalogues of FFPE samples leads to major mis-assignment of signature activities. To correct for this, we introduce FFPEsig, a computational algorithm to rectify the formalin-induced artefacts in the mutational catalogue. We demonstrate that FFPEsig enables accurate mutational signature analysis both in simulated and whole-genome sequenced FFPE cancer samples. FFPEsig thus provides an opportunity to unlock additional clinical potential of archival patient tissues.
    DOI:  https://doi.org/10.1038/s41467-022-32041-5
  42. J Biol Rhythms. 2022 Sep 06. 7487304221120966
    Circadian Control of Glial Cell Homeodynamics.
    Daniela Rojo, Anna Badner, Erin M Gibson.
      The molecular mechanisms that maintain circadian rhythms in mammalian as well as non-mammalian systems are well documented in neuronal populations but comparatively understudied in glia. Glia are highly dynamic in form and function, and the circadian clock provides broad dynamic ranges for the maintenance of this homeostasis, thus glia are key to understanding the role of circadian biology in brain function. Here, we highlight the implications of the molecular circadian clock on the homeodynamic nature of glia, underscoring the current gap in understanding the role of the circadian system in oligodendroglia lineage cells and subsequent myelination. Through this perspective, we will focus on the intersection of circadian and glial biology and how it interfaces with global circadian rhythm maintenance associated with normative and aberrant brain function.
    Keywords:  astrocytes; circadian; microglia; neurodegeneration; oligodendroglia
    DOI:  https://doi.org/10.1177/07487304221120966
  43. Nat Ecol Evol. 2022 Sep 09.
    Life through the lens of metabolism.
    Laura Eme, Courtney W Stairs.
      
    DOI:  https://doi.org/10.1038/s41559-022-01880-2
  44. Science. 2022 Sep 08. eabn5637
    Lysosomal enzyme trafficking factor LYSET enables nutritional usage of extracellular proteins.
    Catarina Pechincha, Sven Groessl, Robert Kalis, Melanie de Almeida, Andrea Zanotti, Marten Wittmann, Martin Schneider, Rafael P de Campos, Sarah Rieser, Marlene Brandstetter, Alexander Schleiffer, Karin Müller-Decker, Dominic Helm, Sabrina Jabs, David Haselbach, Marius K Lemberg, Johannes Zuber, Wilhelm Palm.
      Mammalian cells can generate amino acids through macropinocytosis and lysosomal breakdown of extracellular proteins, which is exploited by cancer cells to grow in nutrient-poor tumors. Here, through genetic screens in defined nutrient conditions we characterized LYSET, a transmembrane protein (TMEM251) selectively required when cells consume extracellular proteins. LYSET was found to associate in the Golgi with GlcNAc-1-phosphotransferase, which targets catabolic enzymes to lysosomes through mannose-6-phosphate modification. Without LYSET, GlcNAc-1-phosphotransferase was unstable owing to a hydrophilic transmembrane domain. Consequently, LYSET-deficient cells were depleted of lysosomal enzymes and impaired in turnover of macropinocytic and autophagic cargoes. Thus, LYSET represents a core component of the lysosomal enzyme trafficking pathway, underlies the pathomechanism for hereditary lysosomal storage disorders, and may represent a target to suppress metabolic adaptations in cancer.
    DOI:  https://doi.org/10.1126/science.abn5637
  45. Sci Adv. 2022 Sep 09. 8(36): eabm2427
    Pronounced sequence specificity of the TET enzyme catalytic domain guides its cellular function.
    Mirunalini Ravichandran, Dominik Rafalski, Claudia I Davies, Oscar Ortega-Recalde, Xinsheng Nan, Cassandra R Glanfield, Annika Kotter, Katarzyna Misztal, Andrew H Wang, Marek Wojciechowski, Michał Rażew, Issam M Mayyas, Olga Kardailsky, Uwe Schwartz, Krzysztof Zembrzycki, Ian M Morison, Mark Helm, Dieter Weichenhan, Renata Z Jurkowska, Felix Krueger, Christoph Plass, Martin Zacharias, Matthias Bochtler, Timothy A Hore, Tomasz P Jurkowski.
      TET (ten-eleven translocation) enzymes catalyze the oxidation of 5-methylcytosine bases in DNA, thus driving active and passive DNA demethylation. Here, we report that the catalytic domain of mammalian TET enzymes favor CGs embedded within basic helix-loop-helix and basic leucine zipper domain transcription factor-binding sites, with up to 250-fold preference in vitro. Crystal structures and molecular dynamics calculations show that sequence preference is caused by intrasubstrate interactions and CG flanking sequence indirectly affecting enzyme conformation. TET sequence preferences are physiologically relevant as they explain the rates of DNA demethylation in TET-rescue experiments in culture and in vivo within the zygote and germ line. Most and least favorable TET motifs represent DNA sites that are bound by methylation-sensitive immediate-early transcription factors and octamer-binding transcription factor 4 (OCT4), respectively, illuminating TET function in transcriptional responses and pluripotency support.
    DOI:  https://doi.org/10.1126/sciadv.abm2427
  46. Cancer Res. 2022 Sep 08. pii: CAN-22-1731. [Epub ahead of print]
    Genomic Landscapes and Hallmarks of Mutant RAS in Human Cancers.
    Robert B Scharpf, Archana Balan, Biagio Ricciuti, Jacob Fiksel, Christopher Cherry, Chenguang Wang, Michele L LeNoue-Newton, Hira A Rizvi, James R White, Alexander S Baras, Jordan Anaya, Blair V Landon, Marta Majcherska-Agrawal, Paola Ghanem, Jocelyn Lee, Leon Raskin, Andrew S Park, Huakang Tu, Hil Hsu, Kathryn C Arbour, Mark M Awad, Gregory J Riely, Christine M Lovly, Valsamo Anagnostou.
      The RAS family of small GTPases represents the most commonly activated oncogenes in human cancers. To better understand the prevalence of somatic RAS mutations and the compendium of genes that are co-altered in RAS mutant tumors, we analyzed targeted next-generation sequence data of 607,863 mutations from 66,372 tumors in 51 cancer types in the AACR Project GENIE Registry. Bayesian hierarchical models were implemented to estimate the cancer-specific prevalence of RAS and non-RAS somatic mutations, to evaluate co-occurrence and mutual exclusivity, and to model the effects of tumor mutational burden and mutational signatures on co-mutation patterns. These analyses revealed differential RAS prevalence and co-mutations with non-RAS genes in a cancer lineage and context-dependent manner, with differences across age, sex and ethnic groups. Allele specific RAS co-mutational patterns included an enrichment in NTRK3 and chromatin-regulating gene mutations in KRAS G12C-mutant non-small cell lung cancer. Integrated multi-omic analyses of 10,217 tumors from TCGA revealed distinct genotype-driven gene expression programs pointing to differential recruitment of cancer hallmarks as well as phenotypic differences and immune surveillance states in the tumor microenvironment of RAS mutant tumors. The distinct genomic tracks discovered in RAS mutant tumors reflected differential clinical outcomes in the TCGA cohort and in an independent cohort of patients with KRAS G12C mutant non-small cell lung cancer that received immunotherapy containing regimens. The RAS genetic architecture points to cancer lineage-specific therapeutic vulnerabilities that can be leveraged for rationally combining RAS mutant allele-directed therapies with targeted therapies and immunotherapy.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-22-1731
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