bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2021–11–21
thirty papers selected by
Christian Frezza, , University of Cambridge, MRC Cancer Unit
  1. Beyond mitophagy: mitochondrial-derived vesicles can get the job done!
  2. Methionine synthase is essential for cancer cell proliferation in physiological folate environments.
  3. Methionine synthase supports tumour tetrahydrofolate pools.
  4. The metabolic growth limitations of petite cells lacking the mitochondrial genome.
  5. Balancing of mitochondrial translation through METTL8-mediated m3C modification of mitochondrial tRNAs.
  6. Interplay between Mitochondrial Metabolism and Cellular Redox State Dictates Cancer Cell Survival.
  7. Metabolic resistance to the inhibition of mitochondrial transcription revealed by CRISPR-Cas9 screen.
  8. Folliculin impairs breast tumor growth by repressing TFE3-dependent induction of the Warburg effect and angiogenesis.
  9. DLST-dependence dictates metabolic heterogeneity in TCA-cycle usage among triple-negative breast cancer.
  10. Serine palmitoyltransferase assembles at ER-mitochondria contact sites.
  11. Metabolic Analysis of the Asparagine and Glutamine Dynamics in an Industrial CHO Fed-Batch Process.
  12. Fructose in the kidney: from physiology to pathology.
  13. Histone N-terminal acetyltransferase NAA40 links one-carbon metabolism to chemoresistance.
  14. CRISPR screens unveil signal hubs for nutrient licensing of T cell immunity.
  15. Contribution of branched chain amino acids to energy production and mevalonate synthesis in cancer cells.
  16. Intercellular nanotubes mediate mitochondrial trafficking between cancer and immune cells.
  17. A somatic proteoglycan controls Notch-directed germ cell fate.
  18. Insulin resistance rewires the metabolic gene program and glucose utilization in human white adipocytes.
  19. Cross-comparison of systemic and tissue-specific metabolomes in a mouse model of Leigh syndrome.
  20. Activation of the NRF2 antioxidant program sensitizes tumors to G6PD inhibition.
  21. AMPK adapts metabolism to developmental energy requirement during dendrite pruning in Drosophila.
  22. Sweet sensation: Developing a single-cell fluorescent reporter of glycolytic heterogeneity.
  23. BAd-CRISPR: inducible gene knockout in interscapular brown adipose tissue of adult mice.
  24. A new foe in folate metabolism.
  25. Cell stress response impairs de novo NAD+ biosynthesis in the kidney.
  26. The role of the electron transport chain in immunity.
  27. Mechanisms of YAP/TAZ transcriptional control.
  28. Hydrogen sulfide blocks HIV rebound by maintaining mitochondrial bioenergetics and redox homeostasis.
  29. Sequence logic at enhancers governs a dual mechanism of endodermal organ fate induction by FOXA pioneer factors.
  30. Sulphur metabolism in colon cancer tissues: a case report and literature review.
  1. Autophagy. 2021 Nov 15. 1-3
    Beyond mitophagy: mitochondrial-derived vesicles can get the job done!
    Payel Mondal, Christina Towers.
      Mitochondria are critical organelles that maintain cellular metabolism and overall function. The catabolic pathway of autophagy plays a central role in recycling damaged mitochondria. Although the autophagy pathway is indispensable for some cancer cell survival, our latest study shows that rare autophagy-dependent cancer cells can adapt to loss of this core pathway. In the process, the autophagy-deficient cells acquire unique dependencies on alternate forms of mitochondrial homeostasis. These rare autophagy-deficient clones circumvent the lack of canonical autophagy by increasing mitochondrial dynamics and by recycling damaged mitochondria via mitochondrial-derived vesicles (MDVs). These studies are the first to implicate MDVs in cancer cell metabolism although many unanswered questions remain about this non-canonical pathway.
    Keywords:  Cancer; mitochondrial fusion; mitochondrial-derived vesicles; mitophagy; non-canonical autophagy
    DOI:  https://doi.org/10.1080/15548627.2021.1999562
  2. Nat Metab. 2021 Nov;3(11): 1500-1511
    Methionine synthase is essential for cancer cell proliferation in physiological folate environments.
    Mark R Sullivan, Alicia M Darnell, Montana F Reilly, Tenzin Kunchok, Lena Joesch-Cohen, Daniel Rosenberg, Ahmed Ali, Matthew G Rees, Jennifer A Roth, Caroline A Lewis, Matthew G Vander Heiden.
      Folate metabolism can be an effective target for cancer treatment. However, standard cell culture conditions utilize folic acid, a non-physiological folate source for most tissues. We find that the enzyme that couples folate and methionine metabolic cycles, methionine synthase, is required for cancer cell proliferation and tumour growth when 5-methyl tetrahydrofolate (THF), the major folate found in circulation, is the extracellular folate source. In such physiological conditions, methionine synthase incorporates 5-methyl THF into the folate cycle to maintain intracellular levels of the folates needed for nucleotide production. 5-methyl THF can sustain intracellular folate metabolism in the absence of folic acid. Therefore, cells exposed to 5-methyl THF are more resistant to methotrexate, an antifolate drug that specifically blocks folic acid incorporation into the folate cycle. Together, these data argue that the environmental folate source has a profound effect on folate metabolism, determining how both folate cycle enzymes and antifolate drugs impact proliferation.
    DOI:  https://doi.org/10.1038/s42255-021-00486-5
  3. Nat Metab. 2021 Nov;3(11): 1512-1520
    Methionine synthase supports tumour tetrahydrofolate pools.
    Jonathan M Ghergurovich, Xincheng Xu, Joshua Z Wang, Lifeng Yang, Rolf-Peter Ryseck, Lin Wang, Joshua D Rabinowitz.
      Mammalian cells require activated folates to generate nucleotides for growth and division. The most abundant circulating folate species is 5-methyl tetrahydrofolate (5-methyl-THF), which is used to synthesize methionine from homocysteine via the cobalamin-dependent enzyme methionine synthase (MTR). Cobalamin deficiency traps folates as 5-methyl-THF. Here, we show using isotope tracing that MTR is only a minor source of methionine in cell culture, tissues or xenografted tumours. Instead, MTR is required for cells to avoid folate trapping and assimilate 5-methyl-THF into other folate species. Under conditions of physiological extracellular folates, genetic MTR knockout in tumour cells leads to folate trapping, purine synthesis stalling, nucleotide depletion and impaired growth in cell culture and as xenografts. These defects are rescued by free folate but not one-carbon unit supplementation. Thus, MTR plays a crucial role in liberating THF for use in one-carbon metabolism.
    DOI:  https://doi.org/10.1038/s42255-021-00465-w
  4. Nat Metab. 2021 Nov;3(11): 1521-1535
    The metabolic growth limitations of petite cells lacking the mitochondrial genome.
    Jakob Vowinckel, Johannes Hartl, Hans Marx, Martin Kerick, Kathrin Runggatscher, Markus A Keller, Michael Mülleder, Jason Day, Manuela Weber, Mark Rinnerthaler, Jason S L Yu, Simran Kaur Aulakh, Andrea Lehmann, Diethard Mattanovich, Bernd Timmermann, Nianshu Zhang, Cory D Dunn, James I MacRae, Michael Breitenbach, Markus Ralser.
      Eukaryotic cells can survive the loss of their mitochondrial genome, but consequently suffer from severe growth defects. 'Petite yeasts', characterized by mitochondrial genome loss, are instrumental for studying mitochondrial function and physiology. However, the molecular cause of their reduced growth rate remains an open question. Here we show that petite cells suffer from an insufficient capacity to synthesize glutamate, glutamine, leucine and arginine, negatively impacting their growth. Using a combination of molecular genetics and omics approaches, we demonstrate the evolution of fast growth overcomes these amino acid deficiencies, by alleviating a perturbation in mitochondrial iron metabolism and by restoring a defect in the mitochondrial tricarboxylic acid cycle, caused by aconitase inhibition. Our results hence explain the slow growth of mitochondrial genome-deficient cells with a partial auxotrophy in four amino acids that results from distorted iron metabolism and an inhibited tricarboxylic acid cycle.
    DOI:  https://doi.org/10.1038/s42255-021-00477-6
  5. Mol Cell. 2021 Nov 08. pii: S1097-2765(21)00910-2. [Epub ahead of print]
    Balancing of mitochondrial translation through METTL8-mediated m3C modification of mitochondrial tRNAs.
    Eva Schöller, James Marks, Virginie Marchand, Astrid Bruckmann, Christopher A Powell, Markus Reichold, Christian Daniel Mutti, Katja Dettmer, Regina Feederle, Stefan Hüttelmaier, Mark Helm, Peter Oefner, Michal Minczuk, Yuri Motorin, Markus Hafner, Gunter Meister.
      Mitochondria contain a specific translation machinery for the synthesis of mitochondria-encoded respiratory chain components. Mitochondrial tRNAs (mt-tRNAs) are also generated from the mitochondrial DNA and, similar to their cytoplasmic counterparts, are post-transcriptionally modified. Here, we find that the RNA methyltransferase METTL8 is a mitochondrial protein that facilitates 3-methyl-cytidine (m3C) methylation at position C32 of the mt-tRNASer(UCN) and mt-tRNAThr. METTL8 knockout cells show a reduction in respiratory chain activity, whereas overexpression increases activity. In pancreatic cancer, METTL8 levels are high, which correlates with lower patient survival and an enhanced respiratory chain activity. Mitochondrial ribosome profiling uncovered mitoribosome stalling on mt-tRNASer(UCN)- and mt-tRNAThr-dependent codons. Further analysis of the respiratory chain complexes using mass spectrometry revealed reduced incorporation of the mitochondrially encoded proteins ND6 and ND1 into complex I. The well-balanced translation of mt-tRNASer(UCN)- and mt-tRNAThr-dependent codons through METTL8-mediated m3C32 methylation might, therefore, facilitate the optimal composition and function of the mitochondrial respiratory chain.
    Keywords:  METTL8; RNA modification; m(3)C; mt-tRNA; translation
    DOI:  https://doi.org/10.1016/j.molcel.2021.10.018
  6. Oxid Med Cell Longev. 2021 ;2021 1341604
    Interplay between Mitochondrial Metabolism and Cellular Redox State Dictates Cancer Cell Survival.
    Brittney Joy-Anne Foo, Jie Qing Eu, Jayshree L Hirpara, Shazib Pervaiz.
      Mitochondria are the main powerhouse of the cell, generating ATP through the tricarboxylic acid cycle (TCA) and oxidative phosphorylation (OXPHOS), which drives myriad cellular processes. In addition to their role in maintaining bioenergetic homeostasis, changes in mitochondrial metabolism, permeability, and morphology are critical in cell fate decisions and determination. Notably, mitochondrial respiration coupled with the passage of electrons through the electron transport chain (ETC) set up a potential source of reactive oxygen species (ROS). While low to moderate increase in intracellular ROS serves as secondary messenger, an overwhelming increase as a result of either increased production and/or deficient antioxidant defenses is detrimental to biomolecules, cells, and tissues. Since ROS and mitochondria both regulate cell fate, attention has been drawn to their involvement in the various processes of carcinogenesis. To that end, the link between a prooxidant milieu and cell survival and proliferation as well as a switch to mitochondrial OXPHOS associated with recalcitrant cancers provide testimony for the remarkable metabolic plasticity as an important hallmark of cancers. In this review, the regulation of cell redox status by mitochondrial metabolism and its implications for cancer cell fate will be discussed followed by the significance of mitochondria-targeted therapies for cancer.
    DOI:  https://doi.org/10.1155/2021/1341604
  7. EMBO Rep. 2021 Nov 15. e53054
    Metabolic resistance to the inhibition of mitochondrial transcription revealed by CRISPR-Cas9 screen.
    Mara Mennuni, Roberta Filograna, Andrea Felser, Nina A Bonekamp, Patrick Giavalisco, Oleksandr Lytovchenko, Nils-Göran Larsson.
      Cancer cells depend on mitochondria to sustain their increased metabolic need and mitochondria therefore constitute possible targets for cancer treatment. We recently developed small-molecule inhibitors of mitochondrial transcription (IMTs) that selectively impair mitochondrial gene expression. IMTs have potent antitumor properties in vitro and in vivo, without affecting normal tissues. Because therapy-induced resistance is a major constraint to successful cancer therapy, we investigated mechanisms conferring resistance to IMTs. We employed a CRISPR-Cas9 (clustered regularly interspaced short palindromic repeats)-(CRISP-associated protein 9) whole-genome screen to determine pathways conferring resistance to acute IMT1 treatment. Loss of genes belonging to von Hippel-Lindau (VHL) and mammalian target of rapamycin complex 1 (mTORC1) pathways caused resistance to acute IMT1 treatment and the relevance of these pathways was confirmed by chemical modulation. We also generated cells resistant to chronic IMT treatment to understand responses to persistent mitochondrial gene expression impairment. We report that IMT1-acquired resistance occurs through a compensatory increase of mitochondrial DNA (mtDNA) expression and cellular metabolites. We found that mitochondrial transcription factor A (TFAM) downregulation and inhibition of mitochondrial translation impaired survival of resistant cells. The identified susceptibility and resistance mechanisms to IMTs may be relevant for different types of mitochondria-targeted therapies.
    Keywords:  CRISPR-Cas9 screen; cancer; chemoresistance; inhibitor of mitochondrial transcription; mtDNA
    DOI:  https://doi.org/10.15252/embr.202153054
  8. J Clin Invest. 2021 Nov 15. pii: e144871. [Epub ahead of print]131(22):
    Folliculin impairs breast tumor growth by repressing TFE3-dependent induction of the Warburg effect and angiogenesis.
    Leeanna El-Houjeiri, Marco Biondini, Mathieu Paquette, Helen Kuasne, Alain Pacis, Morag Park, Peter M Siegel, Arnim Pause.
      Growing tumors exist in metabolically compromised environments that require activation of multiple pathways to scavenge nutrients to support accelerated rates of growth. The folliculin (FLCN) tumor suppressor complex (FLCN, FNIP1, FNIP2) is implicated in the regulation of energy homeostasis via 2 metabolic master kinases: AMPK and mTORC1. Loss-of-function mutations of the FLCN tumor suppressor complex have only been reported in renal tumors in patients with the rare Birt-Hogg-Dube syndrome. Here, we revealed that FLCN, FNIP1, and FNIP2 are downregulated in many human cancers, including poor-prognosis invasive basal-like breast carcinomas where AMPK and TFE3 targets are activated compared with the luminal, less aggressive subtypes. FLCN loss in luminal breast cancer promoted tumor growth through TFE3 activation and subsequent induction of several pathways, including autophagy, lysosomal biogenesis, aerobic glycolysis, and angiogenesis. Strikingly, induction of aerobic glycolysis and angiogenesis in FLCN-deficient cells was dictated by the activation of the PGC-1α/HIF-1α pathway, which we showed to be TFE3 dependent, directly linking TFE3 to Warburg metabolic reprogramming and angiogenesis. Conversely, FLCN overexpression in invasive basal-like breast cancer models attenuated TFE3 nuclear localization, TFE3-dependent transcriptional activity, and tumor growth. These findings support a general role of a deregulated FLCN/TFE3 tumor suppressor pathway in human cancers.
    Keywords:  Angiogenesis; Breast cancer; Cancer; Metabolism
    DOI:  https://doi.org/10.1172/JCI144871
  9. Commun Biol. 2021 Nov 16. 4(1): 1289
    DLST-dependence dictates metabolic heterogeneity in TCA-cycle usage among triple-negative breast cancer.
    Ning Shen, Sovannarith Korm, Theodoros Karantanos, Dun Li, Xiaoyu Zhang, Eleni Ritou, Hanfei Xu, Andrew Lam, Justin English, Wei-Xing Zong, Ching-Ti Liu, Orian Shirihai, Hui Feng.
      Triple-negative breast cancer (TNBC) is traditionally considered a glycolytic tumor with a poor prognosis while lacking targeted therapies. Here we show that high expression of dihydrolipoamide S-succinyltransferase (DLST), a tricarboxylic acid (TCA) cycle enzyme, predicts poor overall and recurrence-free survival among TNBC patients. DLST depletion suppresses growth and induces death in subsets of human TNBC cell lines, which are capable of utilizing glutamine anaplerosis. Metabolomics profiling reveals significant changes in the TCA cycle and reactive oxygen species (ROS) related pathways for sensitive but not resistant TNBC cells. Consequently, DLST depletion in sensitive TNBC cells increases ROS levels while N-acetyl-L-cysteine partially rescues cell growth. Importantly, suppression of the TCA cycle through DLST depletion or CPI-613, a drug currently in clinical trials for treating other cancers, decreases the burden and invasion of these TNBC. Together, our data demonstrate differential TCA-cycle usage in TNBC and provide therapeutic implications for the DLST-dependent subsets.
    DOI:  https://doi.org/10.1038/s42003-021-02805-8
  10. Life Sci Alliance. 2022 Feb;pii: e202101278. [Epub ahead of print]5(2):
    Serine palmitoyltransferase assembles at ER-mitochondria contact sites.
    Mari J Aaltonen, Irina Alecu, Tim König, Steffany Al Bennett, Eric A Shoubridge.
      The accumulation of sphingolipid species in the cell contributes to the development of obesity and neurological disease. However, the subcellular localization of sphingolipid-synthesizing enzymes is unclear, limiting the understanding of where and how these lipids accumulate inside the cell and why they are toxic. Here, we show that SPTLC2, a subunit of the serine palmitoyltransferase (SPT) complex, catalyzing the first step in de novo sphingolipid synthesis, localizes dually to the ER and the outer mitochondrial membrane. We demonstrate that mitochondrial SPTLC2 interacts and forms a complex in trans with the ER-localized SPT subunit SPTLC1. Loss of SPTLC2 prevents the synthesis of mitochondrial sphingolipids and protects from palmitate-induced mitochondrial toxicity, a process dependent on mitochondrial ceramides. Our results reveal the in trans assembly of an enzymatic complex at an organellar membrane contact site, providing novel insight into the localization of sphingolipid synthesis and the composition and function of ER-mitochondria contact sites.
    DOI:  https://doi.org/10.26508/lsa.202101278
  11. Biotechnol Bioeng. 2021 Nov 17.
    Metabolic Analysis of the Asparagine and Glutamine Dynamics in an Industrial CHO Fed-Batch Process.
    Brian James Kirsch, Sandra V Bennun, Adam Mendez, Amy S Johnson, Hongxia Wang, Haibo Qiu, Ning Li, Shawn M Lawrence, Hanne Bak, Michael J Betenbaugh.
      Chinese Hamster Ovary (CHO) cell lines are grown in cultures with varying asparagine and glutamine concentrations, but further study is needed to characterize the interplay between these amino acids. By following 13 C-glucose, 13 C-glutamine, and 13 C-asparagine tracers using metabolic flux analysis (MFA), CHO cell metabolism was characterized in an industrially relevant fed-batch process under glutamine supplemented and low glutamine conditions during early and late exponential growth. For both conditions MFA revealed glucose as the primary carbon source to the tricarboxylic acid (TCA) cycle followed by glutamine and asparagine as secondary sources. Early exponential phase CHO cells prefer glutamine over asparagine to support the TCA cycle under the glutamine supplemented condition, while asparagine was critical for TCA activity for the low glutamine condition. Overall TCA fluxes were similar for both conditions due to the trade-offs associated with reliance on glutamine and/or asparagine. However, glutamine supplementation increased fluxes to alanine, lactate and enrichment of glutathione, N-Acetyl-Glucosamine (NAG) and pyrimidine-containing-molecules. The late exponential phase exhibited reduced central carbon metabolism dominated by glucose, while lactate reincorporation and aspartate uptake were preferred over glutamine and asparagine. These 13 C studies demonstrate that metabolic flux is process time dependent and can be modulated by varying feed composition. This article is protected by copyright. All rights reserved.
    Keywords:   13C tracers; Chinese hamster ovary cells; Metabolic Flux Analysis (MFA); asparagine; fed-batch; glucose; glutamine; glutathione; metabolism; pyrimidine synthesis
    DOI:  https://doi.org/10.1002/bit.27993
  12. Kidney Res Clin Pract. 2021 Nov 01.
    Fructose in the kidney: from physiology to pathology.
    Takahiko Nakagawa, Duk-Hee Kang.
      The Warburg effect is a unique property of cancer cells, in which glycolysis is activated instead of mitochondrial respiration despite oxygen availability. However, recent studies found that the Warburg effect also mediates non-cancer disorders, including kidney disease. Currently, diabetes or glucose has been postulated to mediate the Warburg effect in the kidney, but it is of importance that the Warburg effect can be induced under nondiabetic conditions. Fructose is endogenously produced in several organs, including the kidney, under both physiological and pathological conditions. In the kidney, fructose is predominantly metabolized in the proximal tubules; under normal physiologic conditions, fructose is utilized as a substrate for gluconeogenesis and contributes to maintain systemic glucose concentration under starvation conditions. However, when present in excess, fructose likely becomes deleterious, possibly due in part to excessive uric acid, which is a by-product of fructose metabolism. A potential mechanism is that uric acid suppresses aconitase in the Krebs cycle and therefore reduces mitochondrial oxidation. Consequently, fructose favors glycolysis over mitochondrial respiration, a process that is similar to the Warburg effect in cancer cells. Activation of glycolysis also links to several side pathways, including the pentose phosphate pathway, hexosamine pathway, and lipid synthesis, to provide biosynthetic precursors as fuel for renal inflammation and fibrosis. We now hypothesize that fructose could be the mediator for the Warburg effect in the kidney and a potential mechanism for chronic kidney disease.
    Keywords:  Fructose; Glycolysis; Inflammation; Mitochondria; Proximal tubules; Uric acid; Warburg effect
    DOI:  https://doi.org/10.23876/j.krcp.21.138
  13. Oncogene. 2021 Nov 16.
    Histone N-terminal acetyltransferase NAA40 links one-carbon metabolism to chemoresistance.
    Christina Demetriadou, Anastasia Raoukka, Evelina Charidemou, Constantine Mylonas, Christina Michael, Swati Parekh, Costas Koufaris, Paris Skourides, Panagiotis Papageorgis, Peter Tessarz, Antonis Kirmizis.
      Aberrant function of epigenetic modifiers plays an important role not only in the progression of cancer but also the development of drug resistance. N-alpha-acetyltransferase 40 (NAA40) is a highly specific epigenetic enzyme catalyzing the transfer of an acetyl moiety at the N-terminal end of histones H4 and H2A. Recent studies have illustrated the essential oncogenic role of NAA40 in various cancer types but its role in chemoresistance remains unclear. Here, using transcriptomic followed by metabolomic analysis in colorectal cancer (CRC) cells, we demonstrate that NAA40 controls key one-carbon metabolic genes and corresponding metabolites. In particular, through its acetyltransferase activity NAA40 regulates the methionine cycle thereby affecting global histone methylation and CRC cell survival. Importantly, NAA40-mediated metabolic rewiring promotes resistance of CRC cells to antimetabolite chemotherapy in vitro and in xenograft models. Specifically, NAA40 stimulates transcription of the one-carbon metabolic gene thymidylate synthase (TYMS), whose product is targeted by 5-fluorouracil (5-FU) and accordingly in primary CRC tumours NAA40 expression associates with TYMS levels and poorer 5-FU response. Mechanistically, NAA40 activates TYMS by preventing enrichment of repressive H2A/H4S1ph at the nuclear periphery. Overall, these findings define a novel regulatory link between epigenetics and cellular metabolism mediated by NAA40, which is harnessed by cancer cells to evade chemotherapy.
    DOI:  https://doi.org/10.1038/s41388-021-02113-9
  14. Nature. 2021 Nov 18.
    CRISPR screens unveil signal hubs for nutrient licensing of T cell immunity.
    Lingyun Long, Jun Wei, Seon Ah Lim, Jana L Raynor, Hao Shi, Jon P Connelly, Hong Wang, Cliff Guy, Boer Xie, Nicole M Chapman, Guotong Fu, Yanyan Wang, Hongling Huang, Wei Su, Jordy Saravia, Isabel Risch, Yong-Dong Wang, Yuxin Li, Mingming Niu, Yogesh Dhungana, Anil Kc, Peipei Zhou, Peter Vogel, Jiyang Yu, Shondra M Pruett-Miller, Junmin Peng, Hongbo Chi.
      Nutrients are emerging regulators of adaptive immunity1. Selective nutrients interplay with immunological signals to activate mechanistic target of rapamycin complex 1 (mTORC1), a key driver of cell metabolism2-4, but how these environmental signals are integrated for immune regulation remains unclear. Here we use genome-wide CRISPR screening combined with protein-protein interaction networks to identify regulatory modules that mediate immune receptor- and nutrient-dependent signalling to mTORC1 in mouse regulatory T (Treg) cells. SEC31A is identified to promote mTORC1 activation by interacting with the GATOR2 component SEC13 to protect it from SKP1-dependent proteasomal degradation. Accordingly, loss of SEC31A impairs T cell priming and Treg suppressive function in mice. In addition, the SWI/SNF complex restricts expression of the amino acid sensor CASTOR1, thereby enhancing mTORC1 activation. Moreover, we reveal that the CCDC101-associated SAGA complex is a potent inhibitor of mTORC1, which limits the expression of glucose and amino acid transporters and maintains T cell quiescence in vivo. Specific deletion of Ccdc101 in mouse Treg cells results in uncontrolled inflammation but improved antitumour immunity. Collectively, our results establish epigenetic and post-translational mechanisms that underpin how nutrient transporters, sensors and transducers interplay with immune signals for three-tiered regulation of mTORC1 activity and identify their pivotal roles in licensing T cell immunity and immune tolerance.
    DOI:  https://doi.org/10.1038/s41586-021-04109-7
  15. Biochem Biophys Res Commun. 2021 Nov 12. pii: S0006-291X(21)01545-X. [Epub ahead of print]585 61-67
    Contribution of branched chain amino acids to energy production and mevalonate synthesis in cancer cells.
    Valeryia Mikalayeva, Monika Pankevičiūtė, Vaidotas Žvikas, V Arvydas Skeberdis, Sergio Bordel.
      Leucine, isoleucine and valine, known as branched chain amino acids (BCAAs), have been reported to be degraded by different cancer cells, and their biodegradation pathways have been suggested as anticancer targets. However, the mechanisms by which the degradation of BCAAs could support the growth of cancer cells remains unclear. In this work, 13C experiments have been carried out in order to elucidate the metabolic role of BCAA degradation in two breast cancer cell lines (MCF-7 and BCC). The results revealed that up to 36% of the energy production via respiration by MCF-7 cells was supported by the degradation of BCAAs. Also, 67% of the mevalonate (the precursor of cholesterol) synthesized by the cells was coming from the degradation of leucine. The results were lower for BCC cells (14 and 30%, respectively). The non-tumorigenic epythelial cell line MCF-10A was used as a control, showing that 10% of the mitochondrial acetyl-CoA comes from the degradation of BCAAs and no mevalonate production. Metabolic flux analysis around the mevalonate node, also revealed that significant amounts of acetoacetate are being produced from BCAA derived carbon, which could be at the source of lipid synthesis. From these results we can conclude that the degradation of BCAAs is an important energy and carbon source for the proliferation of some cancer cells and its therapeutic targeting could be an interesting option.
    Keywords:  Branched chain amino-acids; Cancer metabolism; Metabolic flux analysis
    DOI:  https://doi.org/10.1016/j.bbrc.2021.11.034
  16. Nat Nanotechnol. 2021 Nov 18.
    Intercellular nanotubes mediate mitochondrial trafficking between cancer and immune cells.
    Tanmoy Saha, Chinmayee Dash, Ruparoshni Jayabalan, Sachin Khiste, Arpita Kulkarni, Kiran Kurmi, Jayanta Mondal, Pradip K Majumder, Aditya Bardia, Hae Lin Jang, Shiladitya Sengupta.
      Cancer progresses by evading the immune system. Elucidating diverse immune evasion strategies is a critical step in the search for next-generation immunotherapies for cancer. Here we report that cancer cells can hijack the mitochondria from immune cells via physical nanotubes. Mitochondria are essential for metabolism and activation of immune cells. By using field-emission scanning electron microscopy, fluorophore-tagged mitochondrial transfer tracing and metabolic quantification, we demonstrate that the nanotube-mediated transfer of mitochondria from immune cells to cancer cells metabolically empowers the cancer cells and depletes the immune cells. Inhibiting the nanotube assembly machinery significantly reduced mitochondrial transfer and prevented the depletion of immune cells. Combining a farnesyltransferase and geranylgeranyltransferase 1 inhibitor, namely, L-778123, which partially inhibited nanotube formation and mitochondrial transfer, with a programmed cell death protein 1 immune checkpoint inhibitor improved the antitumour outcomes in an aggressive immunocompetent breast cancer model. Nanotube-mediated mitochondrial hijacking can emerge as a novel target for developing next-generation immunotherapy agents for cancer.
    DOI:  https://doi.org/10.1038/s41565-021-01000-4
  17. Nat Commun. 2021 Nov 18. 12(1): 6708
    A somatic proteoglycan controls Notch-directed germ cell fate.
    Sandeep Gopal, Aqilah Amran, Andre Elton, Leelee Ng, Roger Pocock.
      Communication between the soma and germline optimizes germ cell fate programs. Notch receptors are key determinants of germ cell fate but how somatic signals direct Notch-dependent germ cell behavior is undefined. Here we demonstrate that SDN-1 (syndecan-1), a somatic transmembrane proteoglycan, controls expression of the GLP-1 (germline proliferation-1) Notch receptor in the Caenorhabditis elegans germline. We find that SDN-1 control of a somatic TRP calcium channel governs calcium-dependent binding of an AP-2 transcription factor (APTF-2) to the glp-1 promoter. Hence, SDN-1 signaling promotes GLP-1 expression and mitotic germ cell fate. Together, these data reveal SDN-1 as a putative communication nexus between the germline and its somatic environment to control germ cell fate decisions.
    DOI:  https://doi.org/10.1038/s41467-021-27039-4
  18. Int J Obes (Lond). 2021 Nov 19.
    Insulin resistance rewires the metabolic gene program and glucose utilization in human white adipocytes.
    Marie S Isidor, Wentao Dong, Rogelio I Servin-Uribe, Julia Villarroel, Ali Altıntaş, J Tonatiuh Ayala-Sumuano, Alfredo Varela-Echavarría, Romain Barrès, Gregory Stephanopoulos, Yazmín Macotela, Brice Emanuelli.
       BACKGROUND: In obesity, adipose tissue dysfunction resulting from excessive fat accumulation leads to systemic insulin resistance (IR), the underlying alteration of Type 2 Diabetes. The specific pathways dysregulated in dysfunctional adipocytes and the extent to which it affects adipose metabolic functions remain incompletely characterized.
    METHODS: We interrogated the transcriptional adaptation to increased adiposity in association with insulin resistance in visceral white adipose tissue from lean men, or men presenting overweight/obesity (BMI from 19 to 33) and discordant for insulin sensitivity. In human adipocytes in vitro, we investigated the direct contribution of IR in altering metabolic gene programming and glucose utilization using 13C-isotopic glucose tracing.
    RESULTS: We found that gene expression associated with impaired glucose and lipid metabolism and inflammation represented the strongest association with systemic insulin resistance, independently of BMI. In addition, we showed that inducing IR in mature human white adipocytes was sufficient to reprogram the transcriptional profile of genes involved in important metabolic functions such as glycolysis, the pentose phosphate pathway and de novo lipogenesis. Finally, we found that IR induced a rewiring of glucose metabolism, with higher incorporation of glucose into citrate, but not into downstream metabolites within the TCA cycle.
    CONCLUSIONS: Collectively, our data highlight the importance of obesity-derived insulin resistance in impacting the expression of key metabolic genes and impairing the metabolic processes of glucose utilization, and reveal a role for metabolic adaptation in adipose dysfunction in humans.
    DOI:  https://doi.org/10.1038/s41366-021-01021-y
  19. Metabolomics. 2021 Nov 18. 17(12): 101
    Cross-comparison of systemic and tissue-specific metabolomes in a mouse model of Leigh syndrome.
    Karin Terburgh, Jeremie Z Lindeque, Francois H van der Westhuizen, Roan Louw.
       INTRODUCTION: The value of metabolomics in multi-systemic mitochondrial disease research has been increasingly recognized, with the ability to investigate a variety of biofluids and tissues considered a particular advantage. Although minimally invasive biofluids are the generally favored sample type, it remains unknown whether systemic metabolomes provide a clear reflection of tissue-specific metabolic alterations.
    OBJECTIVES: Here we cross-compare urine and tissue-specific metabolomes in the Ndufs4 knockout mouse model of Leigh syndrome-a complex neurometabolic MD defined by progressive focal lesions in specific brain regions-to identify and evaluate the extent of common and unique metabolic alterations on a systemic and brain regional level.
    METHODS: Untargeted and semi-targeted multi-platform metabolomics were performed on urine, four brain regions, and two muscle types of Ndufs4 KO (n≥19) vs wildtype (n≥20) mice.
    RESULTS: Widespread alterations were evident in alanine, aspartate, glutamate, and arginine metabolism in Ndufs4 KO mice; while brain-region specific metabolic signatures include the accumulation of branched-chain amino acids, proline, and glycolytic intermediates. Furthermore, we describe a systemic dysregulation in one-carbon metabolism and the tricarboxylic acid cycle, which was not clearly reflected in the Ndufs4 KO brain.
    CONCLUSION: Our results confirm the value of urinary metabolomics when evaluating MD-associated metabolites, while cautioning against mechanistic studies relying solely on systemic biofluids.
    Keywords:  Brain regions; Complex I deficiency; Leigh syndrome; Metabolomics; Mitochondrial disease; Ndufs4 knockout mice
    DOI:  https://doi.org/10.1007/s11306-021-01854-8
  20. Sci Adv. 2021 Nov 19. 7(47): eabk1023
    Activation of the NRF2 antioxidant program sensitizes tumors to G6PD inhibition.
    Hongyu Ding, Zihong Chen, Katherine Wu, Shih Ming Huang, Warren L Wu, Sarah E LeBoeuf, Ray G Pillai, Joshua D Rabinowitz, Thales Papagiannakopoulos.
      [Figure: see text].
    DOI:  https://doi.org/10.1126/sciadv.abk1023
  21. Cell Rep. 2021 Nov 16. pii: S2211-1247(21)01506-0. [Epub ahead of print]37(7): 110024
    AMPK adapts metabolism to developmental energy requirement during dendrite pruning in Drosophila.
    Marco Marzano, Svende Herzmann, Leonardo Elsbroek, Neeraja Sanal, Katsiaryna Tarbashevich, Erez Raz, Michael P Krahn, Sebastian Rumpf.
      To reshape neuronal connectivity in adult stages, Drosophila sensory neurons prune their dendrites during metamorphosis using a genetic degeneration program that is induced by the steroid hormone ecdysone. Metamorphosis is a nonfeeding stage that imposes metabolic constraints on development. We find that AMP-activated protein kinase (AMPK), a regulator of energy homeostasis, is cell-autonomously required for dendrite pruning. AMPK is activated by ecdysone and promotes oxidative phosphorylation and pyruvate usage, likely to enable neurons to use noncarbohydrate metabolites such as amino acids for energy production. Loss of AMPK or mitochondrial deficiency causes specific defects in pruning factor translation and the ubiquitin-proteasome system. Our findings distinguish pruning from pathological neurite degeneration, which is often induced by defects in energy production, and highlight how metabolism is adapted to fit energy-costly developmental transitions.
    Keywords:  AMPK; dendrite; proteasome; pruning; pyruvate; translation
    DOI:  https://doi.org/10.1016/j.celrep.2021.110024
  22. Cell Chem Biol. 2021 Nov 18. pii: S2451-9456(21)00477-3. [Epub ahead of print]28(11): 1539-1541
    Sweet sensation: Developing a single-cell fluorescent reporter of glycolytic heterogeneity.
    Diane B Karloff, Jennifer M Heemstra.
      Conversion of in vitro selected aptamers into functional metabolic sensors is hampered by reduced in vivo aptamer binding and limited tunability of cellular metabolite levels. In this issue of Cell Chemical Biology, Ortega et al. (2021) construct RNA sensors of fructose-6-bisphosphate (FBP) that report on metabolite levels within single yeast cells.
    DOI:  https://doi.org/10.1016/j.chembiol.2021.10.013
  23. J Biol Chem. 2021 Nov 11. pii: S0021-9258(21)01209-6. [Epub ahead of print] 101402
    BAd-CRISPR: inducible gene knockout in interscapular brown adipose tissue of adult mice.
    Steven M Romanelli, Kenneth T Lewis, Akira Nishii, Alan C Rupp, Ziru Li, Hiroyuki Mori, Rebecca L Schill, Brian S Learman, Christopher J Rhodes, Ormond A MacDougald.
      CRISPR/Cas9 has enabled inducible gene knockout in numerous tissues; however, its use has not been reported in brown adipose tissue (BAT). Here we developed brown adipocyte CRISPR (BAd-CRISPR) methodology to rapidly interrogate function of one or multiple genes. With BAd-CRISPR, an adeno-associated virus (AAV8) expressing a single guide RNA (sgRNA) is administered directly to BAT of mice expressing Cas9 in brown adipocytes. We show that local administration of AAV8-sgRNA to interscapular BAT of adult mice robustly transduced brown adipocytes and ablated expression of adiponectin (Adipoq), adipose triglyceride lipase (Atgl), fatty acid synthase (Fasn), perilipin 1 (Plin1), or stearoyl-CoA desaturase 1 (Scd1) by >90%. Administration of multiple AAV8 sgRNAs led to simultaneous knockout of up to three genes. BAd-CRISPR induced frameshift mutations and suppressed target gene mRNA expression but did not lead to substantial accumulation of off-target mutations in BAT. We used BAd-CRISPR to create an inducible uncoupling protein 1 (Ucp1) knockout mouse to assess effects of UCP1 loss on adaptive thermogenesis in adult mice. Inducible Ucp1 knockout did not alter core body temperature; however, BAd-CRISPR Ucp1 mice had elevated circulating concentrations of fibroblast growth factor 21 (FGF21), and changes in BAT gene expression consistent with heat production through increased peroxisomal lipid oxidation. Other molecular adaptations predict additional cellular inefficiencies, with an increase in both protein synthesis and turnover, and mitochondria with reduced reliance on mitochondrial-encoded gene expression and increased expression of nuclear-encoded mitochondrial genes. These data suggest that BAd-CRISPR is an efficient tool to speed discoveries in adipose tissue biology.
    Keywords:  CRISPR/Cas; adipocyte; adiponectin; adipose tissue; adipose triglyceride lipase (ATGL); brown adipose tissue; fatty acid synthase (FASN); perilipin; stearoyl CoA desaturase I (SCD1); uncoupling protein
    DOI:  https://doi.org/10.1016/j.jbc.2021.101402
  24. Nat Metab. 2021 Nov;3(11): 1436-1438
    A new foe in folate metabolism.
    Zhengwei Wu, Wai Leong Tam.
      
    DOI:  https://doi.org/10.1038/s42255-021-00474-9
  25. JCI Insight. 2021 Nov 18. pii: e153019. [Epub ahead of print]
    Cell stress response impairs de novo NAD+ biosynthesis in the kidney.
    Yohan Bignon, Anna Rinaldi, Zahia Nadour, Virginie Poindessous, Ivan Nemazanyy, Olivia Lenoir, Baptiste Fohlen, Pierre Weill-Raynal, Alexandre Hertig, Alexandre Karras, Pierre Galichon, Maarten Naesens, Dany Anglicheau, Pietro E Cippà, Nicolas Pallet.
      The biosynthetic routes leading to de novo Nicotinamine Adenine Dinucleotide (NAD+) production are involved in acute kidney injury (AKI) with a critical role for Quinolinate Phosphoribosyl Transferase (QPRT), a bottleneck enzyme of de novo NAD+ biosynthesis. However, the molecular mechanisms determining reduced QPRT in AKI, and the role of impaired NAD+ biosynthesis in the progression to chronic kidney disease (CKD) are unknown. We demonstrate that a high urinary quinolinate to tryptophan ratio, an indirect indicator of impaired QPRT activity and reduced de novo NAD+ biosynthesis in the kidney, is a clinically applicable early marker of AKI after cardiopulmonary bypass, and is predictive of progression to chronic kidney disease (CKD) in kidney transplant recipients. We also provide evidence that the Endoplasmic Reticulum (ER) stress response impairs de novo NAD+ biosynthesis by repressing QPRT transcription. In conclusion, NAD+ biosynthesis impairment is an early event in AKI embedded with the ER stress response, and persistent reduction of QPRT expression is associated with AKI to CKD progression. This defines non-invasive metabolic biomarkers of kidney injury with prognostic and therapeutic implications.
    Keywords:  Bioenergetics; Cell stress; Diagnostics; Metabolism; Nephrology
    DOI:  https://doi.org/10.1172/jci.insight.153019
  26. FASEB J. 2021 Dec;35(12): e21974
    The role of the electron transport chain in immunity.
    Maureen Yin, Luke A J O'Neill.
      The electron transport chain (ETC) couples oxidative phosphorylation (OXPHOS) with ATP synthase to drive the generation of ATP. In immune cells, research surrounding the ETC has drifted away from bioenergetics since the discovery of cytochrome c (Cyt c) release as a signal for programmed cell death. Complex I has been shown to generate reactive oxygen species (ROS), with key roles identified in inflammatory macrophages and T helper 17 cells (TH 17) cells. Complex II is the site of reverse electron transport (RET) in inflammatory macrophages and is also responsible for regulating fumarate levels linking to epigenetic changes. Complex III also produces ROS which activate hypoxia-inducible factor 1-alpha (HIF-1α) and can participate in regulatory T cell (Treg ) function. Complex IV is required for T cell activation and differentiation and the proper development of Treg subsets. Complex V is required for TH 17 differentiation and can be expressed on the surface of tumor cells where it is recognized by anti-tumor T and NK cells. In this review, we summarize these findings and speculate on the therapeutic potential of targeting the ETC as an anti-inflammatory strategy.
    Keywords:  T-lymphocytes; electron transport chain (ETC); immunometabolism; macrophage; mitochondria; oxidative phosphorylation
    DOI:  https://doi.org/10.1096/fj.202101161R
  27. Cell Stress. 2021 Nov;5(11): 167-172
    Mechanisms of YAP/TAZ transcriptional control.
    Giusy Battilana, Francesca Zanconato, Stefano Piccolo.
      Dysregulated gene expression is intrinsic to cell transformation, tumorigenesis and metastasis. Cancer-specific gene-expression profiles stem from gene regulatory networks fueled by genetic and epigenetic defects, and by abnormal signals of the tumor microenvironment. These oncogenic signals ultimately engage the transcriptional machinery on the cis -regulatory elements of a host of effector genes, through recruitment of transcription factors (TFs), co-activators and chromatin regulators. That said, whether gene-expression in cancer cells is the chaotic product of myriad regulations or rather a relatively ordered process orchestrated by few TFs (master regulators) has long remained enigmatic. Recent work on the YAP/TAZ co-activators has been instrumental to break new ground into this outstanding issue, revealing that tumor cells hijack growth programs that are active during development and regeneration through engagement of a small set of interconnected TFs and their nuclear partners.
    Keywords:  AP-1; Brd4; Hippo; Mechanotransduction; YAP/TAZ; cancer; proliferation
    DOI:  https://doi.org/10.15698/cst2021.11.258
  28. Elife. 2021 Nov 18. pii: e68487. [Epub ahead of print]10
    Hydrogen sulfide blocks HIV rebound by maintaining mitochondrial bioenergetics and redox homeostasis.
    Virender Kumar Pal, Ragini Agrawal, Srabanti Rakshit, Pooja Shekar, Diwakar Tumkur Narasimha Murthy, Annapurna Vyakarnam, Amit Singh.
      A fundamental challenge in HIV eradication is to understand how the virus establishes latency, maintains stable cellular reservoirs, and promotes rebound upon interruption of antiretroviral treatment (ART). Here, we discovered an unexpected role of the ubiquitous gasotransmitter hydrogen sulfide (H2S) in HIV latency and reactivation. We show that reactivation of HIV-1 is associated with down-regulation of the key H2S producing enzyme cystathionine-g-lyase (CTH) and reduction in endogenous H2S. Genetic silencing of CTH disrupts redox homeostasis, impairs mitochondrial function, and remodels the transcriptome of latent cells to trigger HIV reactivation. Chemical complementation of CTH activity using a slow-releasing H2S donor, GYY4137, suppressed HIV reactivation and diminished virus replication. Mechanistically, GYY4137 blocked HIV reactivation by inducing the Keap1-Nrf2 pathway, inhibiting NF-kB, and recruiting the epigenetic silencer, YY1, to the HIV promoter. In latently infected CD4+ T cells from ART-suppressed human subjects, GYY4137 in combination with ART prevented viral rebound and improved mitochondrial bioenergetics. Moreover, prolonged exposure to GYY4137 exhibited no adverse influence on proviral content or CD4+ T cell subsets, indicating that diminished viral rebound is due to a loss of transcription rather than a selective loss of infected cells. In summary, this work provides mechanistic insight into H2S-mediated suppression of viral rebound and suggests exploration of H2S donors to maintain HIV in a latent form.
    Keywords:  biochemistry; chemical biology; infectious disease; microbiology; viruses
    DOI:  https://doi.org/10.7554/eLife.68487
  29. Nat Commun. 2021 Nov 17. 12(1): 6636
    Sequence logic at enhancers governs a dual mechanism of endodermal organ fate induction by FOXA pioneer factors.
    Ryan J Geusz, Allen Wang, Dieter K Lam, Nicholas K Vinckier, Konstantinos-Dionysios Alysandratos, David A Roberts, Jinzhao Wang, Samy Kefalopoulou, Araceli Ramirez, Yunjiang Qiu, Joshua Chiou, Kyle J Gaulton, Bing Ren, Darrell N Kotton, Maike Sander.
      FOXA pioneer transcription factors (TFs) associate with primed enhancers in endodermal organ precursors. Using a human stem cell model of pancreas differentiation, we here discover that only a subset of pancreatic enhancers is FOXA-primed, whereas the majority is unprimed and engages FOXA upon lineage induction. Primed enhancers are enriched for signal-dependent TF motifs and harbor abundant and strong FOXA motifs. Unprimed enhancers harbor fewer, more degenerate FOXA motifs, and FOXA recruitment to unprimed but not primed enhancers requires pancreatic TFs. Strengthening FOXA motifs at an unprimed enhancer near NKX6.1 renders FOXA recruitment pancreatic TF-independent, induces priming, and broadens the NKX6.1 expression domain. We make analogous observations about FOXA binding during hepatic and lung development. Our findings suggest a dual role for FOXA in endodermal organ development: first, FOXA facilitates signal-dependent lineage initiation via enhancer priming, and second, FOXA enforces organ cell type-specific gene expression via indirect recruitment by lineage-specific TFs.
    DOI:  https://doi.org/10.1038/s41467-021-26950-0
  30. J Int Med Res. 2021 Nov;49(11): 3000605211059936
    Sulphur metabolism in colon cancer tissues: a case report and literature review.
    Hironori Fukuoka, Tomohiro Andou, Takeo Moriya, Koji Narita, Ken Kasahara, Daisuke Miura, Yuji Sekiguchi, Shinsuke Suzuki, Kazuya Nakagawa, Mayumi Ozawa, Atsushi Ishibe, Itaru Endo.
      Sulphur-containing compounds have been linked to colorectal cancer by factors such as the presence of methyl mercaptan in intestinal gas and long-term dietary intake associated with sulphur-metabolizing microbiota. Therefore, this current case report hypothesized that active sulphur metabolism in colorectal cancer results in the formation of sulphur compounds in the intestine and, thus, examined sulphur metabolites possibly associated with sulphur respiration in colon cancer tissues. The patient was a 73-year-old female that underwent laparoscopic right hemicolectomy for ascending colon cancer. During the surgery, colon cancer tissues and normal intestinal mucosa samples were collected. After optimizing the sample concentrations for homogenization (pre-treatment), the samples were stabilized using a hydroxyphenyl-containing derivative and the relevant metabolites were quantified using liquid chromatography with tandem mass spectrometry. The results showed that cysteine persulfide and cysteine trisulfide levels were higher in colon cancer tissues than in normal mucosal tissues. Thus, sulphur metabolism, possibly sulphur respiration, is enhanced in colon cancer tissues.
    Keywords:  Case report; colon cancer tissue; cysteine persulfide; cysteine trisulfide; sulphur metabolites
    DOI:  https://doi.org/10.1177/03000605211059936
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