bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2022–05–22
forty papers selected by
Christian Frezza, , University of Cambridge, MRC Cancer Unit
  1. Purine nucleotide depletion prompts cell migration by stimulating the serine synthesis pathway.
  2. Mitochondrial TrxR2 regulates metabolism and protects from metabolic disease through enhanced TCA and ETC function.
  3. Cryo-EM structures define ubiquinone-10 binding to mitochondrial complex I and conformational transitions accompanying Q-site occupancy.
  4. Aspartate metabolism in endothelial cells activates the mTORC1 pathway to initiate translation during angiogenesis.
  5. PHGDH heterogeneity potentiates cancer cell dissemination and metastasis.
  6. Suppression of nuclear GSK3 signaling promotes serine/one-carbon metabolism and confers metabolic vulnerability in lung cancer cells.
  7. Metabolic diversity drives cancer cell invasion.
  8. Lipid droplet degradation by autophagy connects mitochondria metabolism to Prox1-driven expression of lymphatic genes and lymphangiogenesis.
  9. Identification of a modulator of the actin cytoskeleton, mitochondria, nutrient metabolism and lifespan in yeast.
  10. Reflected stemness as a potential driver of the tumour microenvironment.
  11. Mitochondria preserve an autarkic one-carbon cycle to confer growth-independent cancer cell migration and metastasis.
  12. Direct anabolic metabolism of three carbon propionate to a six carbon metabolite occurs in vivo across tissues and species.
  13. Mitochondrial calcium uniporter stabilization preserves energetic homeostasis during Complex I impairment.
  14. Ketotherapy: Cutting carbs to treat cancer.
  15. Cancer evolution: special focus on the immune aspect of cancer.
  16. Toll-9 interacts with Toll-1 to mediate a feedback loop during apoptosis-induced proliferation in Drosophila.
  17. Transcriptional control of energy metabolism by nuclear receptors.
  18. Upregulation of mitochondrial ATPase inhibitory factor 1 (ATPIF1) mediates increased glycolysis in mouse hearts.
  19. Inhibition of mitochondrial complex I reverses NOTCH1-driven metabolic reprogramming in T-cell acute lymphoblastic leukemia.
  20. Prolonged deprivation of arginine or leucine induces PI3K/Akt-dependent reactivation of mTORC1.
  21. Metabolic Reprogramming in Cholangiocarcinoma.
  22. What Is the Role of Mitochondrial Dysfunction in Programmed Axon Death?
  23. Tumor suppressor p53 restrains cancer cell dissemination by modulating mitochondrial dynamics.
  24. The ER-Mitochondria Interface as a Dynamic Hub for T Cell Efficacy in Solid Tumors.
  25. A conserved YAP/Notch/REST network controls the neuroendocrine cell fate in the lungs.
  26. Comparative transcriptomics reveals circadian and pluripotency networks as two pillars of longevity regulation.
  27. Inducing respiratory complex I impairment elicits an increase in PGC1α in ovarian cancer.
  28. Cellular redox imbalance on the crossroad between mitochondrial dysfunction, senescence, and proliferation.
  29. Neoantigen quality predicts immunoediting in survivors of pancreatic cancer.
  30. NOS2 and S-nitrosothiol signaling induces DNA hypomethylation and LINE-1 retrotransposon expression.
  31. Ambra1 deficiency impairs mitophagy in skeletal muscle.
  32. Intracellular lipid surveillance by small G protein geranylgeranylation.
  33. WEE1 inhibition enhances the antitumor immune response to PD-L1 blockade by the concomitant activation of STING and STAT1 pathways in SCLC.
  34. Beyond being an energy supplier, ATP synthase is a sculptor of mitochondrial cristae.
  35. Metabolic control of epigenetic rearrangements in B cell pathophysiology.
  36. Physiological Functions of Intracellular Protein Degradation.
  37. The Tumor Suppressor Kinase LKB1: Metabolic Nexus.
  38. TALEDs complete the toolkit for editing human mitochondrial DNA.
  39. Diet-responsive transcriptional regulation of insulin in a single neuron controls systemic metabolism.
  40. Fueling genome maintenance: On the versatile roles of NAD+ in preserving DNA integrity.
  1. Nat Commun. 2022 May 16. 13(1): 2698
    Purine nucleotide depletion prompts cell migration by stimulating the serine synthesis pathway.
    Mona Hoseini Soflaee, Rushendhiran Kesavan, Umakant Sahu, Alpaslan Tasdogan, Elodie Villa, Zied Djabari, Feng Cai, Diem H Tran, Hieu S Vu, Eunus S Ali, Halie Rion, Brendan P O'Hara, Sherwin Kelekar, James Hughes Hallett, Misty Martin, Thomas P Mathews, Peng Gao, John M Asara, Brendan D Manning, Issam Ben-Sahra, Gerta Hoxhaj.
      Purine nucleotides are necessary for various biological processes related to cell proliferation. Despite their importance in DNA and RNA synthesis, cellular signaling, and energy-dependent reactions, the impact of changes in cellular purine levels on cell physiology remains poorly understood. Here, we find that purine depletion stimulates cell migration, despite effective reduction in cell proliferation. Blocking purine synthesis triggers a shunt of glycolytic carbon into the serine synthesis pathway, which is required for the induction of cell migration upon purine depletion. The stimulation of cell migration upon a reduction in intracellular purines required one-carbon metabolism downstream of de novo serine synthesis. Decreased purine abundance and the subsequent increase in serine synthesis triggers an epithelial-mesenchymal transition (EMT) and, in cancer models, promotes metastatic colonization. Thus, reducing the available pool of intracellular purines re-routes metabolic flux from glycolysis into de novo serine synthesis, a metabolic change that stimulates a program of cell migration.
    DOI:  https://doi.org/10.1038/s41467-022-30362-z
  2. Commun Biol. 2022 May 16. 5(1): 467
    Mitochondrial TrxR2 regulates metabolism and protects from metabolic disease through enhanced TCA and ETC function.
    E Sandra Chocron, Kennedy Mdaki, Nisi Jiang, Jodie Cropper, Andrew M Pickering.
      Mitochondrial dysfunction is a key driver of diabetes and other metabolic diseases. Mitochondrial redox state is highly impactful to metabolic function but the mechanism driving this is unclear. We generated a transgenic mouse which overexpressed the redox enzyme Thioredoxin Reductase 2 (TrxR2), the rate limiting enzyme in the mitochondrial thioredoxin system. We found augmentation of TrxR2 to enhance metabolism in mice under a normal diet and to increase resistance to high-fat diet induced metabolic dysfunction by both increasing glucose tolerance and decreasing fat deposition. We show this to be caused by increased mitochondrial function which is driven at least in part by enhancements to the tricarboxylic acid cycle and electron transport chain function. Our findings demonstrate a role for TrxR2 and mitochondrial thioredoxin as metabolic regulators and show a critical role for redox enzymes in controlling functionality of key mitochondrial metabolic systems.
    DOI:  https://doi.org/10.1038/s42003-022-03405-w
  3. Nat Commun. 2022 May 19. 13(1): 2758
    Cryo-EM structures define ubiquinone-10 binding to mitochondrial complex I and conformational transitions accompanying Q-site occupancy.
    Injae Chung, John J Wright, Hannah R Bridges, Bozhidar S Ivanov, Olivier Biner, Caroline S Pereira, Guilherme M Arantes, Judy Hirst.
      Mitochondrial complex I is a central metabolic enzyme that uses the reducing potential of NADH to reduce ubiquinone-10 (Q10) and drive four protons across the inner mitochondrial membrane, powering oxidative phosphorylation. Although many complex I structures are now available, the mechanisms of Q10 reduction and energy transduction remain controversial. Here, we reconstitute mammalian complex I into phospholipid nanodiscs with exogenous Q10. Using cryo-EM, we reveal a Q10 molecule occupying the full length of the Q-binding site in the 'active' (ready-to-go) resting state together with a matching substrate-free structure, and apply molecular dynamics simulations to propose how the charge states of key residues influence the Q10 binding pose. By comparing ligand-bound and ligand-free forms of the 'deactive' resting state (that require reactivating to catalyse), we begin to define how substrate binding restructures the deactive Q-binding site, providing insights into its physiological and mechanistic relevance.
    DOI:  https://doi.org/10.1038/s41467-022-30506-1
  4. Dev Cell. 2022 May 11. pii: S1534-5807(22)00286-6. [Epub ahead of print]
    Aspartate metabolism in endothelial cells activates the mTORC1 pathway to initiate translation during angiogenesis.
    Roxana E Oberkersch, Giovanna Pontarin, Matteo Astone, Marianna Spizzotin, Liaisan Arslanbaeva, Giovanni Tosi, Emiliano Panieri, Sara Ricciardi, Maria Francesca Allega, Alessia Brossa, Paolo Grumati, Benedetta Bussolati, Stefano Biffo, Saverio Tardito, Massimo M Santoro.
      Angiogenesis, the active formation of new blood vessels from pre-existing ones, is a complex and demanding biological process that plays an important role in physiological as well as pathological settings. Recent evidence supports cell metabolism as a critical regulator of angiogenesis. However, whether and how cell metabolism regulates endothelial growth factor receptor levels and nucleotide synthesis remains elusive. We here shown in both human cell lines and mouse models that during developmental and pathological angiogenesis, endothelial cells (ECs) use glutaminolysis-derived glutamate to produce aspartate (Asp) via aspartate aminotransferase (AST/GOT). Asp leads to mTORC1 activation which, in turn, regulates endothelial translation machinery for VEGFR2 and FGFR1 synthesis. Asp-dependent mTORC1 pathway activation also regulates de novo pyrimidine synthesis in angiogenic ECs. These findings identify glutaminolysis-derived Asp as a regulator of mTORC1-dependent endothelial translation and pyrimidine synthesis. Our studies may help overcome anti-VEGF therapy resistance by targeting endothelial growth factor receptor translation.
    Keywords:  angiogenesis; aspartate metabolism; endothelial metabolism; mTOR signalling; tumor angiogenesis
    DOI:  https://doi.org/10.1016/j.devcel.2022.04.018
  5. Nature. 2022 May 18.
    PHGDH heterogeneity potentiates cancer cell dissemination and metastasis.
    Matteo Rossi, Patricia Altea-Manzano, Margherita Demicco, Ginevra Doglioni, Laura Bornes, Marina Fukano, Anke Vandekeere, Alejandro M Cuadros, Juan Fernández-García, Carla Riera-Domingo, Cristina Jauset, Mélanie Planque, H Furkan Alkan, David Nittner, Dongmei Zuo, Lindsay A Broadfield, Sweta Parik, Antonino Alejandro Pane, Francesca Rizzollo, Gianmarco Rinaldi, Tao Zhang, Shao Thing Teoh, Arin B Aurora, Panagiotis Karras, Ines Vermeire, Dorien Broekaert, Joke Van Elsen, Maximilian M L Knott, Martin F Orth, Sofie Demeyer, Guy Eelen, Lacey E Dobrolecki, Ayse Bassez, Thomas Van Brussel, Karl Sotlar, Michael T Lewis, Harald Bartsch, Manfred Wuhrer, Peter van Veelen, Peter Carmeliet, Jan Cools, Sean J Morrison, Jean-Christophe Marine, Diether Lambrechts, Massimiliano Mazzone, Gregory J Hannon, Sophia Y Lunt, Thomas G P Grünewald, Morag Park, Jacco van Rheenen, Sarah-Maria Fendt.
      Cancer metastasis requires the transient activation of cellular programs enabling dissemination and seeding in distant organs1. Genetic, transcriptional and translational heterogeneity contributes to this dynamic process2,3. Metabolic heterogeneity has also been observed4, yet its role in cancer progression is less explored. Here we find that the loss of phosphoglycerate dehydrogenase (PHGDH) potentiates metastatic dissemination. Specifically, we find that heterogeneous or low PHGDH expression in primary tumours of patients with breast cancer is associated with decreased metastasis-free survival time. In mice, circulating tumour cells and early metastatic lesions are enriched with Phgdhlow cancer cells, and silencing Phgdh in primary tumours increases metastasis formation. Mechanistically, Phgdh interacts with the glycolytic enzyme phosphofructokinase, and the loss of this interaction activates the hexosamine-sialic acid pathway, which provides precursors for protein glycosylation. As a consequence, aberrant protein glycosylation occurs, including increased sialylation of integrin αvβ3, which potentiates cell migration and invasion. Inhibition of sialylation counteracts the metastatic ability of Phgdhlow cancer cells. In conclusion, although the catalytic activity of PHGDH supports cancer cell proliferation, low PHGDH protein expression non-catalytically potentiates cancer dissemination and metastasis formation. Thus, the presence of PHDGH heterogeneity in primary tumours could be considered a sign of tumour aggressiveness.
    DOI:  https://doi.org/10.1038/s41586-022-04758-2
  6. Sci Adv. 2022 May 20. 8(20): eabm8786
    Suppression of nuclear GSK3 signaling promotes serine/one-carbon metabolism and confers metabolic vulnerability in lung cancer cells.
    Long He, Jennifer Endress, Sungyun Cho, Zhongchi Li, Yuxiang Zheng, John M Asara, John Blenis.
      Serine/one-carbon metabolism provides critical resources for nucleotide biosynthesis and epigenetic maintenance and is thus necessary in cancer cell growth, although the detailed regulatory mechanisms remain unclear. We uncover a critical role of glycogen synthase kinase 3 (GSK3) in regulating the expression of serine/one-carbon metabolic enzymes. Nuclear enrichment of GSK3 significantly suppresses genes that mediate de novo serine synthesis, including PHGDH, PSAT1, PSPH, and one-carbon metabolism, including SHMT2 and MTHFD2. FRAT1 promotes nuclear exclusion of GSK3, enhances serine/one-carbon metabolism, and, as a result, confers cell vulnerability to inhibitors that target this metabolic process such as SHIN1, a specific SHMT1/2 inhibitor. Furthermore, pharmacological or genetic suppression of GSK3 promotes serine/one-carbon metabolism and exhibits a significant synergistic effect in combination with SHIN1 in suppressing cancer cell proliferation in cultured cells and in vivo. Our observations indicate that inhibition of nuclear GSK3 signaling creates a vulnerability, which results in enhanced efficacy of serine/one-carbon metabolism inhibitors for the treatment of cancer.
    DOI:  https://doi.org/10.1126/sciadv.abm8786
  7. Nature. 2022 May 18.
    Metabolic diversity drives cancer cell invasion.
    Sanjeethan C Baksh, Lydia W S Finley.
      
    Keywords:  Cancer; Medical research; Metabolism
    DOI:  https://doi.org/10.1038/d41586-022-01301-1
  8. Nat Commun. 2022 May 19. 13(1): 2760
    Lipid droplet degradation by autophagy connects mitochondria metabolism to Prox1-driven expression of lymphatic genes and lymphangiogenesis.
    Odeta Meçe, Diede Houbaert, Maria-Livia Sassano, Tania Durré, Hannelore Maes, Marco Schaaf, Sanket More, Maarten Ganne, Melissa García-Caballero, Mila Borri, Jelle Verhoeven, Madhur Agrawal, Kathryn Jacobs, Gabriele Bergers, Silvia Blacher, Bart Ghesquière, Mieke Dewerchin, Johan V Swinnen, Stefan Vinckier, María S Soengas, Peter Carmeliet, Agnès Noël, Patrizia Agostinis.
      Autophagy has vasculoprotective roles, but whether and how it regulates lymphatic endothelial cells (LEC) homeostasis and lymphangiogenesis is unknown. Here, we show that genetic deficiency of autophagy in LEC impairs responses to VEGF-C and injury-driven corneal lymphangiogenesis. Autophagy loss in LEC compromises the expression of main effectors of LEC identity, like VEGFR3, affects mitochondrial dynamics and causes an accumulation of lipid droplets (LDs) in vitro and in vivo. When lipophagy is impaired, mitochondrial ATP production, fatty acid oxidation, acetyl-CoA/CoA ratio and expression of lymphangiogenic PROX1 target genes are dwindled. Enforcing mitochondria fusion by silencing dynamin-related-protein 1 (DRP1) in autophagy-deficient LEC fails to restore LDs turnover and lymphatic gene expression, whereas supplementing the fatty acid precursor acetate rescues VEGFR3 levels and signaling, and lymphangiogenesis in LEC-Atg5-/- mice. Our findings reveal that lipophagy in LEC by supporting FAO, preserves a mitochondrial-PROX1 gene expression circuit that safeguards LEC responsiveness to lymphangiogenic mediators and lymphangiogenesis.
    DOI:  https://doi.org/10.1038/s41467-022-30490-6
  9. Nat Commun. 2022 May 16. 13(1): 2706
    Identification of a modulator of the actin cytoskeleton, mitochondria, nutrient metabolism and lifespan in yeast.
    Cierra N Sing, Enrique J Garcia, Thomas G Lipkin, Thomas M Huckaba, Catherine A Tsang, Arielle C Coughlin, Emily J Yang, Istvan R Boldogh, Ryo Higuchi-Sanabria, Liza A Pon.
      In yeast, actin cables are F-actin bundles that are essential for cell division through their function as tracks for cargo movement from mother to daughter cell. Actin cables also affect yeast lifespan by promoting transport and inheritance of higher-functioning mitochondria to daughter cells. Here, we report that actin cable stability declines with age. Our genome-wide screen for genes that affect actin cable stability identified the open reading frame YKL075C. Deletion of YKL075C results in increases in actin cable stability and abundance, mitochondrial fitness, and replicative lifespan. Transcriptome analysis revealed a role for YKL075C in regulating branched-chain amino acid (BCAA) metabolism. Consistent with this, modulation of BCAA metabolism or decreasing leucine levels promotes actin cable stability and function in mitochondrial quality control. Our studies support a role for actin stability in yeast lifespan, and demonstrate that this process is controlled by BCAA and a previously uncharacterized ORF YKL075C, which we refer to as actin, aging and nutrient modulator protein 1 (AAN1).
    DOI:  https://doi.org/10.1038/s41467-022-30045-9
  10. Trends Cell Biol. 2022 May 16. pii: S0962-8924(22)00108-8. [Epub ahead of print]
    Reflected stemness as a potential driver of the tumour microenvironment.
    Felipe S Rodrigues, Francesca D Ciccarelli, Ilaria Malanchi.
      A fundamental requirement for cancer initiation is the activation of developmental programmes by mutant cells. Oncogenic signals often confer an undifferentiated, stem cell-like phenotype that supports the long-term proliferative potential of cancer cells. Although cancer is a genetically driven disease, mutations in cancer-driver genes alone are insufficient for tumour formation, and the proliferation of cells harbouring oncogenic mutations depends on their microenvironment. In this Opinion article we discuss how the reprogrammed status of cancer cells not only represents the essence of their tumorigenicity but triggers 'reflected stemness' in their surrounding normal counterparts. We propose that this reciprocal interaction underpins the establishment of the tumour microenvironment (TME).
    Keywords:  cancer drivers; metastasis; stem cells; tissue regeneration; tumour microenvironment
    DOI:  https://doi.org/10.1016/j.tcb.2022.04.007
  11. Nat Commun. 2022 May 16. 13(1): 2699
    Mitochondria preserve an autarkic one-carbon cycle to confer growth-independent cancer cell migration and metastasis.
    Nicole Kiweler, Catherine Delbrouck, Vitaly I Pozdeev, Laura Neises, Leticia Soriano-Baguet, Kim Eiden, Feng Xian, Mohaned Benzarti, Lara Haase, Eric Koncina, Maryse Schmoetten, Christian Jaeger, Muhammad Zaeem Noman, Alexei Vazquez, Bassam Janji, Gunnar Dittmar, Dirk Brenner, Elisabeth Letellier, Johannes Meiser.
      Metastasis is the most common cause of death in cancer patients. Canonical drugs target mainly the proliferative capacity of cancer cells, which leaves slow-proliferating, persistent cancer cells unaffected. Metabolic determinants that contribute to growth-independent functions are still poorly understood. Here we show that antifolate treatment results in an uncoupled and autarkic mitochondrial one-carbon (1C) metabolism during cytosolic 1C metabolism impairment. Interestingly, antifolate dependent growth-arrest does not correlate with decreased migration capacity. Therefore, using methotrexate as a tool compound allows us to disentangle proliferation and migration to profile the metabolic phenotype of migrating cells. We observe that increased serine de novo synthesis (SSP) supports mitochondrial serine catabolism and inhibition of SSP using the competitive PHGDH-inhibitor BI-4916 reduces cancer cell migration. Furthermore, we show that sole inhibition of mitochondrial serine catabolism does not affect primary breast tumor growth but strongly inhibits pulmonary metastasis. We conclude that mitochondrial 1C metabolism, despite being dispensable for proliferative capacities, confers an advantage to cancer cells by supporting their motility potential.
    DOI:  https://doi.org/10.1038/s41467-022-30363-y
  12. J Lipid Res. 2022 May 11. pii: S0022-2275(22)00057-8. [Epub ahead of print] 100224
    Direct anabolic metabolism of three carbon propionate to a six carbon metabolite occurs in vivo across tissues and species.
    Mary T Doan, Michael D Neinast, Erika L Varner, Kenneth Bedi, David Bartee, Helen Jiang, Sophie Trefely, Peining Xu, Jay P Singh, Cholsoon Jang, Eduardo Rame, Donita Brady, Jordan L Meier, Kenneth Marguiles, Zoltan Arany, Nathaniel W Snyder.
      Anabolic metabolism of carbon in mammals is mediated via the one and two carbon carriers S-adenosyl methionine and acetyl-coenzyme A (acetyl-CoA). In contrast, anabolic metabolism of three-carbon units via propionate has not been shown to extensively occur. Mammals are primarily thought to oxidize the three-carbon short chain fatty acid propionate by shunting propionyl-CoA to succinyl-CoA for entry into the TCA cycle. Here, we found that this may not be absolute as, in mammals, one non-oxidative fate of propionyl-CoA is to condense to two three-carbon units into a six-carbon trans-2-methyl-2-pentenoyl-CoA (2M2PE-CoA). We confirmed this reaction pathway using purified protein extracts provided limited substrates and verified the product via LC-MS using a synthetic standard. In whole-body in vivo stable isotope tracing following infusion of 13C-labeled valine at steady state, 2M2PE-CoA was found to form via propionyl-CoA in multiple murine tissues, including heart, kidney, and to a lesser degree, in brown adipose tissue, liver, and tibialis anterior muscle. Using ex vivo isotope tracing, we found that 2M2PE-CoA also formed in human myocardial tissue incubated with propionate to a limited extent. While the complete enzymology of this pathway remains to be elucidated, these results confirm the in vivo existence of at least one anabolic three to six carbon reaction conserved in humans and mice that utilizes propionate.
    Keywords:  2M2PE-CoA; LC-MS/HRMS; Metabolism; TCA cycle; acetyl-CoA; anabolism; condensation reaction; propionate; stable isotope tracing; valine
    DOI:  https://doi.org/10.1016/j.jlr.2022.100224
  13. Nat Commun. 2022 May 19. 13(1): 2769
    Mitochondrial calcium uniporter stabilization preserves energetic homeostasis during Complex I impairment.
    Enrique Balderas, David R Eberhardt, Sandra Lee, John M Pleinis, Salah Sommakia, Anthony M Balynas, Xue Yin, Mitchell C Parker, Colin T Maguire, Scott Cho, Marta W Szulik, Anna Bakhtina, Ryan D Bia, Marisa W Friederich, Timothy M Locke, Johan L K Van Hove, Stavros G Drakos, Yasemin Sancak, Martin Tristani-Firouzi, Sarah Franklin, Aylin R Rodan, Dipayan Chaudhuri.
      Calcium entering mitochondria potently stimulates ATP synthesis. Increases in calcium preserve energy synthesis in cardiomyopathies caused by mitochondrial dysfunction, and occur due to enhanced activity of the mitochondrial calcium uniporter channel. The signaling mechanism that mediates this compensatory increase remains unknown. Here, we find that increases in the uniporter are due to impairment in Complex I of the electron transport chain. In normal physiology, Complex I promotes uniporter degradation via an interaction with the uniporter pore-forming subunit, a process we term Complex I-induced protein turnover. When Complex I dysfunction ensues, contact with the uniporter is inhibited, preventing degradation, and leading to a build-up in functional channels. Preventing uniporter activity leads to early demise in Complex I-deficient animals. Conversely, enhancing uniporter stability rescues survival and function in Complex I deficiency. Taken together, our data identify a fundamental pathway producing compensatory increases in calcium influx during Complex I impairment.
    DOI:  https://doi.org/10.1038/s41467-022-30236-4
  14. Med (N Y). 2022 Feb 11. pii: S2666-6340(22)00040-X. [Epub ahead of print]3(2): 87-89
    Ketotherapy: Cutting carbs to treat cancer.
    Megan D Radyk, Samuel A Kerk, Costas A Lyssiotis.
      Dietary interventions hold promise in cancer treatments. However, clinical application has been limited by a lack of mechanistic understanding of the metabolic effects. In this issue, Yang et al. use mouse models and isotope tracing to demonstrate that the ketogenic diet induces reductive stress and primes pancreatic tumors for chemotherapy.1.
    DOI:  https://doi.org/10.1016/j.medj.2022.01.005
  15. Semin Cancer Biol. 2022 May 16. pii: S1044-579X(22)00117-1. [Epub ahead of print]
    Cancer evolution: special focus on the immune aspect of cancer.
    Xiao Hu, Zhengxi Chen, Zheng Wang, Qian Xiao.
      Cancer is an evolutionary disease. Intra-tumor heterogeneity (ITH), which describes the diversity within individual tumors, sets the foundation for evolution. The fitness of tumor cells is determined by their microenvironment, which exerts intense selection pressure that generally favors cells with survival and proliferation advantages. It has been revealed that host immunity dramatically influences the evolutionary trajectory of cancer. As technologies advance, a refined map of the immune system's involvement in cancer evolution has gradually come to our knowledge. Here we specifically view cancer through the lens of evolutionary immunological biology. We will cover the neoplastic evolution under immunosurveillance, including how the host immunity shapes the tumor evolutionary trajectory and how progressive tumors modulate the host immunity to survive. A comprehensive understanding of the interplay between cancer evolution and cancer immunity provides clues to combating cancer strategically.
    Keywords:  Cancer evolution; Cancer immunity; Immune modulation; Intra-tumor heterogeneity; Systemic and intratumoral immunity; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.semcancer.2022.05.006
  16. Cell Rep. 2022 May 17. pii: S2211-1247(22)00588-5. [Epub ahead of print]39(7): 110817
    Toll-9 interacts with Toll-1 to mediate a feedback loop during apoptosis-induced proliferation in Drosophila.
    Alicia Shields, Alla Amcheslavsky, Elizabeth Brown, Tom V Lee, Yingchao Nie, Takahiro Tanji, Y Tony Ip, Andreas Bergmann.
      Drosophila Toll-1 and all mammalian Toll-like receptors regulate innate immunity. However, the functions of the remaining eight Toll-related proteins in Drosophila are not fully understood. Here, we show that Drosophila Toll-9 is necessary and sufficient for a special form of compensatory proliferation after apoptotic cell loss (undead apoptosis-induced proliferation [AiP]). Mechanistically, for AiP, Toll-9 interacts with Toll-1 to activate the intracellular Toll-1 pathway for nuclear translocation of the NF-κB-like transcription factor Dorsal, which induces expression of the pro-apoptotic genes reaper and hid. This activity contributes to the feedback amplification loop that operates in undead cells. Given that Toll-9 also functions in loser cells during cell competition, we define a general role of Toll-9 in cellular stress situations leading to the expression of pro-apoptotic genes that trigger apoptosis and apoptosis-induced processes such as AiP. This work identifies conceptual similarities between cell competition and AiP.
    Keywords:  CP: Cell biology; Drosophila; Toll-1; Toll-9; amplification loop; apoptosis-induced proliferation; hid; nuclear translocation of dorsal; reaper; undead cells
    DOI:  https://doi.org/10.1016/j.celrep.2022.110817
  17. Nat Rev Mol Cell Biol. 2022 May 16.
    Transcriptional control of energy metabolism by nuclear receptors.
    Charlotte Scholtes, Vincent Giguère.
      Transcriptional regulation of catabolic pathways is a central mechanism by which cells respond to physiological cues to generate the energy required for anabolic pathways, transport of molecules and mechanical work. Nuclear receptors are members of a superfamily of transcription factors that transduce hormonal, nutrient, metabolite and redox signals into specific metabolic gene programmes, and thus hold a major status as regulators of cellular energy generation. Nuclear receptors also regulate the expression of genes involved in cellular processes that are implicated in energy production, including mitochondrial biogenesis and autophagy. Recent advances in genome-wide approaches have considerably expanded the repertoire of both nuclear receptors and metabolic genes under their direct transcriptional control. To fine-tune the expression of their target genes, nuclear receptors must act cooperatively with other transcription factors and coregulator proteins, integrate signals from key metabolic sensory systems such as the AMP-activated protein kinase (AMPK) and mechanistic target of rapamycin (mTOR) complexes and synchronize their activities with the biological clock. Therefore, nuclear receptors must function as more than molecular switches for small lipophilic ligands - as initially ascribed - but rather must be capable of orchestrating a large ensemble of input signals. Therefore, a primary role for several nuclear receptors is to serve as the focal point of transcriptional hubs in energy metabolism: their molecular task is to receive and transduce multiple systemic and intracellular metabolic signals to maintain energy homeostasis from individual cells to the whole organism.
    DOI:  https://doi.org/10.1038/s41580-022-00486-7
  18. J Clin Invest. 2022 May 16. pii: e155333. [Epub ahead of print]132(10):
    Upregulation of mitochondrial ATPase inhibitory factor 1 (ATPIF1) mediates increased glycolysis in mouse hearts.
    Bo Zhou, Arianne Caudal, Xiaoting Tang, Juan D Chavez, Timothy S McMillen, Andrew Keller, Outi Villet, Mingyue Zhao, Yaxin Liu, Julia Ritterhoff, Pei Wang, Stephen C Kolwicz, Wang Wang, James E Bruce, Rong Tian.
      In hypertrophied and failing hearts, fuel metabolism is reprogrammed to increase glucose metabolism, especially glycolysis. This metabolic shift favors biosynthetic function at the expense of ATP production. Mechanisms responsible for the switch are poorly understood. We found that inhibitory factor 1 of the mitochondrial FoF1-ATP synthase (ATPIF1), a protein known to inhibit ATP hydrolysis by the reverse function of ATP synthase during ischemia, was significantly upregulated in pathological cardiac hypertrophy induced by pressure overload, myocardial infarction, or α-adrenergic stimulation. Chemical cross-linking mass spectrometry analysis of hearts hypertrophied by pressure overload suggested that increased expression of ATPIF1 promoted the formation of FoF1-ATP synthase nonproductive tetramer. Using ATPIF1 gain- and loss-of-function cell models, we demonstrated that stalled electron flow due to impaired ATP synthase activity triggered mitochondrial ROS generation, which stabilized HIF1α, leading to transcriptional activation of glycolysis. Cardiac-specific deletion of ATPIF1 in mice prevented the metabolic switch and protected against the pathological remodeling during chronic stress. These results uncover a function of ATPIF1 in nonischemic hearts, which gives FoF1-ATP synthase a critical role in metabolic rewiring during the pathological remodeling of the heart.
    Keywords:  Cardiology; Heart failure; Metabolism; Mitochondria; Structural biology
    DOI:  https://doi.org/10.1172/JCI155333
  19. Nat Commun. 2022 May 19. 13(1): 2801
    Inhibition of mitochondrial complex I reverses NOTCH1-driven metabolic reprogramming in T-cell acute lymphoblastic leukemia.
    Natalia Baran, Alessia Lodi, Yogesh Dhungana, Shelley Herbrich, Meghan Collins, Shannon Sweeney, Renu Pandey, Anna Skwarska, Shraddha Patel, Mathieu Tremblay, Vinitha Mary Kuruvilla, Antonio Cavazos, Mecit Kaplan, Marc O Warmoes, Diogo Troggian Veiga, Ken Furudate, Shanti Rojas-Sutterin, Andre Haman, Yves Gareau, Anne Marinier, Helen Ma, Karine Harutyunyan, May Daher, Luciana Melo Garcia, Gheath Al-Atrash, Sujan Piya, Vivian Ruvolo, Wentao Yang, Sriram Saravanan Shanmugavelandy, Ningping Feng, Jason Gay, Di Du, Jun J Yang, Fieke W Hoff, Marcin Kaminski, Katarzyna Tomczak, R Eric Davis, Daniel Herranz, Adolfo Ferrando, Elias J Jabbour, M Emilia Di Francesco, David T Teachey, Terzah M Horton, Steven Kornblau, Katayoun Rezvani, Guy Sauvageau, Mihai Gagea, Michael Andreeff, Koichi Takahashi, Joseph R Marszalek, Philip L Lorenzi, Jiyang Yu, Stefano Tiziani, Trang Hoang, Marina Konopleva.
      T-cell acute lymphoblastic leukemia (T-ALL) is commonly driven by activating mutations in NOTCH1 that facilitate glutamine oxidation. Here we identify oxidative phosphorylation (OxPhos) as a critical pathway for leukemia cell survival and demonstrate a direct relationship between NOTCH1, elevated OxPhos gene expression, and acquired chemoresistance in pre-leukemic and leukemic models. Disrupting OxPhos with IACS-010759, an inhibitor of mitochondrial complex I, causes potent growth inhibition through induction of metabolic shut-down and redox imbalance in NOTCH1-mutated and less so in NOTCH1-wt T-ALL cells. Mechanistically, inhibition of OxPhos induces a metabolic reprogramming into glutaminolysis. We show that pharmacological blockade of OxPhos combined with inducible knock-down of glutaminase, the key glutamine enzyme, confers synthetic lethality in mice harboring NOTCH1-mutated T-ALL. We leverage on this synthetic lethal interaction to demonstrate that IACS-010759 in combination with chemotherapy containing L-asparaginase, an enzyme that uncovers the glutamine dependency of leukemic cells, causes reduced glutaminolysis and profound tumor reduction in pre-clinical models of human T-ALL. In summary, this metabolic dependency of T-ALL on OxPhos provides a rational therapeutic target.
    DOI:  https://doi.org/10.1038/s41467-022-30396-3
  20. J Biol Chem. 2022 May 13. pii: S0021-9258(22)00470-7. [Epub ahead of print] 102030
    Prolonged deprivation of arginine or leucine induces PI3K/Akt-dependent reactivation of mTORC1.
    Gwen R Buel, Huy Dang, John M Asara, John Blenis, Anders P Mutvei.
      The mechanistic target of rapamycin complex 1 (mTORC1) is a serine/threonine kinase complex that promotes anabolic processes including protein, lipid, and nucleotide synthesis, while suppressing catabolic processes such as macroautophagy. mTORC1 activity is regulated by growth factors and amino acids which signal through distinct but integrated molecular pathways: growth factors largely signal through the PI3K/Akt-dependent pathway, whereas the availabilities of amino acids leucine and arginine are communicated to mTORC1 by the Rag-GTPase pathway. While it is relatively well described how acute changes in leucine and arginine levels affect mTORC1 signaling, the effects of prolonged amino acid deprivation remain less well understood. Here, we demonstrate that prolonged deprivation of arginine and/or leucine leads to reactivation of mTORC1 activity, which reaches activation levels similar to those observed in nutrient-rich conditions. Surprisingly, we find that this reactivation is independent of the regeneration of amino acids by canonical autophagy or proteasomal degradation, but is dependent on PI3K/Akt signaling. Together, our data identify a novel crosstalk between the amino acid and PI3K/Akt signaling pathways upstream of mTORC1. These observations extend our understanding of the role of mTORC1 in growth-related diseases and indicate that dietary intervention by removal of leucine and/or arginine may be an ineffective therapeutic approach.
    DOI:  https://doi.org/10.1016/j.jbc.2022.102030
  21. J Hepatol. 2022 May 17. pii: S0168-8278(22)00314-2. [Epub ahead of print]
    Metabolic Reprogramming in Cholangiocarcinoma.
    Chiara Raggi, Maria Letizia Taddei, Colin Rae, Chiara Braconi, Fabio Marra.
      Metabolic reprogramming is a hallmark of cancer and allows tumor cells to meet the increased energy demands required for rapid proliferation, invasion, and metastasis. Indeed, many tumor cells acquire distinctive metabolic and bioenergetic features to survive under conditions of limited resources, mainly using alternative nutrients. Several recent studies have explored the metabolic plasticity of cancer cells with the aim to identify new druggable targets, and therapeutic strategies aimed to limit the access to nutrients have been successfully applied to the treatment of some tumors. Cholangiocarcinoma (CCA), a highly heterogeneous tumor, is the second most common form of primary liver cancer. It is characterized by resistance to chemotherapy and poor prognosis, with 5-year survival lower than 20%. Deregulation of metabolic pathways has been described during the onset and progression of CCA. Increased aerobic glycolysis and glutamine anaplerosis provide CCA cells with the ability to generate biosynthetic intermediates. Other metabolic alterations involving carbohydrates, amino acids and lipids have been shown to sustain cancer cell growth and dissemination. In this review, we discuss the complex metabolic rewiring taking place during CCA development, leading to unique nutrient addiction. The possible role of therapeutic interventions based on metabolic changes is also thoroughly discussed.
    Keywords:  CD36; IDH1/2; PGC1α; cancer stem cells; fatty acids; fatty-acid synthase; glutamine; glycolysis; mTOR; methionine adenosyltransferases; mitochondria; oxidative metabolism
    DOI:  https://doi.org/10.1016/j.jhep.2022.04.038
  22. Neurology. 2022 May 17. 98(20): 836-840
    What Is the Role of Mitochondrial Dysfunction in Programmed Axon Death?
    Eduardo Benarroch.
      
    DOI:  https://doi.org/10.1212/WNL.0000000000200691
  23. Oncogenesis. 2022 May 19. 11(1): 26
    Tumor suppressor p53 restrains cancer cell dissemination by modulating mitochondrial dynamics.
    Trinh T T Phan, Yu-Chun Lin, Yu-Ting Chou, Chien-Wei Wu, Lih-Yuan Lin.
      Tumor suppressor p53 plays a central role in preventing tumorigenesis. Here, we unravel how p53 modulates mitochondrial dynamics to restrain the metastatic properties of cancer cells. p53 inhibits the mammalian target of rapamycin complex 1 (mTORC1) signaling to attenuate the protein level of mitochondrial fission process 1 (MTFP1), which fosters the pro-fission dynamin-related protein 1 (Drp1) phosphorylation. This regulatory mechanism allows p53 to restrict cell migration and invasion governed by Drp1-mediated mitochondrial fission. Downregulating p53 expression or elevating the molecular signature of mitochondrial fission correlates with aggressive tumor phenotypes and poor prognosis in cancer patients. Upon p53 loss, exaggerated mitochondrial fragmentation stimulates the activation of the extracellular signal-regulated kinase 1/2 (ERK1/2) signaling resulting in epithelial-to-mesenchymal transition (EMT)-like changes in cell morphology, accompanied by accelerated matrix metalloproteinase 9 (MMP9) expression and invasive cell migration. Notably, blocking the activation of mTORC1/MTFP1/Drp1/ERK1/2 axis completely abolishes the p53 deficiency-driven cellular morphological switch, MMP9 expression, and cancer cell dissemination. Our findings unveil a hitherto unrecognized mitochondria-dependent molecular mechanism underlying the metastatic phenotypes of p53-compromised cancers.
    DOI:  https://doi.org/10.1038/s41389-022-00401-x
  24. Front Cell Dev Biol. 2022 ;10 867341
    The ER-Mitochondria Interface as a Dynamic Hub for T Cell Efficacy in Solid Tumors.
    Elizabeth G Hunt, Alex M Andrews, Sydney R Larsen, Jessica E Thaxton.
      The endoplasmic reticulum (ER) is a large continuous membranous organelle that plays a central role as the hub of protein and lipid synthesis while the mitochondria is the principal location for energy production. T cells are an immune subset exhibiting robust dependence on ER and mitochondrial function based on the need for protein synthesis and secretion and metabolic dexterity associated with foreign antigen recognition and cytotoxic effector response. Intimate connections exist at mitochondrial-ER contact sites (MERCs) that serve as the structural and biochemical platforms for cellular metabolic homeostasis through regulation of fission and fusion as well as glucose, Ca2+, and lipid exchange. Work in the tumor immunotherapy field indicates that the complex interplay of nutrient deprivation and tumor antigen stimulation in the tumor microenvironment places stress on the ER and mitochondria, causing dysfunction in organellar structure and loss of metabolic homeostasis. Here, we assess prior literature that establishes how the structural interface of these two organelles is impacted by the stress of solid tumors along with recent advances in the manipulation of organelle homeostasis at MERCs in T cells. These findings provide strong evidence for increased tumor immunity using unique therapeutic avenues that recharge cellular metabolic homeostasis in T cells.
    Keywords:  ER stress; MERCs; T cell; cancer immunotherapy; endoplasmic recticulum (ER); metabolism; tumor microenvironment
    DOI:  https://doi.org/10.3389/fcell.2022.867341
  25. Nat Commun. 2022 May 16. 13(1): 2690
    A conserved YAP/Notch/REST network controls the neuroendocrine cell fate in the lungs.
    Yan Ting Shue, Alexandros P Drainas, Nancy Yanzhe Li, Sarah M Pearsall, Derrick Morgan, Nasa Sinnott-Armstrong, Susan Q Hipkins, Garry L Coles, Jing Shan Lim, Anthony E Oro, Kathryn L Simpson, Caroline Dive, Julien Sage.
      The Notch pathway is a conserved cell-cell communication pathway that controls cell fate decisions. Here we sought to determine how Notch pathway activation inhibits the neuroendocrine cell fate in the lungs, an archetypal process for cell fate decisions orchestrated by Notch signaling that has remained poorly understood at the molecular level. Using intratumoral heterogeneity in small-cell lung cancer as a tractable model system, we uncovered a role for the transcriptional regulators REST and YAP as promoters of the neuroendocrine to non-neuroendocrine transition. We further identified the specific neuroendocrine gene programs repressed by REST downstream of Notch in this process. Importantly, we validated the importance of REST and YAP in neuroendocrine to non-neuroendocrine cell fate switches in both developmental and tissue repair processes in the lungs. Altogether, these experiments identify conserved roles for REST and YAP in Notch-driven inhibition of the neuroendocrine cell fate in embryonic lungs, adult lungs, and lung cancer.
    DOI:  https://doi.org/10.1038/s41467-022-30416-2
  26. Cell Metab. 2022 May 10. pii: S1550-4131(22)00138-3. [Epub ahead of print]
    Comparative transcriptomics reveals circadian and pluripotency networks as two pillars of longevity regulation.
    J Yuyang Lu, Matthew Simon, Yang Zhao, Julia Ablaeva, Nancy Corson, Yongwook Choi, KayLene Y H Yamada, Nicholas J Schork, Wendy R Hood, Geoffrey E Hill, Richard A Miller, Andrei Seluanov, Vera Gorbunova.
      Mammals differ more than 100-fold in maximum lifespan. Here, we conducted comparative transcriptomics on 26 species with diverse lifespans. We identified thousands of genes with expression levels negatively or positively correlated with a species' maximum lifespan (Neg- or Pos-MLS genes). Neg-MLS genes are primarily involved in energy metabolism and inflammation. Pos-MLS genes show enrichment in DNA repair, microtubule organization, and RNA transport. Expression of Neg- and Pos-MLS genes is modulated by interventions, including mTOR and PI3K inhibition. Regulatory networks analysis showed that Neg-MLS genes are under circadian regulation possibly to avoid persistent high expression, whereas Pos-MLS genes are targets of master pluripotency regulators OCT4 and NANOG and are upregulated during somatic cell reprogramming. Pos-MLS genes are highly expressed during embryogenesis but significantly downregulated after birth. This work provides targets for anti-aging interventions by defining pathways correlating with longevity across mammals and uncovering circadian and pluripotency networks as central regulators of longevity.
    Keywords:  aging; circadian clock; comparative transcriptomics; epigenetic reprogramming; functional genomics; longevity; pluripotency
    DOI:  https://doi.org/10.1016/j.cmet.2022.04.011
  27. Sci Rep. 2022 May 16. 12(1): 8020
    Inducing respiratory complex I impairment elicits an increase in PGC1α in ovarian cancer.
    Monica De Luise, Manuela Sollazzo, Eleonora Lama, Camelia Alexandra Coadă, Licia Bressi, Maria Iorio, Beatrice Cavina, Luigi D'Angelo, Sara Milioni, Lorena Marchio, Stefano Miglietta, Sara Coluccelli, Greta Tedesco, Anna Ghelli, Silvia Lemma, Anna Myriam Perrone, Ivana Kurelac, Luisa Iommarini, Anna Maria Porcelli, Giuseppe Gasparre.
      Anticancer strategies aimed at inhibiting Complex I of the mitochondrial respiratory chain are increasingly being attempted in solid tumors, as functional oxidative phosphorylation is vital for cancer cells. Using ovarian cancer as a model, we show that a compensatory response to an energy crisis induced by Complex I genetic ablation or pharmacological inhibition is an increase in the mitochondrial biogenesis master regulator PGC1α, a pleiotropic coactivator of transcription regulating diverse biological processes within the cell. We associate this compensatory response to the increase in PGC1α target gene expression, setting the basis for the comprehension of the molecular pathways triggered by Complex I inhibition that may need attention as drawbacks before these approaches are implemented in ovarian cancer care.
    DOI:  https://doi.org/10.1038/s41598-022-11620-y
  28. Redox Biol. 2022 May 13. pii: S2213-2317(22)00109-4. [Epub ahead of print]53 102337
    Cellular redox imbalance on the crossroad between mitochondrial dysfunction, senescence, and proliferation.
    Rumiana Bakalova, Ichio Aoki, Zhivko Zhelev, Tatsuya Higashi.
      Recent studies demonstrate that redox imbalance of NAD+/NADH and NADP+/NADPH pairs due to impaired respiration may trigger two "hidden" metabolic pathways on the crossroad between mitochondrial dysfunction, senescence, and proliferation: "β-oxidation shuttle" and "hydride transfer complex (HTC) cycle". The "β-oxidation shuttle" induces NAD+/NADH redox imbalance in mitochondria, while HTC cycle maintains the redox balance of cytosolic NAD+/NADH, increasing the redox disbalance of NADP+/NADPH. Senescence appears to depend on high cytoplasmic NADH but low NADPH, while proliferation depends on high cytoplasmic NAD+ and NADPH that are under mitochondrial control. Thus, activating or deactivating the HTC cycle can be crucial to cell fate - senescence or proliferation. These pathways are a source of enormous cataplerosis. They support the production of large amounts of NADPH and intermediates for lipid synthesis and membrane biogenesis, as well as for DNA synthesis.
    DOI:  https://doi.org/10.1016/j.redox.2022.102337
  29. Nature. 2022 May 19.
    Neoantigen quality predicts immunoediting in survivors of pancreatic cancer.
    Marta Łuksza, Zachary M Sethna, Luis A Rojas, Jayon Lihm, Barbara Bravi, Yuval Elhanati, Kevin Soares, Masataka Amisaki, Anton Dobrin, David Hoyos, Pablo Guasp, Abderezak Zebboudj, Rebecca Yu, Adrienne Kaya Chandra, Theresa Waters, Zagaa Odgerel, Joanne Leung, Rajya Kappagantula, Alvin Makohon-Moore, Amber Johns, Anthony Gill, Mathieu Gigoux, Jedd Wolchok, Taha Merghoub, Michel Sadelain, Erin Patterson, Remi Monasson, Thierry Mora, Aleksandra M Walczak, Simona Cocco, Christine Iacobuzio-Donahue, Benjamin D Greenbaum, Vinod P Balachandran.
      Cancer immunoediting1 is a hallmark of cancer2 that predicts that lymphocytes kill more immunogenic cancer cells to cause less immunogenic clones to dominate a population. Although proven in mice1,3, whether immunoediting occurs naturally in human cancers remains unclear. Here, to address this, we investigate how 70 human pancreatic cancers evolved over 10 years. We find that, despite having more time to accumulate mutations, rare long-term survivors of pancreatic cancer who have stronger T cell activity in primary tumours develop genetically less heterogeneous recurrent tumours with fewer immunogenic mutations (neoantigens). To quantify whether immunoediting underlies these observations, we infer that a neoantigen is immunogenic (high-quality) by two features-'non-selfness'  based on neoantigen similarity to known antigens4,5, and 'selfness'  based on the antigenic distance required for a neoantigen to differentially bind to the MHC or activate a T cell compared with its wild-type peptide. Using these features, we estimate cancer clone fitness as the aggregate cost of T cells recognizing high-quality neoantigens offset by gains from oncogenic mutations. With this model, we predict the clonal evolution of tumours to reveal that long-term survivors of pancreatic cancer develop recurrent tumours with fewer high-quality neoantigens. Thus, we submit evidence that that the human immune system naturally edits neoantigens. Furthermore, we present a model to predict how immune pressure induces cancer cell populations to evolve over time. More broadly, our results argue that the immune system fundamentally surveils host genetic changes to suppress cancer.
    DOI:  https://doi.org/10.1038/s41586-022-04735-9
  30. Proc Natl Acad Sci U S A. 2022 May 24. 119(21): e2200022119
    NOS2 and S-nitrosothiol signaling induces DNA hypomethylation and LINE-1 retrotransposon expression.
    Christopher H Switzer, Hyun-Ju Cho, Thomas R Eykyn, Paul Lavender, Philip Eaton.
      SignificanceNitric oxide is a multifaceted signaling molecule that affects multiple pathways and cellular systems. Here, we report that inducible nitric oxide synthase expression, which is strongly correlated with inflammation and poor outcomes in patients with cancer, substantially alters DNA methylation to regulate cellular plasticity. Our data connect inflammation mechanistically with stress signals, DNA demethylation, and genotoxic retrotransposon expression. Passive DNA demethylation occurs during conditions of reduced DNA (cytosine-5)-methyltransferase 1 (DNMT1) activity; however, the cellular pathways that control passive demethylation are not clear. Our results show that sustained cellular stress signals result in DNMT1 protein loss and DNA hypomethylation, similar to DNMT1 inhibition by 5-azacytidine. This implies that chronic inflammation drives cellular transformation via DNA hypomethylation and retrotransposon activation.
    Keywords:  DNA methylation; NOS2; S-nitrosation; nitric oxide; retrotransposon
    DOI:  https://doi.org/10.1073/pnas.2200022119
  31. J Cachexia Sarcopenia Muscle. 2022 May 20.
    Ambra1 deficiency impairs mitophagy in skeletal muscle.
    Lisa Gambarotto, Samuele Metti, Martina Chrisam, Cristina Cerqua, Patrizia Sabatelli, Andrea Armani, Carlo Zanon, Marianna Spizzotin, Silvia Castagnaro, Flavie Strappazzon, Paolo Grumati, Matilde Cescon, Paola Braghetta, Eva Trevisson, Francesco Cecconi, Paolo Bonaldo.
       BACKGROUND: Maintaining healthy mitochondria is mandatory for muscle viability and function. An essential surveillance mechanism targeting defective and harmful mitochondria to degradation is the selective form of autophagy called mitophagy. Ambra1 is a multifaceted protein with well-known autophagic and mitophagic functions. However, the study of its role in adult tissues has been extremely limited due to the embryonic lethality caused by full-body Ambra1 deficiency.
    METHODS: To establish the role of Ambra1 as a positive regulator of mitophagy, we exploited in vivo overexpression of a mitochondria-targeted form of Ambra1 in skeletal muscle. To dissect the consequence of Ambra1 inactivation in skeletal muscle, we generated muscle-specific Ambra1 knockout (Ambra1fl/fl :Mlc1f-Cre) mice. Mitochondria-enriched fractions were obtained from muscles of fed and starved animals to investigate the dynamics of the mitophagic flux.
    RESULTS: Our data show that Ambra1 has a critical role in the mitophagic flux of adult murine skeletal muscle and that its genetic inactivation leads to mitochondria alterations and myofibre remodelling. Ambra1 overexpression in wild-type muscles is sufficient to enhance mitochondria clearance through the autophagy-lysosome system. Consistently with this, Ambra1-deficient muscles display an abnormal accumulation of the mitochondrial marker TOMM20 by +76% (n = 6-7; P < 0.05), a higher presence of myofibres with swollen mitochondria by +173% (n = 4; P < 0.05), and an alteration in the maintenance of the mitochondrial membrane potential and a 34% reduction in the mitochondrial respiratory complex I activity (n = 4; P < 0.05). Lack of Ambra1 in skeletal muscle leads to impaired mitophagic flux, without affecting the bulk autophagic process. This is due to a significantly decreased recruitment of DRP1 (n = 6-7 mice; P < 0.01) and Parkin (n = 6-7 mice; P < 0.05) to the mitochondrial compartment, when compared with controls. Ambra1-deficient muscles also show a marked dysregulation of the endolysosome compartment, as the incidence of myofibres with lysosomal accumulation is 20 times higher than wild-type muscles (n = 4; P < 0.05). Histologically, Ambra1-deficient muscles of both 3- and 6-month-old animals display a significant decrease of myofibre cross-sectional area and a 52% reduction in oxidative fibres (n = 6-7; P < 0.05), thus highlighting a role for Ambra1 in the proper structure and activity of skeletal muscle.
    CONCLUSIONS: Our study indicates that Ambra1 is critical for skeletal muscle mitophagy and for the proper maintenance of functional mitochondria.
    Keywords:  Ambra1; Mitochondria; Mitophagy; Skeletal muscle
    DOI:  https://doi.org/10.1002/jcsm.13010
  32. Nature. 2022 May 18.
    Intracellular lipid surveillance by small G protein geranylgeranylation.
    Abigail Watterson, Lexus Tatge, Naureen Wajahat, Sonja L B Arneaud, Rene Solano Fonseca, Shaghayegh T Beheshti, Patrick Metang, Melina Mihelakis, Kielen R Zuurbier, Chase D Corley, Ishmael Dehghan, Jeffrey G McDonald, Peter M Douglas.
      Imbalances in lipid homeostasis can have deleterious effects on health1,2. Yet how cells sense metabolic demand due to lipid depletion and respond by increasing nutrient absorption remains unclear. Here we describe a mechanism for intracellular lipid surveillance in Caenorhabditis elegans that involves transcriptional inactivation of the nuclear hormone receptor NHR-49 through its cytosolic sequestration to endocytic vesicles via geranylgeranyl conjugation to the small G protein RAB-11.1. Defective de novo isoprenoid synthesis caused by lipid depletion limits RAB-11.1 geranylgeranylation, which promotes nuclear translocation of NHR-49 and activation of rab-11.2 transcription to enhance transporter residency at the plasma membrane. Thus, we identify a critical lipid sensed by the cell, its conjugated G protein, and the nuclear receptor whose dynamic interactions enable cells to sense metabolic demand due to lipid depletion and respond by increasing nutrient absorption and lipid metabolism.
    DOI:  https://doi.org/10.1038/s41586-022-04729-7
  33. Cell Rep. 2022 May 17. pii: S2211-1247(22)00585-X. [Epub ahead of print]39(7): 110814
    WEE1 inhibition enhances the antitumor immune response to PD-L1 blockade by the concomitant activation of STING and STAT1 pathways in SCLC.
    Hirokazu Taniguchi, Rebecca Caeser, Shweta S Chavan, Yingqian A Zhan, Andrew Chow, Parvathy Manoj, Fathema Uddin, Hidenori Kitai, Rui Qu, Omar Hayatt, Nisargbhai S Shah, Álvaro Quintanal Villalonga, Viola Allaj, Evelyn M Nguyen, Joseph Chan, Adam O Michel, Hiroshi Mukae, Elisa de Stanchina, Charles M Rudin, Triparna Sen.
      Small cell lung cancers (SCLCs) have high mutational burden but are relatively unresponsive to immune checkpoint blockade (ICB). Using SCLC models, we demonstrate that inhibition of WEE1, a G2/M checkpoint regulator induced by DNA damage, activates the STING-TBK1-IRF3 pathway, which increases type I interferons (IFN-α and IFN-β) and pro-inflammatory chemokines (CXCL10 and CCL5), facilitating an immune response via CD8+ cytotoxic T cell infiltration. We further show that WEE1 inhibition concomitantly activates the STAT1 pathway, increasing IFN-γ and PD-L1 expression. Consistent with these findings, combined WEE1 inhibition (AZD1775) and PD-L1 blockade causes remarkable tumor regression, activation of type I and II interferon pathways, and infiltration of cytotoxic T cells in multiple immunocompetent SCLC genetically engineered mouse models, including an aggressive model with stabilized MYC. Our study demonstrates cell-autonomous and immune-stimulating activity of WEE1 inhibition in SCLC models. Combined inhibition of WEE1 plus PD-L1 blockade represents a promising immunotherapeutic approach in SCLC.
    Keywords:  CD8(+) T cells; CP: Cancer; CP: Immunology; PD-L1; SCLC; STAT1 pathway; STING pathway; WEE1 inhibition; immune checkpoint blockade; immunotherapy; interferon
    DOI:  https://doi.org/10.1016/j.celrep.2022.110814
  34. Biochim Biophys Acta Bioenerg. 2022 May 14. pii: S0005-2728(22)00038-X. [Epub ahead of print]1863(6): 148569
    Beyond being an energy supplier, ATP synthase is a sculptor of mitochondrial cristae.
    Héctor Miranda-Astudillo, Marcos Ostolga-Chavarría, Pierre Cardol, Diego González-Halphen.
      Mitochondrial F1FO-ATP synthase plays a key role in cellular bioenergetics; this enzyme is present in all eukaryotic linages except in amitochondriate organisms. Despite its ancestral origin, traceable to the alpha proteobacterial endosymbiotic event, the actual structural diversity of these complexes, due to large differences in their polypeptide composition, reflects an important evolutionary divergence between eukaryotic lineages. We discuss the effect of these structural differences on the oligomerization of the complex and the shape of mitochondrial cristae.
    Keywords:  ATP synthase; F(1)-F(O) ATPase; Lineage-specific subunits; Mitochondrial ATPase
    DOI:  https://doi.org/10.1016/j.bbabio.2022.148569
  35. Open Biol. 2022 May;12(5): 220038
    Metabolic control of epigenetic rearrangements in B cell pathophysiology.
    Beatrice Calciolari, Greta Scarpinello, Laura Quotti Tubi, Francesco Piazza, Alessandro Carrer.
      Both epigenetic and metabolic reprogramming guide lymphocyte differentiation and can be linked, in that metabolic inputs can be integrated into the epigenome to inform cell fate decisions. This framework has been thoroughly investigated in several pathophysiological contexts, including haematopoietic cell differentiation. In fact, metabolite availability dictates chromatin architecture and lymphocyte specification, a multi-step process where haematopoietic stem cells become terminally differentiated lymphocytes (effector or memory) to mount the adaptive immune response. B and T cell precursors reprogram their cellular metabolism across developmental stages, not only to meet ever-changing energetic demands but to impose chromatin accessibility and regulate the function of master transcription factors. Metabolic control of the epigenome has been extensively investigated in T lymphocytes, but how this impacts type-B life cycle remains poorly appreciated. This assay will review our current understanding of the connection between cell metabolism and epigenetics at crucial steps of B cell maturation and how its dysregulation contributes to malignant transformation.
    Keywords:  B cell; epigenetics; lymphoma; metabolism
    DOI:  https://doi.org/10.1098/rsob.220038
  36. Annu Rev Cell Dev Biol. 2022 May 19.
    Physiological Functions of Intracellular Protein Degradation.
    Erik McShane, Matthias Selbach.
      While cellular proteins were initially thought to be stable, research over the last decades has firmly established that intracellular protein degradation is an active and highly regulated process: Lysosomal, proteasomal, and mitochondrial degradation systems were identified and found to be involved in a staggering number of biological functions. Here, we provide a global overview of the diverse roles of cellular protein degradation using seven categories: homeostasis, regulation, quality control, stoichiometry control, proteome remodeling, immune surveillance, and baseline turnover. Using selected examples, we outline how proteins are degraded and why this is functionally relevant. Expected final online publication date for the Annual Review of Cell and Developmental Biology Volume 38 is October 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
    DOI:  https://doi.org/10.1146/annurev-cellbio-120420-091943
  37. Front Cell Dev Biol. 2022 ;10 881297
    The Tumor Suppressor Kinase LKB1: Metabolic Nexus.
    Mohammed Bourouh, Paola A Marignani.
      Liver kinase B1 (LKB1) is a multitasking tumor suppressor kinase that is implicated in multiple malignancies such as lung, gastrointestinal, pancreatic, and breast. LKB1 was first identified as the gene responsible for Peutz-Jeghers syndrome (PJS) characterized by hamartomatous polyps and oral mucotaneous pigmentation. LKB1 functions to activate AMP-activated protein kinase (AMPK) during energy stress to shift metabolic processes from active anabolic pathways to active catabolic pathways to generate ATP. Genetic loss or inactivation of LKB1 promotes metabolic reprogramming and metabolic adaptations of cancer cells that fuel increased growth and division rates. As a result, LKB1 loss is associated with increased aggressiveness and treatment options for patients with LKB1 mutant tumors are limited. Recently, there has been new insights into the role LKB1 has on metabolic regulation and the identification of potential vulnerabilities in LKB1 mutant tumors. In this review, we discuss the tumor suppressive role of LKB1 and the impact LKB1 loss has on metabolic reprograming in cancer cells, with a focus on lung cancer. We also discuss potential therapeutic avenues to treat malignancies associated with LKB1 loss by targeting aberrant metabolic pathways associated with LKB1 loss.
    Keywords:  AMPK; LKB1; cancer metabolism; glycolysis; lung cancer; mTOR; tumor suppressor
    DOI:  https://doi.org/10.3389/fcell.2022.881297
  38. Nat Struct Mol Biol. 2022 May;29(5): 415
    TALEDs complete the toolkit for editing human mitochondrial DNA.
    Carolina N Perdigoto.
      
    DOI:  https://doi.org/10.1038/s41594-022-00781-z
  39. PLoS Biol. 2022 May 20. 20(5): e3001655
    Diet-responsive transcriptional regulation of insulin in a single neuron controls systemic metabolism.
    Ava Handley, Qiuli Wu, Tessa Sherry, Rebecca Cornell, Roger Pocock.
      Metabolic homeostasis is coordinated through a robust network of signaling pathways acting across all tissues. A key part of this network is insulin-like signaling, which is fundamental for surviving glucose stress. Here, we show that Caenorhabditis elegans fed excess dietary glucose reduce insulin-1 (INS-1) expression specifically in the BAG glutamatergic sensory neurons. We demonstrate that INS-1 expression in the BAG neurons is directly controlled by the transcription factor ETS-5, which is also down-regulated by glucose. We further find that INS-1 acts exclusively from the BAG neurons, and not other INS-1-expressing neurons, to systemically inhibit fat storage via the insulin-like receptor DAF-2. Together, these findings reveal an intertissue regulatory pathway where regulation of insulin expression in a specific neuron controls systemic metabolism in response to excess dietary glucose.
    DOI:  https://doi.org/10.1371/journal.pbio.3001655
  40. J Biol Chem. 2022 May 17. pii: S0021-9258(22)00477-X. [Epub ahead of print] 102037
    Fueling genome maintenance: On the versatile roles of NAD+ in preserving DNA integrity.
    Joanna A Ruszkiewicz, Alexander Bürkle, Aswin Mangerich.
      Nicotinamide adenine dinucleotide (NAD+) is a versatile biomolecule acting as a master regulator and substrate in various cellular processes, including redox regulation, metabolism, and various signaling pathways. In this article, we concisely and critically review the role of NAD+ in mechanisms promoting genome maintenance. Numerous NAD+-dependent reactions are involved in the preservation of genome stability, the cellular DNA damage response, and other pathways regulating nucleic acid metabolism, such as gene expression and cell proliferation pathways. Of note, NAD+ serves as a substrate to ADP-ribosyltransferases (ARTs), sirtuins (SIRTs), and potentially also eukaryotic DNA ligases, all of which regulate various aspects of DNA integrity, damage repair, and gene expression. Finally, we critically analyze recent developments in the field as well as discuss challenges associated with therapeutic actions intended to raise NAD+ levels.
    Keywords:  ARTs; DNA repair; Nicotinamide adenine dinucleotide; PARPs; sirtuins
    DOI:  https://doi.org/10.1016/j.jbc.2022.102037
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