bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2020‒03‒29
47 papers selected by
Christian Frezza,

  1. Compartmentalised acyl-CoA metabolism and roles in chromatin regulation.
  2. Dietary fructose feeds hepatic lipogenesis via microbiota-derived acetate.
  3. Metabolic reprogramming in tumors: Contributions of the tumor microenvironment.
  4. AMPK activation induces mitophagy and promotes mitochondrial fission while activating TBK1 in a PINK1-Parkin independent manner.
  5. Subpopulation targeting of pyruvate dehydrogenase and GLUT1 decouples metabolic heterogeneity during collective cancer cell invasion.
  6. Glutathione Restricts Serine Metabolism to Preserve Regulatory T Cell Function.
  7. Two genomes, one cell: Mitochondrial-nuclear coordination via epigenetic pathways.
  8. Peroxiredoxin 5 deficiency exacerbates iron overload-induced neuronal death via ER-mediated mitochondrial fission in mouse hippocampus.
  9. c-Src Promotes Tumorigenesis and Tumor Progression by Activating PFKFB3.
  10. Copper is an essential regulator of the autophagic kinases ULK1/2 to drive lung adenocarcinoma.
  11. Codependency of Metabolism and Epigenetics Drives Cancer Progression: A Review.
  12. Cell Senescence, DNA Damage and Metabolism.
  13. Enhanced immunogenicity of mitochondrial-localized proteins in cancer cells.
  14. Bioenergetic functions in subpopulations of heart mitochondria are preserved in a non-obese type 2 diabetes rat model (Goto-Kakizaki).
  15. Mitophagy in Cardiovascular Diseases.
  16. Mature myelin maintenance requires Qki to coactivate PPARβ-RXRα-mediated lipid metabolism.
  17. A role for keratins in supporting mitochondrial organization and function in skin keratinocytes.
  18. Mechanisms Linking Mitochondrial Dysfunction and Proteostasis Failure.
  19. Mitochondrial DNA in inflammation and immunity.
  20. Consideration of Ketogenic Metabolic Therapy as a Complementary or Alternative Approach for Managing Breast Cancer.
  21. Coalescing Lessons from Oxygen Sensing, Tumor Metabolism, and Epigenetics to Target VHL loss in Kidney Cancer.
  22. Got glycogen? An energy resource in HIF-mediated prevention of ischemic kidney injury.
  23. Acute kidney injury promotes development of papillary renal cell adenoma and carcinoma from renal progenitor cells.
  24. The multifunctional nature of mitochondrial contact site proteins.
  25. STAT3-driven hematopoiesis and lymphopoiesis abnormalities are dependent on serine phosphorylation.
  26. Wild-Type IDH1 and Mutant IDH1 Opposingly Regulate Podoplanin Expression in Glioma.
  27. Catabolic degradation of endothelial VEGFA via autophagy.
  28. Methyl-Metabolite Depletion Elicits Adaptive Responses to Support Heterochromatin Stability and Epigenetic Persistence.
  29. Oncogenic human herpesvirus hijacks proline metabolism for tumorigenesis.
  30. Building blocks are synthesized on demand during the yeast cell cycle.
  31. Serine-dependent redox homeostasis regulates glioblastoma cell survival.
  32. Restoration of L-OPA1 alleviates acute ischemic stroke injury in rats via inhibiting neuronal apoptosis and preserving mitochondrial function.
  33. Dietary modifications for enhanced cancer therapy.
  34. Cisd2: A promising new target in Alzheimer's disease.
  35. The essential role of fructose-1,6-bisphosphatase 2 enzyme in thermal homeostasis upon cold stress.
  36. Metabolic-sensing of the skeletal muscle clock coordinates fuel oxidation.
  37. Mitochondrial Functions in Infection and Immunity.
  38. Repression of the Type I Interferon pathway underlies MYC & KRAS-dependent evasion of NK & B cells in Pancreatic Ductal Adenocarcinoma.
  39. Role of respiratory NADH oxidation in the regulation of Staphylococcus aureus virulence.
  40. Ghostly metabolic messages from dying cells.
  41. Perturbation of phosphoglycerate kinase 1 (PGK1) only marginally affects glycolysis in cancer cells.
  42. Transient non-integrative expression of nuclear reprogramming factors promotes multifaceted amelioration of aging in human cells.
  43. Metabolic Plasticity in Chemotherapy Resistance.
  44. Tracing insights into de novo lipogenesis in liver and adipose tissues.
  45. Metabolic reprogram associated with epithelial-mesenchymal transition in tumor progression and metastasis.
  46. YAP/TAZ phase separation for transcription.
  47. Mitochondrial hyperfusion: a friend or a foe.
  1. Mol Metab. 2020 Feb 14. pii: S2212-8778(20)30007-7. [Epub ahead of print] 100941
    Compartmentalised acyl-CoA metabolism and roles in chromatin regulation.
    Sophie Trefely, Claudia D Lovell, Nathaniel W Snyder, Kathryn E Wellen.
      BACKGROUND: Many metabolites serve as important signalling molecules to adjust cellular activities and functions based on nutrient availability. Links between acetyl-CoA metabolism, histone lysine acetylation, and gene expression have been documented and studied over the past decade. In recent years, several additional acyl modifications to histone lysine residues have been identified, which depend on acyl-coenzyme A thioesters (acyl-CoAs) as acyl donors. Acyl-CoAs are intermediates of multiple distinct metabolic pathways, and substantial evidence has emerged that histone acylation is metabolically sensitive. Nevertheless, the metabolic sources of acyl-CoAs used for chromatin modification in most cases remain poorly understood. Elucidating how these diverse chemical modifications are coupled to and regulated by cellular metabolism is important in deciphering their functional significance.SCOPE OF REVIEW: In this article, we review the metabolic pathways that produce acyl-CoAs, as well as emerging evidence for functional roles of diverse acyl-CoAs in chromatin regulation. Because acetyl-CoA has been extensively reviewed elsewhere, we will focus on four other acyl-CoA metabolites integral to major metabolic pathways that are also known to modify histones: succinyl-CoA, propionyl-CoA, crotonoyl-CoA, and butyryl-CoA. We also briefly mention several other acyl-CoA species, which present opportunities for further research; malonyl-CoA, glutaryl-CoA, 3-hydroxybutyryl-CoA, 2-hydroxyisobutyryl-CoA, and lactyl-CoA. Each acyl-CoA species has distinct roles in metabolism, indicating the potential to report shifts in the metabolic status of the cell. For each metabolite, we consider the metabolic pathways in which it participates and the nutrient sources from which it is derived, the compartmentalisation of its metabolism, and the factors reported to influence its abundance and potential nuclear availability. We also highlight reported biological functions of these metabolically-linked acylation marks. Finally, we aim to illuminate key questions in acyl-CoA metabolism as they relate to the control of chromatin modification.
    MAJOR CONCLUSIONS: A majority of acyl-CoA species are annotated to mitochondrial metabolic processes. Since acyl-CoAs are not known to be directly transported across mitochondrial membranes, they must be synthesized outside of mitochondria and potentially within the nucleus to participate in chromatin regulation. Thus, subcellular metabolic compartmentalisation likely plays a key role in the regulation of histone acylation. Metabolite tracing in combination with targeting of relevant enzymes and transporters will help to map the metabolic pathways that connect acyl-CoA metabolism to chromatin modification. The specific function of each acyl-CoA may be determined in part by biochemical properties that affect its propensity for enzymatic versus non-enzymatic protein modification, as well as the various enzymes that can add, remove and bind each modification. Further, competitive and inhibitory effects of different acyl-CoA species on these enzymes make determining the relative abundance of acyl-CoA species in specific contexts important to understand the regulation of chromatin acylation. An improved and more nuanced understanding of metabolic regulation of chromatin and its roles in physiological and disease-related processes will emerge as these questions are answered.
    Keywords:  Acyl-CoA; Acylation; Compartmentalisation; Histone; Metabolism
    DOI:  https://doi.org/10.1016/j.molmet.2020.01.005
  2. Nature. 2020 Mar;579(7800): 586-591
    Dietary fructose feeds hepatic lipogenesis via microbiota-derived acetate.
    Steven Zhao, Cholsoon Jang, Joyce Liu, Kahealani Uehara, Michael Gilbert, Luke Izzo, Xianfeng Zeng, Sophie Trefely, Sully Fernandez, Alessandro Carrer, Katelyn D Miller, Zachary T Schug, Nathaniel W Snyder, Terence P Gade, Paul M Titchenell, Joshua D Rabinowitz, Kathryn E Wellen.
      Consumption of fructose has risen markedly in recent decades owing to the use of sucrose and high-fructose corn syrup in beverages and processed foods1, and this has contributed to increasing rates of obesity and non-alcoholic fatty liver disease2-4. Fructose intake triggers de novo lipogenesis in the liver4-6, in which carbon precursors of acetyl-CoA are converted into fatty acids. The ATP citrate lyase (ACLY) enzyme cleaves cytosolic citrate to generate acetyl-CoA, and is upregulated after consumption of carbohydrates7. Clinical trials are currently pursuing the inhibition of ACLY as a treatment for metabolic diseases8. However, the route from dietary fructose to hepatic acetyl-CoA and lipids remains unknown. Here, using in vivo isotope tracing, we show that liver-specific deletion of Acly in mice is unable to suppress fructose-induced lipogenesis. Dietary fructose is converted to acetate by the gut microbiota9, and this supplies lipogenic acetyl-CoA independently of ACLY10. Depletion of the microbiota or silencing of hepatic ACSS2, which generates acetyl-CoA from acetate, potently suppresses the conversion of bolus fructose into hepatic acetyl-CoA and fatty acids. When fructose is consumed more gradually to facilitate its absorption in the small intestine, both citrate cleavage in hepatocytes and microorganism-derived acetate contribute to lipogenesis. By contrast, the lipogenic transcriptional program is activated in response to fructose in a manner that is independent of acetyl-CoA metabolism. These data reveal a two-pronged mechanism that regulates hepatic lipogenesis, in which fructolysis within hepatocytes provides a signal to promote the expression of lipogenic genes, and the generation of microbial acetate feeds lipogenic pools of acetyl-CoA.
    DOI:  https://doi.org/10.1038/s41586-020-2101-7
  3. Genes Dis. 2020 Jun;7(2): 185-198
    Metabolic reprogramming in tumors: Contributions of the tumor microenvironment.
    Andrew N Lane, Richard M Higashi, Teresa W-M Fan.
      The genetic alterations associated with cell transformation are in large measure expressed in the metabolic phenotype as cancer cells proliferate and change their local environment, and prepare for metastasis. Qualitatively, the fundamental biochemistry of cancer cells is generally the same as in the untransformed cells, but the cancer cells produce a local environment, the TME, that is hostile to the stromal cells, and compete for nutrients. In order to proliferate, cells need sufficient nutrients, either those that cannot be made by the cells themselves, or must be made from simpler precursors. However, in solid tumors, the nutrient supply is often limiting given the potential for rapid proliferation, and the poor quality of the vasculature. Thus, cancer cells may employ a variety of strategies to obtain nutrients for survival, growth and metastasis. Although much has been learned using established cell lines in standard culture conditions, it is becoming clear from in vivo metabolic studies that this can also be misleading, and which nutrients are used for energy production versus building blocks for synthesis of macromolecules can vary greatly from tumor to tumor, and even within the same tumor. Here we review the operation of metabolic networks, and how recent understanding of nutrient supply in the TME and utilization are being revealed using stable isotope tracers in vivo as well as in vitro.
    Keywords:  2OG, 2-oxoglutarate; ACO1,2, aconitase 1,2; CP-MAS, Cross polarization Magic Angle Spinning; Cancer metabolism; DMEM, Dulbeccos Modified Eagles Medium; ECAR, extracellular acidification rate; ECM, extracellular matrix; EMP, Embden-Meyerhof Pathway; IDH1,2, isocitrate dehydrogenase 1,2 (NADP+dependent); IF, interstitial fluid; ME, malic enzyme; Metabolic flux; Nutrient supply; RPMI, Roswell Park Memorial Institute; SIRM, Stable Isotope Resolved Metabolomics; Stable isotope resolved metabolomics; TIL, tumor infiltrating lymphocyte; TIM/TPI, triose phosphate isomerase; TME, Tumor Micro Environment; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.gendis.2019.10.007
  4. FASEB J. 2020 Mar 22.
    AMPK activation induces mitophagy and promotes mitochondrial fission while activating TBK1 in a PINK1-Parkin independent manner.
    Alex P Seabright, Nicholas H F Fine, Jonathan P Barlow, Samuel O Lord, Ibrahim Musa, Alexander Gray, Jack A Bryant, Manuel Banzhaf, Gareth G Lavery, D Grahame Hardie, David J Hodson, Andrew Philp, Yu-Chiang Lai.
      Mitophagy is a key process regulating mitochondrial quality control. Several mechanisms have been proposed to regulate mitophagy, but these have mostly been studied using stably expressed non-native proteins in immortalized cell lines. In skeletal muscle, mitophagy and its molecular mechanisms require more thorough investigation. To measure mitophagy directly, we generated a stable skeletal muscle C2C12 cell line, expressing a mitophagy reporter construct (mCherry-green fluorescence protein-mtFIS1101-152 ). Here, we report that both carbonyl cyanide m-chlorophenyl hydrazone (CCCP) treatment and adenosine monophosphate activated protein kinase (AMPK) activation by 991 promote mitochondrial fission via phosphorylation of MFF and induce mitophagy by ~20%. Upon CCCP treatment, but not 991, ubiquitin phosphorylation, a read-out of PTEN-induced kinase 1 (PINK1) activity, and Parkin E3 ligase activity toward CDGSH iron sulfur domain 1 (CISD1) were increased. Although the PINK1-Parkin signaling pathway is active in response to CCCP treatment, we observed no change in markers of mitochondrial protein content. Interestingly, our data shows that TANK-binding kinase 1 (TBK1) phosphorylation is increased after both CCCP and 991 treatments, suggesting TBK1 activation to be independent of both PINK1 and Parkin. Finally, we confirmed in non-muscle cell lines that TBK1 phosphorylation occurs in the absence of PINK1 and is regulated by AMPK-dependent signaling. Thus, AMPK activation promotes mitophagy by enhancing mitochondrial fission (via MFF phosphorylation) and autophagosomal engulfment (via TBK1 activation) in a PINK1-Parkin independent manner.
    Keywords:  endogenous; mitophagy; skeletal muscle; tandem ubiquitin-binding entity (TUBE); ubiquitin
    DOI:  https://doi.org/10.1096/fj.201903051R
  5. Nat Commun. 2020 Mar 24. 11(1): 1533
    Subpopulation targeting of pyruvate dehydrogenase and GLUT1 decouples metabolic heterogeneity during collective cancer cell invasion.
    R Commander, C Wei, A Sharma, J K Mouw, L J Burton, E Summerbell, D Mahboubi, R J Peterson, J Konen, W Zhou, Y Du, H Fu, M Shanmugam, A I Marcus.
      Phenotypic heterogeneity exists within collectively invading packs of tumor cells, suggesting that cellular subtypes cooperate to drive invasion and metastasis. Here, we take a chemical biology approach to probe cell:cell cooperation within the collective invasion pack. These data reveal metabolic heterogeneity within invasive chains, in which leader cells preferentially utilize mitochondrial respiration and trailing follower cells rely on elevated glucose uptake. We define a pyruvate dehydrogenase (PDH) dependency in leader cells that can be therapeutically exploited with the mitochondria-targeting compound alexidine dihydrochloride. In contrast, follower cells highly express glucose transporter 1 (GLUT1), which sustains an elevated level of glucose uptake required to maintain proliferation. Co-targeting of both leader and follower cells with PDH and GLUT1 inhibitors, respectively, inhibits cell growth and collective invasion. Taken together, our work reveals metabolic heterogeneity within the lung cancer collective invasion pack and provides rationale for co-targeting PDH and GLUT1 to inhibit collective invasion.
    DOI:  https://doi.org/10.1038/s41467-020-15219-7
  6. Cell Metab. 2020 Mar 16. pii: S1550-4131(20)30119-4. [Epub ahead of print]
    Glutathione Restricts Serine Metabolism to Preserve Regulatory T Cell Function.
    Henry Kurniawan, Davide G Franchina, Luana Guerra, Lynn Bonetti, Leticia Soriano -Baguet, Melanie Grusdat, Lisa Schlicker, Oliver Hunewald, Catherine Dostert, Myriam P Merz, Carole Binsfeld, Gordon S Duncan, Sophie Farinelle, Yannic Nonnenmacher, Jillian Haight, Dennis Das Gupta, Anouk Ewen, Rabia Taskesen, Rashi Halder, Ying Chen, Christian Jäger, Markus Ollert, Paul Wilmes, Vasilis Vasiliou, Isaac S Harris, Christiane B Knobbe-Thomsen, Jonathan D Turner, Tak W Mak, Michael Lohoff, Johannes Meiser, Karsten Hiller, Dirk Brenner.
      Regulatory T cells (Tregs) maintain immune homeostasis and prevent autoimmunity. Serine stimulates glutathione (GSH) synthesis and feeds into the one-carbon metabolic network (1CMet) essential for effector T cell (Teff) responses. However, serine's functions, linkage to GSH, and role in stress responses in Tregs are unknown. Here, we show, using mice with Treg-specific ablation of the catalytic subunit of glutamate cysteine ligase (Gclc), that GSH loss in Tregs alters serine import and synthesis and that the integrity of this feedback loop is critical for Treg suppressive capacity. Although Gclc ablation does not impair Treg differentiation, mutant mice exhibit severe autoimmunity and enhanced anti-tumor responses. Gclc-deficient Tregs show increased serine metabolism, mTOR activation, and proliferation but downregulated FoxP3. Limitation of cellular serine in vitro and in vivo restores FoxP3 expression and suppressive capacity of Gclc-deficient Tregs. Our work reveals an unexpected role for GSH in restricting serine availability to preserve Treg functionality.
    Keywords:  FoxP3; ROS; Treg; autoimmunity; cancer; diet; glutamate cysteine ligase; glutathione; one carbon metabolism; serine metabolism
    DOI:  https://doi.org/10.1016/j.cmet.2020.03.004
  7. Mol Metab. 2020 Feb 15. pii: S2212-8778(20)30008-9. [Epub ahead of print] 100942
    Two genomes, one cell: Mitochondrial-nuclear coordination via epigenetic pathways.
    Meike Wiese, Andrew J Bannister.
      BACKGROUND: Virtually all eukaryotic cells contain spatially distinct genomes, a single nuclear genome that harbours the vast majority of genes and much smaller genomes found in mitochondria present at thousands of copies per cell. To generate a coordinated gene response to various environmental cues, the genomes must communicate with each another. Much of this bi-directional crosstalk relies on epigenetic processes, including DNA, RNA, and histone modification pathways. Crucially, these pathways, in turn depend on many metabolites generated in specific pools throughout the cell, including the mitochondria. They also involve the transport of metabolites as well as the enzymes that catalyse these modifications between nuclear and mitochondrial genomes.SCOPE OF REVIEW: This study examines some of the molecular mechanisms by which metabolites influence the activity of epigenetic enzymes, ultimately affecting gene regulation in response to metabolic cues. We particularly focus on the subcellular localisation of metabolite pools and the crosstalk between mitochondrial and nuclear proteins and RNAs. We consider aspects of mitochondrial-nuclear communication involving histone proteins, and potentially their epigenetic marks, and discuss how nuclear-encoded enzymes regulate mitochondrial function through epitranscriptomic pathways involving various classes of RNA molecules within mitochondria.
    MAJOR CONCLUSIONS: Epigenetic communication between nuclear and mitochondrial genomes occurs at multiple levels, ultimately ensuring a coordinated gene expression response between different genetic environments. Metabolic changes stimulated, for example, by environmental factors, such as diet or physical activity, alter the relative abundances of various metabolites, thereby directly affecting the epigenetic machinery. These pathways, coupled to regulated protein and RNA transport mechanisms, underpin the coordinated gene expression response. Their overall importance to the fitness of a cell is highlighted by the identification of many mutations in the pathways we discuss that have been linked to human disease including cancer.
    Keywords:  Chromatin; Enzymes; Epigenetics; Histones; Metabolites; Mitochondria; RNA modification
    DOI:  https://doi.org/10.1016/j.molmet.2020.01.006
  8. Cell Death Dis. 2020 Mar 23. 11(3): 204
    Peroxiredoxin 5 deficiency exacerbates iron overload-induced neuronal death via ER-mediated mitochondrial fission in mouse hippocampus.
    Dong Gil Lee, Min Kyoung Kam, Sang-Rae Lee, Hong Jun Lee, Dong-Seok Lee.
      Iron is an essential element for cellular functions, including those of neuronal cells. However, an imbalance of iron homeostasis, such as iron overload, has been observed in several neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease. Iron overload causes neuronal toxicity through mitochondrial fission, dysregulation of Ca2+, ER-stress, and ROS production. Nevertheless, the precise mechanisms between iron-induced oxidative stress and iron toxicity related to mitochondria and endoplasmic reticulum (ER) in vivo are not fully understood. Here, we demonstrate the role of peroxiredoxin 5 (Prx5) in iron overload-induced neurotoxicity using Prx5-deficient mice. Iron concentrations and ROS levels in mice fed a high iron diet were significantly higher in Prx5-/- mice than wildtype (WT) mice. Prx5 deficiency also exacerbated ER-stress and ER-mediated mitochondrial fission via Ca2+/calcineurin-mediated dephosphorylation of Drp1 at Serine 637. Moreover, immunoreactive levels of cleaved caspase3 in the CA3 region of the hippocampus were higher in iron-loaded Prx5-/- mice than WT mice. Furthermore, treatment with N-acetyl-cysteine, a reactive oxygen species (ROS) scavenger, attenuated iron overload-induced hippocampal damage by inhibiting ROS production, ER-stress, and mitochondrial fission in iron-loaded Prx5-/- mice. Therefore, we suggest that iron overload-induced oxidative stress and ER-mediated mitochondrial fission may be essential for understanding iron-mediated neuronal cell death in the hippocampus and that Prx5 may be useful as a novel therapeutic target in the treatment of iron overload-mediated diseases and neurodegenerative diseases.
    DOI:  https://doi.org/10.1038/s41419-020-2402-7
  9. Cell Rep. 2020 Mar 24. pii: S2211-1247(20)30303-X. [Epub ahead of print]30(12): 4235-4249.e6
    c-Src Promotes Tumorigenesis and Tumor Progression by Activating PFKFB3.
    Huanhuan Ma, Jia Zhang, Lin Zhou, Shixiong Wen, Hsiang-Yu Tang, Bin Jiang, Fengqiong Zhang, Muhammad Suleman, Dachao Sun, Ai Chen, Wentao Zhao, Furong Lin, Ming-Tong Tsau, Lu-Min Shih, Changchuan Xie, Xiaotong Li, Donghai Lin, Li-Man Hung, Mei-Ling Cheng, Qinxi Li.
      Reprogramming of glucose metabolism is a key event in tumorigenesis and progression. Here, we show that active c-Src stimulates glycolysis by phosphorylating (Tyr194) and activating PFKFB3, a key enzyme that boosts glycolysis by producing fructose-2,6-bisphosphate and activating PFK1. Increased glycolysis intermediates replenish non-oxidative pentose phosphate pathway (PPP) and serine pathway for biosynthesis of cancer cells. PFKFB3 knockout (KO) cells and their counterpart reconstituted with PFKFB3-Y194F show comparably impaired abilities for proliferation, migration, and xenograft formation. Furthermore, PFKFB3-Y194F knockin mice show impaired glycolysis and, mating of these mice with APCmin/+ mice attenuates spontaneous colon cancer formation in APCmin/+ mice. In summary, we identify a specific mechanism by which c-Src mediates glucose metabolism to meet cancer cells' requirements for maximal biosynthesis and proliferation. The PFKFB3-Tyr194 phosphorylation level highly correlates with c-Src activity in clinical tumor samples, indicating its potential as an evaluation for tumor prognosis.
    DOI:  https://doi.org/10.1016/j.celrep.2020.03.005
  10. Nat Cell Biol. 2020 Mar 16.
    Copper is an essential regulator of the autophagic kinases ULK1/2 to drive lung adenocarcinoma.
    Tiffany Tsang, Jessica M Posimo, Andrea A Gudiel, Michelle Cicchini, David M Feldser, Donita C Brady.
      Although the transition metal copper (Cu) is an essential nutrient that is conventionally viewed as a static cofactor within enzyme active sites, a non-traditional role for Cu as a modulator of kinase signalling is emerging. Here, we found that Cu is required for the activity of the autophagic kinases ULK1 and ULK2 (ULK1/2) through a direct Cu-ULK1/2 interaction. Genetic loss of the Cu transporter Ctr1 or mutations in ULK1 that disrupt the binding of Cu reduced ULK1/2-dependent signalling and the formation of autophagosome complexes. Increased levels of intracellular Cu are associated with starvation-induced autophagy and are sufficient to enhance ULK1 kinase activity and, in turn, autophagic flux. The growth and survival of lung tumours driven by KRASG12D is diminished in the absence of Ctr1, is dependent on ULK1 Cu binding and is associated with reduced levels of autophagy and signalling. These findings suggest a molecular basis for exploiting Cu-chelation therapy to prevent autophagy signalling to limit proliferation and improve patient survival in cancer.
    DOI:  https://doi.org/10.1038/s41556-020-0481-4
  11. Acta Histochem Cytochem. 2020 Feb 28. 53(1): 1-10
    Codependency of Metabolism and Epigenetics Drives Cancer Progression: A Review.
    Kenta Masui, Mio Harachi, Webster K Cavenee, Paul S Mischel, Noriyuki Shibata.
      Cancer is widely considered to be a set of genetic diseases that are currently classified by tissue and cell type of origin and, increasingly, by its molecular characteristics. This latter aspect is based primarily upon oncogene gains, tumor suppressor losses, and associated transcriptional profiles. However, cancers are also characterized by profound alterations in cellular metabolism and epigenetic landscape. It is particularly noteworthy that cancer-causing genomic defects not only activate cell cycle progression, but regulate the opportunistic uptake and utilization of nutrients, effectively enabling tumors to maximize growth and drug resistance in changing tissue and systemic microenvironments. Shifts in chromatin architecture are central to this dynamic behavior. Further, changes in nutrient uptake and utilization directly affect chromatin structure. In this review, we describe a set of recent discoveries of metabolic and epigenetic reprogramming in cancer, and especially focus on the genomically well-characterized brain tumor, glioblastoma. Further, we discuss a new mode of metabolic regulation driven by epigenetic mechanisms, that enables cancer cells to autonomously activate iron metabolism for their survival. Together, these underscore the integration of genetic mutations with metabolic reprogramming and epigenetic shifts in cancer, suggesting a new means to identifying patient subsets suitable for specific precision therapeutics.
    Keywords:  cancer metabolism; epigenetics; glioblastoma; histone acetylation; iron metabolism
    DOI:  https://doi.org/10.1267/ahc.20002
  12. Antioxid Redox Signal. 2020 Mar 25.
    Cell Senescence, DNA Damage and Metabolism.
    Riva Shmulevich, Valery Krizhanovsky.
      SIGNIFICANCE: Senescence is an essential biological process that blocks tumorigenesis, limits tissue damage and aids embryonic development. However, once senescent cells accumulate in tissues during aging, they promote development of age-related disease and limit healthspan. It is therefore crucial to gain a better understanding of the mechanisms controlling cellular senescence. Recent Advances: Cellular metabolism plays a significant role in regulation of various signaling process involved in cell senescence. In recent years, our understanding of the intimate relationship between cell metabolism, cell signaling, and cellular senescence has greatly improved.CRITICAL ISSUES: In this review, we discuss metabolic pathways in senescent cells and the impact of these pathways on DNA damage response and senescence associated secretory phenotype (SASP).
    FUTURE DIRECTIONS: Future research should elucidate metabolic mechanisms that promote specific alterations in senescent cell phenotype, with the final aim of developing new therapeutic strategies.
    DOI:  https://doi.org/10.1089/ars.2020.8043
  13. Cancer Immunol Res. 2020 Mar 23. pii: canimm.0467.2019. [Epub ahead of print]
    Enhanced immunogenicity of mitochondrial-localized proteins in cancer cells.
    Gennaro Prota, Uzi Gileadi, Margarida Rei, Ana Victoria Lechuga-Vieco, Ji-Li Chen, Silvia Galiani, Melissa Bedard, Vivian Wing Chong Lau, Lorenzo F Fanchi, Mara Artibani, Zhiyuan Hu, Siamon Gordon, Jan Rehwinkel, Jose A Enríquez, Ahmed A Ahmed, Ton N Schumacher, Vincenzo Cerundolo.
      Epitopes derived from mutated cancer proteins elicit strong antitumor T-cell responses that correlate with clinical efficacy in a proportion of patients. However, it remains unclear whether the subcellular localization of mutated proteins influences the efficiency of T-cell priming. To address this question we compared the immunogenicity of NY-ESO-1 and OVA localized either in the cytosol or in mitochondria. We showed that tumors expressing mitochondrial-localized NY-ESO-1 and OVA proteins elicit significantly higher frequencies of antigen-specific CD8+ T cells in vivo. We also demonstrated that this stronger immune response is dependent on the mitochondrial location of the antigenic proteins, which contributes to their higher steady state amount, compared with cytosolic-localized proteins. Consistent with these findings, we showed that injection of mitochondria purified from B16 melanoma cells can protect mice from a challenge with B16 cells, but not with irrelevant tumors. Finally, we extended these findings to cancer patients by demonstrating the presence of T-cell responses specific for mutated mitochondrial-localized proteins. These findings highlight the utility of prioritizing epitopes derived from mitochondrial-localized mutated proteins as targets for cancer vaccination strategies.
    DOI:  https://doi.org/10.1158/2326-6066.CIR-19-0467
  14. Sci Rep. 2020 Mar 25. 10(1): 5444
    Bioenergetic functions in subpopulations of heart mitochondria are preserved in a non-obese type 2 diabetes rat model (Goto-Kakizaki).
    N Lai, C M Kummitha, F Loy, R Isola, C L Hoppel.
      A distinct bioenergetic impairment of heart mitochondrial subpopulations in diabetic cardiomyopathy is associated with obesity; however, many type 2 diabetic (T2DM) patients with high-risk for cardiovascular disease are not obese. In the absence of obesity, it is unclear whether bioenergetic function in the subpopulations of mitochondria is affected in heart with T2DM. To address this issue, a rat model of non-obese T2DM was used to study heart mitochondrial energy metabolism, measuring bioenergetics and enzyme activities of the electron transport chain (ETC). Oxidative phosphorylation in the presence of substrates for ETC and ETC activities in both populations of heart mitochondria in T2DM rats were unchanged. Despite the preservation of mitochondrial function, aconitase activity in T2DM heart was reduced, suggesting oxidative stress in mitochondria. Our study indicate that metabolic function of heart mitochondria is unchanged in the face of oxidative stress and point to a critical role of obesity in T2DM cardiomyopathy.
    DOI:  https://doi.org/10.1038/s41598-020-62370-8
  15. J Clin Med. 2020 Mar 24. pii: E892. [Epub ahead of print]9(3):
    Mitophagy in Cardiovascular Diseases.
    Giampaolo Morciano, Simone Patergnani, Massimo Bonora, Gaia Pedriali, Anna Tarocco, Esmaa Bouhamida, Saverio Marchi, Gina Ancora, Gabriele Anania, Mariusz R Wieckowski, Carlotta Giorgi, Paolo Pinton.
      Cardiovascular diseases are one of the leading causes of death. Increasing evidence has shown that pharmacological or genetic targeting of mitochondria can ameliorate each stage of these pathologies, which are strongly associated with mitochondrial dysfunction. Removal of inefficient and dysfunctional mitochondria through the process of mitophagy has been reported to be essential for meeting the energetic requirements and maintaining the biochemical homeostasis of cells. This process is useful for counteracting the negative phenotypic changes that occur during cardiovascular diseases, and understanding the molecular players involved might be crucial for the development of potential therapies. Here, we summarize the current knowledge on mitophagy (and autophagy) mechanisms in the context of heart disease with an important focus on atherosclerosis, ischemic heart disease, cardiomyopathies, heart failure, hypertension, arrhythmia, congenital heart disease and peripheral vascular disease. We aim to provide a complete background on the mechanisms of action of this mitochondrial quality control process in cardiology and in cardiac surgery by also reviewing studies on the use of known compounds able to modulate mitophagy for cardioprotective purposes.
    Keywords:  autophagy; cardiovascular diseases; mitochondria; mitophagy
    DOI:  https://doi.org/10.3390/jcm9030892
  16. J Clin Invest. 2020 Mar 23. pii: 131800. [Epub ahead of print]
    Mature myelin maintenance requires Qki to coactivate PPARβ-RXRα-mediated lipid metabolism.
    Xin Zhou, Chenxi He, Jiangong Ren, Congxin Dai, Sharon R Stevens, Qianghu Wang, Daniel Zamler, Takashi Shingu, Liang Yuan, Chythra R Chandregowda, Yunfei Wang, Visweswaran Ravikumar, Arvind Uk Rao, Feng Zhou, Hongwu Zheng, Matthew N Rasband, Yiwen Chen, Fei Lan, Amy B Heimberger, Benjamin M Segal, Jian Hu.
      Lipid-rich myelin forms electrically insulating, axon-wrapping multilayers that are essential for neural function, and mature myelin is traditionally considered metabolically inert. Surprisingly, we discovered that mature myelin lipids undergo rapid turnover, and quaking (Qki) is a major regulator of myelin lipid homeostasis. Oligodendrocyte-specific Qki depletion, without affecting oligodendrocyte survival, resulted in rapid demyelination, within 1 week, and gradually neurological deficits in adult mice. Myelin lipids, especially the monounsaturated fatty acids and very-long-chain fatty acids, were dramatically reduced by Qki depletion, whereas the major myelin proteins remained intact, and the demyelinating phenotypes of Qki-depleted mice were alleviated by a high-fat diet. Mechanistically, Qki serves as a coactivator of the PPARβ-RXRα complex, which controls the transcription of lipid-metabolism genes, particularly those involved in fatty acid desaturation and elongation. Treatment of Qki-depleted mice with PPARβ/RXR agonists significantly alleviated neurological disability and extended survival durations. Furthermore, a subset of lesions from patients with primary progressive multiple sclerosis were characterized by preferential reductions in myelin lipid contents, activities of various lipid metabolism pathways, and expression level of QKI-5 in human oligodendrocytes. Together, our results demonstrate that continuous lipid synthesis is indispensable for mature myelin maintenance and highlight an underappreciated role of lipid metabolism in demyelinating diseases.
    Keywords:  Demyelinating disorders; Metabolism; Multiple sclerosis; Neuroscience
    DOI:  https://doi.org/10.1172/JCI131800
  17. Mol Biol Cell. 2020 Mar 26. mbcE19100565
    A role for keratins in supporting mitochondrial organization and function in skin keratinocytes.
    Kaylee Steen, Desu Chen, Fengrong Wang, Ritankar Majumdar, Song Chen, Surinder Kumar, David B Lombard, Roberto Weigert, Abigail G Zieman, Carole A Parent, Pierre A Coulombe.
      Mitochondria fulfill essential roles in ATP production, metabolic regulation, calcium signaling, generation of reactive oxygen species (ROS) and additional determinants of cellular health. Recent studies have highlighted a role for mitochondria during cell differentiation, including in skin epidermis. The observation of oxidative stress in keratinocytes from Krt16 null mouse skin, a model for pachyonychia congenita (PC)-associated palmoplantar keratoderma, prompted us to examine the role of Keratin (K) 16 protein and its partner K6 in regulating the structure and function of mitochondria. Electron microscopy revealed major anomalies in mitochondrial ultrastructure in late stage, E18.5, Krt6a/Krt6b null embryonic mouse skin. Follow-up studies utilizing biochemical, metabolic, and live imaging readouts showed that, relative to controls, skin keratinocytes null for Krt6a/Krt6b or Krt16 exhibit elevated ROS, reduced mitochondrial respiration, intracellular distribution differences and altered movement of mitochondria within the cell. These findings highlight a novel role for K6 and K16 in regulating mitochondrial morphology, dynamics and function and shed new light on the causes of oxidative stress observed in PC and related keratin-based skin disorders. [Media: see text] [Media: see text] [Media: see text] [Media: see text].
    DOI:  https://doi.org/10.1091/mbc.E19-10-0565
  18. Trends Cell Biol. 2020 Apr;pii: S0962-8924(20)30020-9. [Epub ahead of print]30(4): 317-328
    Mechanisms Linking Mitochondrial Dysfunction and Proteostasis Failure.
    Bingwei Lu, Su Guo.
      Maintaining cellular protein homeostasis (proteostasis) is an essential task for all eukaryotes. Proteostasis failure worsens with aging and is considered a cause of and a therapeutic target for age-related diseases including neurodegenerative disorders. The cellular networks regulating proteostasis and the pathogenic events driving proteostasis failure in disease remain poorly understood. Model organism studies in yeast and Drosophila reveal an intriguing link between mitochondrial function and proteostasis. In this review we examine recent findings on mitochondrial outer membrane (MOM)-associated mRNA translation, how this process is sensitive to mitochondrial dysfunction and constantly surveyed by ribosome-associated quality control (RQC), and how defects in this process generate aberrant proteins with unusual C-terminal extensions (CTEs) that promote aggregation and drive proteostasis failure. We also discuss the implications for human diseases.
    Keywords:  CAT-tailing; MISTERMINATE; co-translational mitochondrial import; mitochondrial dysfunction; protein homeostasis (proteostasis); ribosome-associated quality control
    DOI:  https://doi.org/10.1016/j.tcb.2020.01.008
  19. EMBO Rep. 2020 Mar 23. e49799
    Mitochondrial DNA in inflammation and immunity.
    Joel S Riley, Stephen Wg Tait.
      Mitochondria are cellular organelles that orchestrate a vast range of biological processes, from energy production and metabolism to cell death and inflammation. Despite this seemingly symbiotic relationship, mitochondria harbour within them a potent agonist of innate immunity: their own genome. Release of mitochondrial DNA into the cytoplasm and out into the extracellular milieu activates a plethora of different pattern recognition receptors and innate immune responses, including cGAS-STING, TLR9 and inflammasome formation leading to, among others, robust type I interferon responses. In this Review, we discuss how mtDNA can be released from the mitochondria, the various inflammatory pathways triggered by mtDNA release and its myriad biological consequences for health and disease.
    Keywords:  cell death; immunity; inflammation; mitochondria; mtDNA
    DOI:  https://doi.org/10.15252/embr.201949799
  20. Front Nutr. 2020 ;7 21
    Consideration of Ketogenic Metabolic Therapy as a Complementary or Alternative Approach for Managing Breast Cancer.
    Thomas N Seyfried, Purna Mukherjee, Mehmet S Iyikesici, Abdul Slocum, Miriam Kalamian, Jean-Pierre Spinosa, Christos Chinopoulos.
      Breast cancer remains as a significant cause of morbidity and mortality in women. Ultrastructural and biochemical evidence from breast biopsy tissue and cancer cells shows mitochondrial abnormalities that are incompatible with energy production through oxidative phosphorylation (OxPhos). Consequently, breast cancer, like most cancers, will become more reliant on substrate level phosphorylation (fermentation) than on oxidative phosphorylation (OxPhos) for growth consistent with the mitochondrial metabolic theory of cancer. Glucose and glutamine are the prime fermentable fuels that underlie therapy resistance and drive breast cancer growth through substrate level phosphorylation (SLP) in both the cytoplasm (Warburg effect) and the mitochondria (Q-effect), respectively. Emerging evidence indicates that ketogenic metabolic therapy (KMT) can reduce glucose availability to tumor cells while simultaneously elevating ketone bodies, a non-fermentable metabolic fuel. It is suggested that KMT would be most effective when used together with glutamine targeting. Information is reviewed for suggesting how KMT could reduce systemic inflammation and target tumor cells without causing damage to normal cells. Implementation of KMT in the clinic could improve progression free and overall survival for patients with breast cancer.
    Keywords:  fermentation; glutaminolysis; glycolysis; inflammation; metastasis; non-toxic; survival
    DOI:  https://doi.org/10.3389/fnut.2020.00021
  21. Semin Cancer Biol. 2020 Mar 21. pii: S1044-579X(20)30078-X. [Epub ahead of print]
    Coalescing Lessons from Oxygen Sensing, Tumor Metabolism, and Epigenetics to Target VHL loss in Kidney Cancer.
    Abhishek A Chakraborty.
      Inactivation of the von Hippel Lindau tumor suppressor protein (pVHL) is a hallmark of clear cell Renal Cell Carcinoma (ccRCC), which is the most common form of kidney cancer in adults. In complex with Elongin B/C, pVHL functions as the substrate recognition subunit of a ubiquitin ligase, perhaps best known to target the hypoxia inducible factor (HIF) transcription factor for ubiquitin-dependent proteolysis. Beyond kidney cancer, the pseudo-hypoxic state caused due to chronic HIF activation in pVHL-deficient cells has become a biological model to study hypoxia's profound effects on tumor angiogenesis, metabolism, and epigenetics. However, a number of HIF-independent substrates of pVHL, which function in a broad range of biological pathways, have also been discovered. Independently, the development of high-throughput chemical and genetic screening strategies have enabled the identification of novel, HIF-independent, targetable dependencies in ccRCC. In this review we summarize the history of pVHL and HIF mediated oxygen sensing, discuss the current status of this field, and identify critical challenges that need to be overcome. The confluence of historical discovery, development of unbiased screening strategies, and the evolution of medicinal chemistry has allowed us to begin therapeutically targeting vulnerabilities that emerge due to pVHL loss in ccRCC. Ongoing mechanistic studies on the biological consequences of pVHL loss, therefore, are likely to become the cornerstones of modern therapeutics in renal cancer.
    Keywords:  Chemical Screens; EglN; Epigenetics; Genetic Screens; HIF; Hypoxia; Immunotherapy; Oxygen sensing; PHD; Proteolysis; RTK; Renal Cancer; TKI; Tumor Metabolism; Ubiquitin; Von Hippel-Lindau; Warburg Effect; ccRCC
    DOI:  https://doi.org/10.1016/j.semcancer.2020.03.012
  22. Kidney Int. 2020 Apr;pii: S0085-2538(20)30011-9. [Epub ahead of print]97(4): 645-647
    Got glycogen? An energy resource in HIF-mediated prevention of ischemic kidney injury.
    Volker H Haase.
      Hypoxia-inducible factor activation reprograms glucose metabolism and leads to glycogen accumulation in multiple cell types. In this issue of Kidney International, Ito and colleagues demonstrate that pharmacologic inhibition of hypoxia-inducible factor-prolyl hydroxylase domain oxygen sensors in renal epithelial cells enhances glycogen synthesis and protects from subsequent hypoxia and glucose deprivation. In vivo studies advance the concept that renal glycogen metabolism contributes to cytoprotection afforded by pre-ischemic hypoxia-inducible factor-prolyl hydroxylase domain inhibition.
    DOI:  https://doi.org/10.1016/j.kint.2019.11.036
  23. Sci Transl Med. 2020 Mar 25. pii: eaaw6003. [Epub ahead of print]12(536):
    Acute kidney injury promotes development of papillary renal cell adenoma and carcinoma from renal progenitor cells.
    Anna Julie Peired, Giulia Antonelli, Maria Lucia Angelotti, Marco Allinovi, Francesco Guzzi, Alessandro Sisti, Roberto Semeraro, Carolina Conte, Benedetta Mazzinghi, Sara Nardi, Maria Elena Melica, Letizia De Chiara, Elena Lazzeri, Laura Lasagni, Tiziano Lottini, Samuela Landini, Sabrina Giglio, Andrea Mari, Fabrizio Di Maida, Alessandro Antonelli, Francesco Porpiglia, Riccardo Schiavina, Vincenzo Ficarra, Davide Facchiano, Mauro Gacci, Sergio Serni, Marco Carini, George J Netto, Rosa Maria Roperto, Alberto Magi, Christian Fynbo Christiansen, Mario Rotondi, Helen Liapis, Hans-Joachim Anders, Andrea Minervini, Maria Rosaria Raspollini, Paola Romagnani.
      Acute tissue injury causes DNA damage and repair processes involving increased cell mitosis and polyploidization, leading to cell function alterations that may potentially drive cancer development. Here, we show that acute kidney injury (AKI) increased the risk for papillary renal cell carcinoma (pRCC) development and tumor relapse in humans as confirmed by data collected from several single-center and multicentric studies. Lineage tracing of tubular epithelial cells (TECs) after AKI induction and long-term follow-up in mice showed time-dependent onset of clonal papillary tumors in an adenoma-carcinoma sequence. Among AKI-related pathways, NOTCH1 overexpression in human pRCC associated with worse outcome and was specific for type 2 pRCC. Mice overexpressing NOTCH1 in TECs developed papillary adenomas and type 2 pRCCs, and AKI accelerated this process. Lineage tracing in mice identified single renal progenitors as the cell of origin of papillary tumors. Single-cell RNA sequencing showed that human renal progenitor transcriptome showed similarities to PT1, the putative cell of origin of human pRCC. Furthermore, NOTCH1 overexpression in cultured human renal progenitor cells induced tumor-like 3D growth. Thus, AKI can drive tumorigenesis from local tissue progenitor cells. In particular, we find that AKI promotes the development of pRCC from single progenitors through a classical adenoma-carcinoma sequence.
    DOI:  https://doi.org/10.1126/scitranslmed.aaw6003
  24. Curr Opin Cell Biol. 2020 Mar 21. pii: S0955-0674(20)30033-8. [Epub ahead of print]65 58-65
    The multifunctional nature of mitochondrial contact site proteins.
    Clare S Harper, Antoineen J White, Laura L Lackner.
      Mitochondria make physical contact with nearly every other membrane in the cell, and these contacts have a wide variety of functions that are carried out by proteins that reside at the sites of contact. Over the past decade, tremendous insight into the identity and functions of proteins localized to mitochondrial contact sites has been gained. In doing so, it has become clear that one protein or protein complex can contribute to contact site formation and function in a wide variety of ways. Thus, complex and often surprising relationships between the roles of a mitochondrial contact site and its multifunctional resident proteins continue to be unraveled.
    Keywords:  Membrane contact sites; Mitochondria; Mitochondrial contact sites
    DOI:  https://doi.org/10.1016/j.ceb.2020.02.010
  25. Cytokine. 2020 Mar 19. pii: S1043-4666(20)30075-2. [Epub ahead of print]130 155059
    STAT3-driven hematopoiesis and lymphopoiesis abnormalities are dependent on serine phosphorylation.
    Jesse J Balic, Christine L White, Ruby Dawson, Daniel Gough, Matthew P McCormack, Brendan J Jenkins.
      Deregulated activation of the latent transcription factor STAT3 has been implicated in the pathogenesis of myeloproliferative and lymphoproliferative hematologic disorders. The uncontrolled activation of STAT3 has traditionally been assigned to its elevated phosphorylation at tyrosine 705 (pY705) and associated nuclear transcriptional activity. By contrast, a transcriptional role for serine 727 phosphorylation (pS727) of STAT3 has recently emerged, suggesting that pS727 may account for the pathological activity of STAT3 in certain disease settings. Here, by coupling pS727-STAT3-deficient Stat3SA/SA mice with a STAT3-driven mouse model (gp130F/F) for myeloproliferative and lymphoproliferative pathologies, we reveal a key role for pS727-STAT3 in promoting multiple hematologic pathologies. The genetic blockade of pS727-STAT3 in gp130F/F:Stat3SA/SA mice ameliorated the neutrophilia, thrombocytosis, splenomegaly and lymphadenopathy that are features of gp130F/F mice. The protection against thrombocytosis in gp130F/F:Stat3SA/SA mice coincided with normalized megakaryopoiesis in both bone marrow and spleen compartments. Interestingly, pS727-STAT3-mediated abnormal lymphopoiesis in gp130F/F mice was more pronounced in lymph nodes compared to thymus, and was characterized by elevated numbers of B cells at the expense of T cells. Furthermore, pS727-STAT3 dependency for these hematologic pathologies coincided with transcriptional activity on STAT3-regulated genes, rather than its effect on mitochondrial and metabolic genes. Collectively, these findings suggest that pS727 plays a critical pathological role in modulating the transcriptional activity of STAT3 in hematologic disorders.
    Keywords:  Hematopoiesis; Lymphopoiesis; Neutrophilia; STAT3; Serine phosphorylation; Splenomegaly; Thrombocytosis; Transcription
    DOI:  https://doi.org/10.1016/j.cyto.2020.155059
  26. Transl Oncol. 2020 Mar 21. pii: S1936-5233(20)30005-X. [Epub ahead of print]13(4): 100758
    Wild-Type IDH1 and Mutant IDH1 Opposingly Regulate Podoplanin Expression in Glioma.
    Chao Sun, Liming Xiao, Yuanlin Zhao, Jiankuan Shi, Yuan Yuan, Yu Gu, Feng Zhang, Xing Gao, Ying Yang, Risheng Yang, Junhui Qin, Jin Zhang, Chao Wang, Yingmei Wang, Zhe Wang, Peizhen Hu, Ting Chang, Liang Wang, Gang Wang, Huangtao Chen, Zhuyi Li, Jing Ye.
      Isocitrate dehydrogenase (IDH) mutations occur frequently in lower-grade gliomas, which result in genome-wide epigenetic alterations. The wild-type IDH1 is reported to participate in lipid biosynthesis and amino acid metabolism, but its role in tumorigenesis is still unclear. In this study, the expressions of IDH1 and podoplanin (Pdpn) were determined in IDH-mutated and IDH-wild-type gliomas, and their relationships in glioma were further analyzed. In addition, the regulation of wild-type IDH1 and mutant IDH1 on Pdpn expression was investigated by luciferase assays and promoter methylation analysis. Our study showed that Pdpn was almost undetectable in IDH-mutated glioma but strongly expressed in higher-grade IDH-wild-type glioma. Pdpn overexpression promoted the migration of glioma cells but had little effect on cell growth. Moreover, Pdpn expression was positively correlated with the increased wild-type IDH1 levels in IDH-wild-type glioma. Consistently, the wild-type IDH1 greatly promoted the transcription and expression of Pdpn, but the mutant IDH1 and D-2-hydroxyglutarate significantly suppressed Pdpn expression in glioma cells. Besides, our results revealed that the methylation of CpG islands in the Pdpn promoter was opposingly regulated by wild-type and mutant IDH1 in glioma. Collectively, our results indicated that wild-type and mutant IDH1 opposingly controlled the Pdpn expression in glioma by regulating its promoter methylation, which provides a basis for understanding the relationship between wild-type and mutant IDH1 in epigenetic regulation and tumorigenesis.
    DOI:  https://doi.org/10.1016/j.tranon.2020.100758
  27. J Biol Chem. 2020 Mar 24. pii: jbc.RA120.012593. [Epub ahead of print]
    Catabolic degradation of endothelial VEGFA via autophagy.
    Thomas Neill, Carolyn G Chen, Simone Buraschi, Renato V Iozzo.
      Extracellular matrix-evoked angiostasis and autophagy within the tumor microenvironment represent two critical, but unconnected, functions of the small leucine-rich proteoglycan, decorin. Acting as a partial agonist of vascular endothelial growth factor 2 (VEGFR2), soluble decorin signals via the energy sensing protein, AMP-activated protein kinase (AMPK), in the autophagic degradation of intracellular vascular endothelial growth factor A (VEGFA). Here, we discovered that soluble decorin evokes intracellular catabolism of endothelial VEGFA that is mechanistically independent of mTOR, but requires an autophagic regulator, paternally expressed gene 3 (PEG3). We found that administration of autophagic inhibitors such as chloroquine or bafilomycin A1, or depletion of autophagy related 5 (ATG5), results in accumulation of intracellular VEGFA, indicating that VEGFA is a basal autophagic substrate. Mechanistically, decorin increased the VEGFA clearance rate by augmenting autophagic flux, a process that required RAB24 member RAS oncogene family (RAB24), a small GTPase that facilitates the disposal of autophagic compartments. We validated these findings by demonstrating the physiological relevance of this process in vivo. Mice starved for 48 h exhibited a sharp decrease in overall cardiac and aortic VEGFA that could be blocked by systemic chloroquine treatment. Thus, our findings reveal a unified mechanism for the metabolic control of endothelial VEGFA for autophagic clearance in response to decorin and canonical pro-autophagic stimuli.  We posit that the VEGFR2-AMPK-PEG3 axis integrates the anti-angiogenic and pro-autophagic bioactivities of decorin as the molecular basis for tumorigenic suppression. These results support future therapeutic use of decorin as a next-generation protein therapy to combat cancer.
    Keywords:  AICAR; AMPK; HUVEC; Peg3; VEGFR2; angiogenesis; autophagy; cell signaling; endothelial cell; proteoglycan
    DOI:  https://doi.org/10.1074/jbc.RA120.012593
  28. Mol Cell. 2020 Mar 13. pii: S1097-2765(20)30152-0. [Epub ahead of print]
    Methyl-Metabolite Depletion Elicits Adaptive Responses to Support Heterochromatin Stability and Epigenetic Persistence.
    Spencer A Haws, Deyang Yu, Cunqi Ye, Coral K Wille, Long C Nguyen, Kimberly A Krautkramer, Jay L Tomasiewicz, Shany E Yang, Blake R Miller, Wallace H Liu, Kazuhiko Igarashi, Rupa Sridharan, Benjamin P Tu, Vincent L Cryns, Dudley W Lamming, John M Denu.
      S-adenosylmethionine (SAM) is the methyl-donor substrate for DNA and histone methyltransferases that regulate epigenetic states and subsequent gene expression. This metabolism-epigenome link sensitizes chromatin methylation to altered SAM abundance, yet the mechanisms that allow organisms to adapt and protect epigenetic information during life-experienced fluctuations in SAM availability are unknown. We identified a robust response to SAM depletion that is highlighted by preferential cytoplasmic and nuclear mono-methylation of H3 Lys 9 (H3K9) at the expense of broad losses in histone di- and tri-methylation. Under SAM-depleted conditions, H3K9 mono-methylation preserves heterochromatin stability and supports global epigenetic persistence upon metabolic recovery. This unique chromatin response was robust across the mouse lifespan and correlated with improved metabolic health, supporting a significant role for epigenetic adaptation to SAM depletion in vivo. Together, these studies provide evidence for an adaptive response that enables epigenetic persistence to metabolic stress.
    Keywords:  SAM; aging; chromatin; epigenetics; histone; metabolism; methionine; methylation; persistence
    DOI:  https://doi.org/10.1016/j.molcel.2020.03.004
  29. Proc Natl Acad Sci U S A. 2020 Mar 25. pii: 201918607. [Epub ahead of print]
    Oncogenic human herpesvirus hijacks proline metabolism for tumorigenesis.
    Un Yung Choi, Jae Jin Lee, Angela Park, Wei Zhu, Hye-Ra Lee, Youn Jung Choi, Ji-Seung Yoo, Claire Yu, Pinghui Feng, Shou-Jiang Gao, Shaochen Chen, Hyungjin Eoh, Jae U Jung.
      Three-dimensional (3D) cell culture is well documented to regain intrinsic metabolic properties and to better mimic the in vivo situation than two-dimensional (2D) cell culture. Particularly, proline metabolism is critical for tumorigenesis since pyrroline-5-carboxylate (P5C) reductase (PYCR/P5CR) is highly expressed in various tumors and its enzymatic activity is essential for in vitro 3D tumor cell growth and in vivo tumorigenesis. PYCR converts the P5C intermediate to proline as a biosynthesis pathway, whereas proline dehydrogenase (PRODH) breaks down proline to P5C as a degradation pathway. Intriguingly, expressions of proline biosynthesis PYCR gene and proline degradation PRODH gene are up-regulated directly by c-Myc oncoprotein and p53 tumor suppressor, respectively, suggesting that the proline-P5C metabolic axis is a key checkpoint for tumor cell growth. Here, we report a metabolic reprogramming of 3D tumor cell growth by oncogenic Kaposi's sarcoma-associated herpesvirus (KSHV), an etiological agent of Kaposi's sarcoma and primary effusion lymphoma. Metabolomic analyses revealed that KSHV infection increased nonessential amino acid metabolites, specifically proline, in 3D culture, not in 2D culture. Strikingly, the KSHV K1 oncoprotein interacted with and activated PYCR enzyme, increasing intracellular proline concentration. Consequently, the K1-PYCR interaction promoted tumor cell growth in 3D spheroid culture and tumorigenesis in nude mice. In contrast, depletion of PYCR expression markedly abrogated K1-induced tumor cell growth in 3D culture, not in 2D culture. This study demonstrates that an increase of proline biosynthesis induced by K1-PYCR interaction is critical for KSHV-mediated transformation in in vitro 3D culture condition and in vivo tumorigenesis.
    Keywords:  K1; Kaposi's sarcoma-associated herpesvirus (KSHV); cancer metabolism; proline metabolism; pyrroline-5-carboxylate reductase (PYCR)
    DOI:  https://doi.org/10.1073/pnas.1918607117
  30. Proc Natl Acad Sci U S A. 2020 Mar 25. pii: 201919535. [Epub ahead of print]
    Building blocks are synthesized on demand during the yeast cell cycle.
    Kate Campbell, Jakub Westholm, Sergo Kasvandik, Francesca Di Bartolomeo, Maurizio Mormino, Jens Nielsen.
      For cells to replicate, a sufficient supply of biosynthetic precursors is needed, necessitating the concerted action of metabolism and protein synthesis during progressive phases of cell division. A global understanding of which biosynthetic processes are involved and how they are temporally regulated during replication is, however, currently lacking. Here, quantitative multiomics analysis is used to generate a holistic view of the eukaryal cell cycle, using the budding yeast Saccharomyces cerevisiae Protein synthesis and central carbon pathways such as glycolysis and amino acid metabolism are shown to synchronize their respective abundance profiles with division, with pathway-specific changes in metabolite abundance also being reflected by a relative increase in mitochondrial volume, as shown by quantitative fluorescence microscopy. These results show biosynthetic precursor production to be temporally regulated to meet phase-specific demands of eukaryal cell division.
    Keywords:  Saccharomyces cerevisiae; absolute quantitation; cell cycle; metabolism; multiomics
    DOI:  https://doi.org/10.1073/pnas.1919535117
  31. Br J Cancer. 2020 Mar 17.
    Serine-dependent redox homeostasis regulates glioblastoma cell survival.
    Anna L Engel, Nadja I Lorenz, Kevin Klann, Christian Münch, Cornelia Depner, Joachim P Steinbach, Michael W Ronellenfitsch, Anna-Luisa Luger.
      BACKGROUND: The amino acid serine is an important substrate for biosynthesis and redox homeostasis. We investigated whether glioblastoma (GBM) cells are dependent on serine for survival under conditions of the tumour microenvironment.METHODS: Serine availability in GBM cells was modulated pharmacologically, genetically and by adjusting serine and glycine concentrations in the culture medium. Cells were investigated for regulation of serine metabolism, proliferation, sensitivity to hypoxia-induced cell death and redox homeostasis.
    RESULTS: Hypoxia-induced expression of phosphoglycerate dehydrogenase (PHGDH) and the mitochondrial serine hydroxymethyltransferase (SHMT2) was observed in three of five tested glioma cell lines. Nuclear factor erythroid 2-related factor (Nrf) 2 activation also induced PHGDH and SHMT2 expression in GBM cells. Low levels of endogenous PHGDH as well as PHGDH gene suppression resulted in serine dependency for cell growth. Pharmacological inhibition of PHGDH with CBR-5884 reduced proliferation and sensitised cells profoundly to hypoxia-induced cell death. This effect was accompanied by an increase in reactive oxygen species and a decrease in the NADPH/NADP+ ratio. Similarly, hypoxia-induced cell death was enhanced by PHGDH gene suppression and reduced by PHGDH overexpression.
    CONCLUSIONS: Serine facilitates adaptation of GBM cells to conditions of the tumour microenvironment and its metabolism could be a plausible therapeutic target.
    DOI:  https://doi.org/10.1038/s41416-020-0794-x
  32. Redox Biol. 2020 Mar 13. pii: S2213-2317(19)31508-3. [Epub ahead of print] 101503
    Restoration of L-OPA1 alleviates acute ischemic stroke injury in rats via inhibiting neuronal apoptosis and preserving mitochondrial function.
    Yongxing Lai, Peiqiang Lin, Manli Chen, Yixian Zhang, Jianhao Chen, Mouwei Zheng, Ji Liu, Houwei Du, Ronghua Chen, Xiaodong Pan, Nan Liu, Hongbin Chen.
      BACKGROUND: Ischemic stroke can induce changes in mitochondrial morphology and function. As a regulatory gene in mitochondria, optic atrophy 1 (OPA1) plays a pivotal role in the regulation of mitochondrial dynamics and other related functions. However, its roles in cerebral ischemia-related conditions are barely understood.METHODS: Cultured rat primary cortical neurons were respectively transfected with OPA1-v1ΔS1-encoding and OPA1-v1-encoding lentivirus before exposure to 2-h oxygen-glucose deprivation (OGD) and subsequent reoxygenation (OGD/R). Adult male SD rats received an intracranial injection of AAV-OPA1-v1ΔS1 and were subjected to 90 min of transient middle cerebral artery occlusion (tMCAO) followed by reperfusion. OPA1 expression and function were detected by in vitro and in vivo assays.
    RESULTS: OPA1 was excessively cleaved after cerebral ischemia/reperfusion injury, both in vitro and in vivo. Under OGD/R condition, compared with that of the LV-OPA1-v1-treated group, the expression of OPA1-v1ΔS1 efficiently restored L-OPA1 level and alleviated neuronal death and mitochondrial morphological damage. Meanwhile, the expression of OPA1-v1ΔS1 markedly improved cerebral ischemia/reperfusion-induced motor function damage, attenuated brain infarct volume, neuronal apoptosis, mitochondrial bioenergetics deficits, oxidative stress, and restored the morphology of mitochondrial cristae and mitochondrial length. It also preserved the mitochondrial integrity and reinforced the mtDNA content and expression of mitochondrial biogenesis factors in ischemic rats.
    INTERPRETATION: Our results demonstrate that the stabilization of L-OPA1 protects ischemic brains by reducing neuronal apoptosis and preserving mitochondrial function, suggesting its significance as a promising therapeutic target for stroke prevention and treatment.
    Keywords:  Apoptosis; Ischemia/reperfusion; Mitochondria function; OPA1; Oxidative stress
    DOI:  https://doi.org/10.1016/j.redox.2020.101503
  33. Nature. 2020 Mar;579(7800): 507-517
    Dietary modifications for enhanced cancer therapy.
    Naama Kanarek, Boryana Petrova, David M Sabatini.
      Tumours depend on nutrients supplied by the host for their growth and survival. Modifications to the host's diet can change nutrient availability in the tumour microenvironment, which might represent a promising strategy for inhibiting tumour growth. Dietary modifications can limit tumour-specific nutritional requirements, alter certain nutrients that target the metabolic vulnerabilities of the tumour, or enhance the cytotoxicity of anti-cancer drugs. Recent reports have suggested that modification of several nutrients in the diet can alter the efficacy of cancer therapies, and some of the newest developments in this quickly expanding field are reviewed here. The results discussed indicate that the dietary habits and nutritional state of a patient must be taken into account during cancer research and therapy.
    DOI:  https://doi.org/10.1038/s41586-020-2124-0
  34. J Pathol. 2020 Mar 24.
    Cisd2: A promising new target in Alzheimer's disease.
    Nobili Annalisa, Paraskevi Krashia, Marcello D'Amelio.
      The CISD2 gene encodes the CDGSH iron-sulfur domain-containing protein 2. Cisd2 is involved in mammalian life-span control, the unfolded protein response, Ca2+ buffering and autophagy regulation. It has been demonstrated previously that Cisd2 deficiency causes an accelerated ageing phenotype characterised by the accumulation of damaged mitochondria, while Cisd2 overexpression leads to mitochondrial protection against typical age-associated alterations. Accumulating data suggest that neuronal amyloid-beta (Aβ) deposition, Ca2+ dysregulation, impairment of autophagic flux and accumulation of damaged organelles including mitochondria play an important role in Alzheimer's disease (AD) pathogenesis. In a recent issue of The Journal of Pathology, Yi-Fan Chen and collaborators put together all these experimental observations and demonstrated that Cisd2 overexpression attenuates AD pathogenesis by guaranteeing mitochondrial quality and synaptic functions. The authors report convincing evidence to highlight the role of Cisd2 in Aβ-mediated mitochondrial damage and, interestingly, this neuroprotection could be dependent on other molecular mechanisms beyond the canonical and previously described roles of Cisd2. Collectively, these data open up new avenues in neuroprotection and highlight Cisd2 as a promising new target in AD. This article is protected by copyright. All rights reserved.
    Keywords:  NAF-1; amyloid; autophagy; calcium homeostasis; mitochondria; synapse degeneration
    DOI:  https://doi.org/10.1002/path.5436
  35. Exp Mol Med. 2020 Mar 16.
    The essential role of fructose-1,6-bisphosphatase 2 enzyme in thermal homeostasis upon cold stress.
    Hyun-Jun Park, Hye Rim Jang, Shi-Young Park, Young-Bum Kim, Hui-Young Lee, Cheol Soo Choi.
      Skeletal muscle is a major organ for glucose disposal and thermogenesis. While hepatic fructose-1,6-bisphosphatase is well known as a key enzyme for gluconeogenesis, the role of muscle fructose-1,6-bisphosphatase 2 (Fbp2) in glucose disposal and thermogenesis is unknown. Here, using Fbp2 knockout (KO) mice, we assessed the physiological role of Fbp2 in energy and glucose metabolism and thermogenesis. In vivo assessments of energy metabolism, glucose metabolism, and thermogenesis were performed by indirect calorimetry, hyperinsulinemic-euglycemic clamp, and cold challenge studies, respectively. Under both feeding and fasting conditions, Fbp2 KO mice showed similar phenotypes regarding energy and glucose metabolism compared to wild-type (WT) mice. However, Fbp2 KO mice were severely intolerant to cold challenge under fasting conditions. Mechanistically, the cold-induced intramuscular conversion of lactate to glycogen (glyconeogenesis) is completely abolished in the KO muscle, which leads to a lack of glycogen source for thermogenesis in Fbp2 KO mice. The cold-intolerant phenotype of KO mice disappeared after feeding, and the KO mice were equally as cold tolerant as the WT mice and survived during the cold challenge for three weeks. Taken together, these data demonstrate that Fbp2 is essential for muscle thermogenesis by replenishing the intramuscular glycogen pool through glyconeogenesis when the exogenous glucose source is limited. These data imply the physiological importance of Fbp2 in thermal homeostasis and suggest a potential novel therapy targeted to increase glycogen replenishment upon cold stress.
    DOI:  https://doi.org/10.1038/s12276-020-0402-4
  36. FASEB J. 2020 Mar 24.
    Metabolic-sensing of the skeletal muscle clock coordinates fuel oxidation.
    Hongshan Yin, Weini Li, Somik Chatterjee, Xuekai Xiong, Pradip Saha, Vijay Yechoor, Ke Ma.
      Circadian clock confers temporal control in metabolism, with its disruption leading to the development of insulin resistance. Metabolic substrate utilization in skeletal muscle is coordinated with diurnal nutrient cycles. However, whether the molecular clock is involved in this coordination is largely unknown. Using a myocyte-selective genetic ablation mouse model of the essential clock activator Bmal1, here we identify muscle-intrinsic clock as a sensor of feeding cues to orchestrate skeletal muscle oxidation required for global nutrient flux. Bmal1 in skeletal muscle responds robustly to feeding in vivo and insulin induces its expression. Muscle Bmal1 deficiency impaired the transcriptional control of glucose metabolic pathway, resulting in markedly attenuated glucose utilization and fasting hyperglycemia. Notably, the loss of Bmal1 response to feeding abolished fasting-to-feeding metabolic fuel switch from fatty acids to glucose in skeletal muscle, leading to the activation of energy-sensing pathways for fatty acid oxidation. These altered metabolic substrate oxidations in Bmal1-deficient muscle ultimately depleted circulating lipid levels that prevented hepatic steatosis. Collectively, our findings highlight the key role of the metabolic-sensing function of skeletal muscle clock in partitioning nutrient flux between muscle and liver to maintain whole-body lipid and glucose homeostasis.
    Keywords:  circadian clock; fatty acid metabolism; glucose metabolism; hepatic steatosis; skeletal muscle
    DOI:  https://doi.org/10.1096/fj.201903226RR
  37. Trends Cell Biol. 2020 Apr;pii: S0962-8924(20)30018-0. [Epub ahead of print]30(4): 263-275
    Mitochondrial Functions in Infection and Immunity.
    Varnesh Tiku, Man-Wah Tan, Ivan Dikic.
      Mitochondria have a central role in regulating a range of cellular activities and host responses upon bacterial infection. Multiple pathogens affect mitochondria dynamics and functions to influence their intracellular survival or evade host immunity. On the other side, major host responses elicited against infections are directly dependent on mitochondrial functions, thus placing mitochondria centrally in maintaining homeostasis upon infection. In this review, we summarize how different bacteria and viruses impact morphological and functional changes in host mitochondria and how this manipulation can influence microbial pathogenesis as well as the host cell metabolism and immune responses.
    Keywords:  bacteria; cell death; innate immunity; mitochondrial metabolism; mitochondrial morphology; viruses
    DOI:  https://doi.org/10.1016/j.tcb.2020.01.006
  38. Cancer Discov. 2020 Mar 21. pii: CD-19-0620. [Epub ahead of print]
    Repression of the Type I Interferon pathway underlies MYC & KRAS-dependent evasion of NK & B cells in Pancreatic Ductal Adenocarcinoma.
    Nathiya Muthalagu, Tiziana Monteverde, Ximena Raffo-Iraolagoitia, Robert Wiesheu, Declan Whyte, Ann Hedley, Sarah Laing, Bjorn Kruspig, Rosanna Upstill-Goddard, Robin Shaw, Sarah Neidler, Curtis Rink, Saadia A Karim, Katarina Gyuraszova, Colin Nixon, William Clark, Andrew V Biankin, Leo M Carlin, Seth B Coffelt, Owen J Sansom, Jennifer P Morton, Daniel J Murphy.
      MYC is implicated in the development and progression of Pancreatic cancer, yet the precise level of MYC deregulation required to contribute to tumour development has been difficult to define. We used modestly elevated expression of human MYC, driven from the Rosa26 locus, to investigate the pancreatic phenotypes arising in mice from an approximation of MYC trisomy. We show that this level of MYC alone suffices to drive pancreatic neuroendocrine tumours, and to accelerate progression of KRAS-initiated precursor lesions to metastatic pancreatic ductal adenocarcinoma. Our phenotype exposed suppression of the Type I Interferon pathway by the combined actions of MYC and KRAS and we present evidence of repressive MYC/MIZ1 complexes binding directly to the promoters of type I Interferon regulators IRF5, IRF7, STAT1 and STAT2. De-repression of Interferon regulators allows pancreatic tumour infiltration of B and NK cells, resulting in increased survival.
    DOI:  https://doi.org/10.1158/2159-8290.CD-19-0620
  39. EMBO Rep. 2020 Mar 23. e45832
    Role of respiratory NADH oxidation in the regulation of Staphylococcus aureus virulence.
    Lici A Schurig-Briccio, Paola K Parraga Solorzano, Andrea M Lencina, Jana N Radin, Grischa Y Chen, John-Demian Sauer, Thomas E Kehl-Fie, Robert B Gennis.
      The success of Staphylococcus aureus as a pathogen is due to its capability of fine-tuning its cellular physiology to meet the challenges presented by diverse environments, which allows it to colonize multiple niches within a single vertebrate host. Elucidating the roles of energy-yielding metabolic pathways could uncover attractive therapeutic strategies and targets. In this work, we seek to determine the effects of disabling NADH-dependent aerobic respiration on the physiology of S. aureus. Differing from many pathogens, S. aureus has two type-2 respiratory NADH dehydrogenases (NDH-2s) but lacks the respiratory ion-pumping NDHs. Here, we show that the NDH-2s, individually or together, are not essential either for respiration or growth. Nevertheless, their absence eliminates biofilm formation, production of α-toxin, and reduces the ability to colonize specific organs in a mouse model of systemic infection. Moreover, we demonstrate that the reason behind these phenotypes is the alteration of the fatty acid metabolism. Importantly, the SaeRS two-component system, which responds to fatty acids regulation, is responsible for the link between NADH-dependent respiration and virulence in S. aureus.
    Keywords:   Staphylococcus aureus ; NADH dehydrogenase; NADH/NAD+; respiratory chain; two-component system
    DOI:  https://doi.org/10.15252/embr.201845832
  40. Nature. 2020 Mar 18.
    Ghostly metabolic messages from dying cells.
    Douglas R Green.
      
    Keywords:  Cell biology; Medical research
    DOI:  https://doi.org/10.1038/d41586-020-00641-0
  41. J Biol Chem. 2020 Mar 26. pii: jbc.RA119.012312. [Epub ahead of print]
    Perturbation of phosphoglycerate kinase 1 (PGK1) only marginally affects glycolysis in cancer cells.
    Chengmeng Jin, Xiaobing Zhu, Hao Wu, Yuqi Wang, Xun Hu.
      Phosphoglycerate kinase 1 (PGK1) plays important roles in glycolysis, yet its forward reaction kinetics are unknown, and its role especially in regulating cancer cell glycolysis is unclear. Here, we developed an enzyme assay to measure the kinetic parameters of the PGK1-catalyzed forward reaction. The Km values for 1,3-bisphosphoglyceric acid (1,3-BPG, the forward reaction substrate) were 4.36 μM (yeast PGK1) and 6.86 μM (human PKG1). The Km values for 3-phosphoglycerate (3-PG, the reverse reaction substrate and a serine precursor) were 146 μM (yeast PGK1) and 186 μM (human PGK1). The Vmax of the forward reaction was about 3.5- and 5.8-fold higher than that of the reverse reaction for the human and yeast enzymes, respectively. Consistently, the intracellular steady-state concentrations of 3-PG were between 180 and 550 μM in cancer cells, providing a basis for glycolysis to shuttle 3-PG to the serine synthesis pathway. Using siRNA-mediated PGK1-specific knockdown in five cancer cell lines derived from different tissues, along with titration of PGK1 in a cell-free glycolysis system, we found that the perturbation of PGK1 had no or only marginal effects on the glucose consumption and lactate generation. The PGK1 knockdown increased the concentrations of fructose 1,6-bisphosphate (FBP), dihydroxyacetone phosphate (DHAP), glyceraldehyde 3-phosphate (GA3P), and 1,3-BPG in nearly equal proportions, controlled by the kinetic and thermodynamic states of glycolysis. We conclude that perturbation of PGK1 in cancer cells insignificantly affects the conversion of glucose to lactate in glycolysis.
    Keywords:  PGK1 forward reaction kinetics; Warburg effect; cancer; cellular metabolism; energy homeostasis; glycolysis; lactic acid; phosphoglycerate kinase; serine
    DOI:  https://doi.org/10.1074/jbc.RA119.012312
  42. Nat Commun. 2020 Mar 24. 11(1): 1545
    Transient non-integrative expression of nuclear reprogramming factors promotes multifaceted amelioration of aging in human cells.
    Tapash Jay Sarkar, Marco Quarta, Shravani Mukherjee, Alex Colville, Patrick Paine, Linda Doan, Christopher M Tran, Constance R Chu, Steve Horvath, Lei S Qi, Nidhi Bhutani, Thomas A Rando, Vittorio Sebastiano.
      Aging is characterized by a gradual loss of function occurring at the molecular, cellular, tissue and organismal levels. At the chromatin level, aging associates with progressive accumulation of epigenetic errors that eventually lead to aberrant gene regulation, stem cell exhaustion, senescence, and deregulated cell/tissue homeostasis. Nuclear reprogramming to pluripotency can revert both the age and the identity of any cell to that of an embryonic cell. Recent evidence shows that transient reprogramming can ameliorate age-associated hallmarks and extend lifespan in progeroid mice. However, it is unknown how this form of rejuvenation would apply to naturally aged human cells. Here we show that transient expression of nuclear reprogramming factors, mediated by expression of mRNAs, promotes a rapid and broad amelioration of cellular aging, including resetting of epigenetic clock, reduction of the inflammatory profile in chondrocytes, and restoration of youthful regenerative response to aged, human muscle stem cells, in each case without abolishing cellular identity.
    DOI:  https://doi.org/10.1038/s41467-020-15174-3
  43. Front Oncol. 2020 ;10 281
    Metabolic Plasticity in Chemotherapy Resistance.
    Maria Andrea Desbats, Isabella Giacomini, Tommaso Prayer-Galetti, Monica Montopoli.
      Resistance of cancer cells to chemotherapy is the first cause of cancer-associated death. Thus, new strategies to deal with the evasion of drug response and to improve clinical outcomes are needed. Genetic and epigenetic mechanisms associated with uncontrolled cell growth result in metabolism reprogramming. Cancer cells enhance anabolic pathways and acquire the ability to use different carbon sources besides glucose. An oxygen and nutrient-poor tumor microenvironment determines metabolic interactions among normal cells, cancer cells and the immune system giving rise to metabolically heterogeneous tumors which will partially respond to metabolic therapy. Here we go into the best-known cancer metabolic profiles and discuss several studies that reported tumors sensitization to chemotherapy by modulating metabolic pathways. Uncovering metabolic dependencies across different chemotherapy treatments could help to rationalize the use of metabolic modulators to overcome therapy resistance.
    Keywords:  TCA cycle; Warburg effect; cancer; chemoresistance; metabolic reprogramming; metabolic vulnerabilities
    DOI:  https://doi.org/10.3389/fonc.2020.00281
  44. Semin Cell Dev Biol. 2020 Mar 19. pii: S1084-9521(18)30302-1. [Epub ahead of print]
    Tracing insights into de novo lipogenesis in liver and adipose tissues.
    Martina Wallace, Christian M Metallo.
      Lipids play important roles in biology that include structural compartmentation as membranes, energy storage, and regulatory functions as signaling molecules. These molecules can be obtained via the surrounding environment (e.g. diet) or synthesized de novo. Fatty acid synthesis is an energetically demanding process and must therefore be tightly regulated to balance fatty acid availability with the functional and energetic needs of cells and tissues. Here we review key aspects of de novo lipogenesis (DNL) in mammalian systems. We highlight key nodes in the pathway that are used for quantitation of lipogenic fluxes and regulation of fatty acid diversity across tissues. Next, we discuss key aspects of DNL function in the major lipogenic tissues of mammals: liver, white adipose tissue (WAT), and brown adipose tissue (BAT), highlighting recent molecular discoveries that suggest potential roles for tissue specific DNL. Finally, we propose critical questions that will be important to address using the advanced approaches for DNL quantitation described herein.
    Keywords:  Adipose tissue; De novo lipogenesis; FASN; Fatty acids; Isotope tracing; Liver
    DOI:  https://doi.org/10.1016/j.semcdb.2020.02.012
  45. Genes Dis. 2020 Jun;7(2): 172-184
    Metabolic reprogram associated with epithelial-mesenchymal transition in tumor progression and metastasis.
    Yifan Wang, Chenfang Dong, Binhua P Zhou.
      Epithelial-mesenchymal Transition (EMT) is a de-differentiation program that imparts tumor cells with the phenotypic and cellular plasticity required for drug resistance, metastasis, and recurrence. This dynamic and reversible events is governed by a network of EMT-transcription factors (EMT-TFs) through epigenetic regulation. Many chromatin modifying-enzymes utilize metabolic intermediates as cofactors or substrates; this suggests that EMT is subjected to the metabolic regulation. Conversely, EMT rewires metabolic program to accommodate cellular changes during EMT. Here we summarize the latest findings regarding the epigenetic regulation of EMT, and discuss the mutual interactions among metabolism, epigenetic regulation, and EMT. Finally, we provide perspectives of how this interplay contributes to cellular plasticity, which may result in the clinical manifestation of tumor heterogeneity.
    Keywords:  Epigenetics; Epithelial-mesenchymal transition; Heterogeneity; Metabolism; Plasticity
    DOI:  https://doi.org/10.1016/j.gendis.2019.09.012
  46. Nat Cell Biol. 2020 Mar 23.
    YAP/TAZ phase separation for transcription.
    J Matthew Franklin, Kun-Liang Guan.
      
    DOI:  https://doi.org/10.1038/s41556-020-0498-8
  47. Biochem Soc Trans. 2020 Mar 27. pii: BST20190987. [Epub ahead of print]
    Mitochondrial hyperfusion: a friend or a foe.
    Rajdeep Das, Oishee Chakrabarti.
      The cellular mitochondrial population undergoes repeated cycles of fission and fusion to maintain its integrity, as well as overall cellular homeostasis. While equilibrium usually exists between the fission-fusion dynamics, their rates are influenced by organellar and cellular metabolic and pathogenic conditions. Under conditions of cellular stress, there is a disruption of this fission and fusion balance and mitochondria undergo either increased fusion, forming a hyperfused meshwork or excessive fission to counteract stress and remove damaged mitochondria via mitophagy. While some previous reports suggest that hyperfusion is initiated to ameliorate cellular stress, recent studies show its negative impact on cellular health in disease conditions. The exact mechanism of mitochondrial hyperfusion and its role in maintaining cellular health and homeostasis, however, remain unclear. In this review, we aim to highlight the different aspects of mitochondrial hyperfusion in either promoting or mitigating stress and also its role in immunity and diseases.
    Keywords:  ER-mitochondria cross-talk; fission–fusion dynamics; hyperfusion; mitochondria
    DOI:  https://doi.org/10.1042/BST20190987
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