bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2020‒02‒09
forty-six papers selected by
Christian Frezza
University of Cambridge, MRC Cancer Unit

  1. Mol Metab. 2020 Feb;pii: S2212-8778(19)30951-2. [Epub ahead of print]32 122-135
    Cordes T, Lucas A, Divakaruni AS, Murphy AN, Cabrales P, Metallo CM.
      OBJECTIVES: Cerebral ischemia/reperfusion (IR) drives oxidative stress and injurious metabolic processes that lead to redox imbalance, inflammation, and tissue damage. However, the key mediators of reperfusion injury remain unclear, and therefore, there is considerable interest in therapeutically targeting metabolism and the cellular response to oxidative stress.METHODS: The objective of this study was to investigate the molecular, metabolic, and physiological impact of itaconate treatment to mitigate reperfusion injuries in in vitro and in vivo model systems. We conducted metabolic flux and bioenergetic studies in response to exogenous itaconate treatment in cultures of primary rat cortical neurons and astrocytes. In addition, we administered itaconate to mouse models of cerebral reperfusion injury with ischemia or traumatic brain injury followed by hemorrhagic shock resuscitation. We quantitatively characterized the metabolite levels, neurological behavior, markers of redox stress, leukocyte adhesion, arterial blood flow, and arteriolar diameter in the brains of the treated/untreated mice.
    RESULTS: We demonstrate that the "immunometabolite" itaconate slowed tricarboxylic acid (TCA) cycle metabolism and buffered redox imbalance via succinate dehydrogenase (SDH) inhibition and induction of anti-oxidative stress response in primary cultures of astrocytes and neurons. The addition of itaconate to reperfusion fluids after mouse cerebral IR injury increased glutathione levels and reduced reactive oxygen/nitrogen species (ROS/RNS) to improve neurological function. Plasma organic acids increased post-reperfusion injury, while administration of itaconate normalized these metabolites. In mouse cranial window models, itaconate significantly improved hemodynamics while reducing leukocyte adhesion. Further, itaconate supplementation increased survival in mice experiencing traumatic brain injury (TBI) and hemorrhagic shock.
    CONCLUSIONS: We hypothesize that itaconate transiently inhibits SDH to gradually "awaken" mitochondrial function upon reperfusion that minimizes ROS and tissue damage. Collectively, our data indicate that itaconate acts as a mitochondrial regulator that controls redox metabolism to improve physiological outcomes associated with IR injury.
    Keywords:  Brain injury; Cerebral ischemia/reperfusion (IR); Itaconate; Mitochondrial metabolism; Redox stress; Succinate dehydrogenase (SDH)
  2. Nat Commun. 2020 Feb 04. 11(1): 698
    Palmieri EM, Gonzalez-Cotto M, Baseler WA, Davies LC, Ghesquière B, Maio N, Rice CM, Rouault TA, Cassel T, Higashi RM, Lane AN, Fan TW, Wink DA, McVicar DW.
      Profound metabolic changes are characteristic of macrophages during classical activation and have been implicated in this phenotype. Here we demonstrate that nitric oxide (NO) produced by murine macrophages is responsible for TCA cycle alterations and citrate accumulation associated with polarization. 13C tracing and mitochondrial respiration experiments map NO-mediated suppression of metabolism to mitochondrial aconitase (ACO2). Moreover, we find that inflammatory macrophages reroute pyruvate away from pyruvate dehydrogenase (PDH) in an NO-dependent and hypoxia-inducible factor 1α (Hif1α)-independent manner, thereby promoting glutamine-based anaplerosis. Ultimately, NO accumulation leads to suppression and loss of mitochondrial electron transport chain (ETC) complexes. Our data reveal that macrophages metabolic rewiring, in vitro and in vivo, is dependent on NO targeting specific pathways, resulting in reduced production of inflammatory mediators. Our findings require modification to current models of macrophage biology and demonstrate that reprogramming of metabolism should be considered a result rather than a mediator of inflammatory polarization.
  3. Mech Ageing Dev. 2020 Feb 01. pii: S0047-6374(20)30006-3. [Epub ahead of print] 111212
    Liu YJ, McIntyre RL, Janssens GE, Houtkooper RH.
      The mitochondria is the major hub to convert energy for cellular processes. Dysregulation of mitochondrial function is one of the classical hallmarks of aging, and mitochondrial interventions have repeatedly been shown to improve outcomes in age-related diseases. Crucial to mitochondrial regulation is the dynamic nature of their network structure. Mitochondria separate and merge using fission and fusion processes in response to changes in energy and stress status. While many mitochondrial processes are already characterized in relation to aging, specific evidence in multicellular organisms causally linking mitochondrial dynamics to the regulation of lifespan is limited. There does exist, however, a large body of evidence connecting mitochondrial dynamics to other aging-related cellular processes and implicates them in a number of human diseases. Here, we discuss the mechanisms of mitochondrial fission and fusion, the current evidence of their role in aging of multicellular organisms, and how these connect to cell cycle regulation, quality control, and transmission of energy status. Finally, we discuss the current evidence implicating these processes in age-related human pathologies, such as neurodegenerative or cardio-metabolic diseases. We suggest that deeper understanding of the regulatory mechanisms within this system and downstream implications could benefit in understanding and intervention of these conditions.
    Keywords:  Mitochondrial dynamics; age-related disease; ageing; fission; fusion
  4. JCI Insight. 2020 Feb 04. pii: 134063. [Epub ahead of print]
    Liu JC, Syder NC, Ghorashi NS, Willingham TB, Parks RJ, Sun J, Fergusson MM, Liu J, Holmström KM, Menazza S, Springer DA, Liu C, Glancy B, Finkel T, Murphy E.
      The mitochondrial calcium uniporter is widely accepted as the primary route of rapid calcium entry into mitochondria, where increases in matrix calcium contribute to bioenergetics but also mitochondrial permeability and cell death. Hence, regulation of uniporter activity is critical to mitochondrial homeostasis. The uniporter subunit EMRE is known to be an essential regulator of the channel-forming protein MCU in cell culture, but EMRE's impact on organismal physiology is less understood. Here we characterize a novel mouse model of EMRE deletion and show that EMRE is indeed required for mitochondrial calcium uniporter function in vivo. EMRE-/- mice are born less frequently; however, the mice which are born are viable, healthy, and do not manifest overt metabolic impairment, at rest or with exercise. Finally, to investigate the role of EMRE in disease processes, we examine the effects of EMRE deletion in a muscular dystrophy model associated with mitochondrial calcium overload.
    Keywords:  Bioenergetics; Calcium; Cardiology; Mitochondria; Muscle Biology
  5. Cell Rep. 2020 Feb 04. pii: S2211-1247(20)30020-6. [Epub ahead of print]30(5): 1542-1552.e7
    Wilson JL, Nägele T, Linke M, Demel F, Fritsch SD, Mayr HK, Cai Z, Katholnig K, Sun X, Fragner L, Miller A, Haschemi A, Popa A, Bergthaler A, Hengstschläger M, Weichhart T, Weckwerth W.
      Mechanistic or mammalian target of rapamycin complex 1 (mTORC1) is an important regulator of effector functions, proliferation, and cellular metabolism in macrophages. The biochemical processes that are controlled by mTORC1 are still being defined. Here, we demonstrate that integrative multiomics in conjunction with a data-driven inverse modeling approach, termed COVRECON, identifies a biochemical node that influences overall metabolic profiles and reactions of mTORC1-dependent macrophage metabolism. Using a combined approach of metabolomics, proteomics, mRNA expression analysis, and enzymatic activity measurements, we demonstrate that Tsc2, a negative regulator of mTORC1 signaling, critically influences the cellular activity of macrophages by regulating the enzyme phosphoglycerate dehydrogenase (Phgdh) in an mTORC1-dependent manner. More generally, while lipopolysaccharide (LPS)-stimulated macrophages repress Phgdh activity, IL-4-stimulated macrophages increase the activity of the enzyme required for the expression of key anti-inflammatory molecules and macrophage proliferation. Thus, we identify Phgdh as a metabolic checkpoint of M2 macrophages.
    Keywords:  Phgdh; Tsc2; biochemical Jacobian; cancer; mTOR; macrophage polarization; macrophage proliferation; metabolic modeling; metabolomics; serine/glycine pathway; tumor-associated macrophages
  6. Nat Cell Biol. 2020 Feb;22(2): 167-174
    Li JT, Yin M, Wang D, Wang J, Lei MZ, Zhang Y, Liu Y, Zhang L, Zou SW, Hu LP, Zhang ZG, Wang YP, Wen WY, Lu HJ, Chen ZJ, Su D, Lei QY.
      Branched-chain amino acid (BCAA) metabolism is potentially linked with development of pancreatic ductal adenocarcinoma (PDAC)1-4. BCAA transaminase 2 (BCAT2) was essential for the collateral lethality conferred by deletion of malic enzymes in PDAC and the BCAA-BCAT metabolic pathway contributed to non-small-cell lung carcinomas (NSCLCs) other than PDAC3,4. However, the underlying mechanism remains undefined. Here we reveal that BCAT2 is elevated in mouse models and in human PDAC. Furthermore, pancreatic tissue-specific knockout of Bcat2 impedes progression of pancreatic intraepithelial neoplasia (PanIN) in LSL-KrasG12D/+; Pdx1-Cre (KC) mice. Functionally, BCAT2 enhances BCAA uptake to sustain BCAA catabolism and mitochondrial respiration. Notably, BCAA enhances growth of pancreatic ductal organoids from KC mice in a dose-dependent manner, whereas addition of branched-chain α-keto acid (BCKA) and nucleobases rescues growth of KC organoids that is suppressed by BCAT2 inhibitor. Moreover, KRAS stabilizes BCAT2, which is mediated by spleen tyrosine kinase (SYK) and E3 ligase tripartite-motif-containing protein 21 (TRIM21). In addition, BCAT2 inhibitor ameliorates PanIN formation in KC mice. Of note, a lower-BCAA diet also impedes PDAC development in mouse models of PDAC. Thus, BCAT2-mediated BCAA catabolism is critical for development of PDAC harbouring KRAS mutations. Targeting BCAT2 or lowering dietary BCAA may have translational significance.
  7. Curr Med Chem. 2020 Feb 06.
    Stepka P, Vsiansky V, Raudenska M, Gumulec J, Adam V, Masarik M.
      Metabolic changes driven by the hostile tumor microenvironment surrounding cancer cells and effect of these changes on tumorigenesis and metastatic potential have been known for a long time. The usual point of interest is glucose and changes in its utilization by cancer cells, mainly in the form of the Warburg effect. However, amino acids, both intra- and extracellular, also represent an important aspect of tumour microenvironment, which can have a significant effect on cancer cell metabolism and overall development of the tumor. Namely alterations in metabolism of amino acids glutamine, sarcosine, aspartate, methionine and cysteine have been previously connected to the tumor progression and aggressivity of prostate cancer. The aim of this review is to pinpoint current gaps in our knowledge of the role of amino acids as a part of the tumor microenvironment and to show effect of various amino acids on cancer cell metabolism and metastatic potential. This review shows limitations and exceptions from the traditionally accepted model of Warburg effect in some cancer tissues, with the emphasis on prostate cancer, because the traditional definition of Warburg effect as a metabolic switch to aerobic glycolysis does not always apply. Prostatic tissue both in healthy and transformed state significantly differs in many metabolic aspects, including the metabolisms of glucose and amino acids, from metabolism of other tissues. Findings from different tissues are therefore not always interchangeable and have to be taken into account during experimentation modifying the environment of tumor tissue by amino acid supplementation or depletion, which could potentially serve as a new therapeutic approach.
    Keywords:  Cancer metabolism ; aspartate; glutamine ; metastasis; methionine; sarcosine
  8. Nat Cell Biol. 2020 Feb;22(2): 225-234
    Lee H, Zandkarimi F, Zhang Y, Meena JK, Kim J, Zhuang L, Tyagi S, Ma L, Westbrook TF, Steinberg GR, Nakada D, Stockwell BR, Gan B.
      Energy stress depletes ATP and induces cell death. Here we identify an unexpected inhibitory role of energy stress on ferroptosis, a form of regulated cell death induced by iron-dependent lipid peroxidation. We found that ferroptotic cell death and lipid peroxidation can be inhibited by treatments that induce or mimic energy stress. Inactivation of AMP-activated protein kinase (AMPK), a sensor of cellular energy status, largely abolishes the protective effects of energy stress on ferroptosis in vitro and on ferroptosis-associated renal ischaemia-reperfusion injury in vivo. Cancer cells with high basal AMPK activation are resistant to ferroptosis and AMPK inactivation sensitizes these cells to ferroptosis. Functional and lipidomic analyses further link AMPK regulation of ferroptosis to AMPK-mediated phosphorylation of acetyl-CoA carboxylase and polyunsaturated fatty acid biosynthesis. Our study demonstrates that energy stress inhibits ferroptosis partly through AMPK and reveals an unexpected coupling between ferroptosis and AMPK-mediated energy-stress signalling.
  9. J Biol Chem. 2020 Feb 04. pii: jbc.AC119.011578. [Epub ahead of print]
    Meng D, Yang Q, Wang H, Melick CH, Navlani R, Frank AR, Jewell JL.
      Nutrient sensing by cells is crucial, and when this sensing mechanism is disturbed human disease can occur. mTOR complex 1 (mTORC1) senses amino acids to control cell growth, metabolism and autophagy. Leucine, arginine, and methionine signal to mTORC1 through the well-characterized Rag GTPase signaling pathway. In contrast, glutamine activates mTORC1 through a Rag GTPase-independent mechanism that requires ADP-ribosylation factor 1 (Arf1). Here, using several biochemical and genetic approaches, we show that eight amino acids filter through the Rag GTPase pathway. Like glutamine, asparagine signals to mTORC1 through Arf1 in the absence of the Rag GTPases. Both the Rag-dependent and Rag-independent pathways required the lysosome and lysosomal function for mTORC1 activation. Our results show that mTORC1 is differentially regulated by amino acids through two distinct pathways.
    Keywords:  Arf1; Rag GTPase; amino acid; asparagine; glutamine; mTOR complex (mTORC); mTORC1; metabolism; signal transduction
  10. Pancreas. 2020 Jan 31.
    Kyuno T, Kohno T, Konno T, Yamaguchi H, Kyuno D, Imamura M, Kimura Y, Kojima T, Takemasa I.
      OBJECTIVES: Transcription factor Forkhead box protein M1 (FOXM1) plays critical roles in the progression of cancer including epithelial-to-mesenchymal transition (EMT). The aim of this study is to characterize the regulatory mechanisms of FOXM1 in EMT via pancreatic cancer metabolism.METHODS: We investigated the regulation of EMT via mitochondrial respiration by FOXM1 using pancreatic cancer cell lines HPAC and PANC-1 and normal human pancreatic duct epithelial cells.
    RESULTS: Forkhead box protein M1 and Snail were strongly expressed in HPAC and PANC-1. Epithelial-to-mesenchymal transition-modulated claudin-1 level was lower in PANC-1 than in HPAC. In both cell lines in low-glucose medium, FOXM1 and Snail were decreased and claudin-1 was increased. Knockdown of FOXM1 increased claudin-1 and decreased Snail in both cell lines. Low-glucose medium and downregulation of FOXM1 inhibited the cell migration in both cell lines. In both cell lines, mitochondrial respiration was at higher levels in low-glucose medium than in high-glucose medium. Downregulation of FOXM1 induced mitochondrial respiration in high-glucose medium. In normal human pancreatic duct epithelial cells, FOXM1 and Snail were low and claudin-1 was highly expressed, whereas overexpression of FOXM1 decreased claudin-1.
    CONCLUSIONS: Glucose-dependent FOXM1 promoted EMT via Snail and pancreatic cancer metabolism.
  11. Cancer Lett. 2020 Feb 04. pii: S0304-3835(20)30050-1. [Epub ahead of print]
    Li AM, Ye J.
      Upregulation of serine biosynthesis pathway activity is an increasingly apparent feature of many cancers. Most notably, the first rate-limiting enzyme of the pathway, phosphoglycerate dehydrogenase (PHGDH), is genomically amplified in some melanomas and breast cancers and can be transcriptionally regulated by various tumor suppressors and oncogenes. Yet emerging evidence suggests that serine-in particular, serine biosynthetic pathway activity-may promote cancer in ways beyond providing the building blocks to support cell proliferation. Here, we summarize how mammalian cells tightly control serine synthesis before discussing alternate ways in which increased serine synthetic flux through PHGDH may benefit cancer cells, such as maintenance of TCA cycle flux through alpha-ketoglutarate (αKG) and modulation of cellular redox balance. We will also provide an overview of the current landscape of therapeutics targeting serine synthesis and offer a perspective on future strategies.
    Keywords:  PHGDH; PSAT1; PSPH; cancer metabolism; one carbon unit; serine
  12. Cells. 2020 Feb 01. pii: E338. [Epub ahead of print]9(2):
    Wang Y, Cai J, Tang C, Dong Z.
      Acute kidney injury (AKI) is a major kidney disease characterized by rapid decline of renal function. Besides its acute consequence of high mortality, AKI has recently been recognized as an independent risk factor for chronic kidney disease (CKD). Maladaptive or incomplete repair of renal tubules after severe or episodic AKI leads to renal fibrosis and, eventually, CKD. Recent studies highlight a key role of mitochondrial pathology in AKI development and abnormal kidney repair after AKI. As such, timely elimination of damaged mitochondria in renal tubular cells represents an important quality control mechanism for cell homeostasis and survival during kidney injury and repair. Mitophagy is a selective form of autophagy that selectively removes redundant or damaged mitochondria. Here, we summarize our recent understanding on the molecular mechanisms of mitophagy, discuss the role of mitophagy in AKI development and kidney repair after AKI, and present future research directions and therapeutic potential.
    Keywords:  acute kidney injury; kidney repair; mitochondria; mitophagy
  13. Cell Metab. 2020 Feb 04. pii: S1550-4131(20)30006-1. [Epub ahead of print]31(2): 250-266.e9
    Roy DG, Chen J, Mamane V, Ma EH, Muhire BM, Sheldon RD, Shorstova T, Koning R, Johnson RM, Esaulova E, Williams KS, Hayes S, Steadman M, Samborska B, Swain A, Daigneault A, Chubukov V, Roddy TP, Foulkes W, Pospisilik JA, Bourgeois-Daigneault MC, Artyomov MN, Witcher M, Krawczyk CM, Larochelle C, Jones RG.
      Epigenetic modifications on DNA and histones regulate gene expression by modulating chromatin accessibility to transcription machinery. Here we identify methionine as a key nutrient affecting epigenetic reprogramming in CD4+ T helper (Th) cells. Using metabolomics, we showed that methionine is rapidly taken up by activated T cells and serves as the major substrate for biosynthesis of the universal methyl donor S-adenosyl-L-methionine (SAM). Methionine was required to maintain intracellular SAM pools in T cells. Methionine restriction reduced histone H3K4 methylation (H3K4me3) at the promoter regions of key genes involved in Th17 cell proliferation and cytokine production. Applied to the mouse model of multiple sclerosis (experimental autoimmune encephalomyelitis), dietary methionine restriction reduced the expansion of pathogenic Th17 cells in vivo, leading to reduced T cell-mediated neuroinflammation and disease onset. Our data identify methionine as a key nutritional factor shaping Th cell proliferation and function in part through regulation of histone methylation.
    Keywords:  EAE; SAM; T cells; Th17 cells; histone methylation; inflammation; metabolism; methionine
  14. J Intern Med. 2020 Feb 03.
    Colina-Tenorio L, Horten P, Pfanner N, Rampelt H.
      Mitochondria play central roles in cellular energetics, metabolism and signaling. Efficient respiration, mitochondrial quality control, apoptosis, and inheritance of mitochondrial DNA depend on the proper architecture of the mitochondrial membranes and a dynamic remodeling of inner membrane cristae. Defects in mitochondrial architecture can result in severe human diseases affecting predominantly the nervous system and the heart. Inner membrane morphology is generated and maintained in particular by the mitochondrial contact site and cristae organizing system (MICOS), the F1 Fo -ATP synthase, the fusion protein OPA1/Mgm1, and the non-bilayer-forming phospholipids cardiolipin and phosphatidylethanolamine. These protein complexes and phospholipids are embedded in a network of functional interactions. They communicate with each other and additional factors, enabling them to balance different aspects of cristae biogenesis and to dynamically remodel the inner mitochondrial membrane. Genetic alterations disturbing these membrane shaping factors can lead to human pathologies including fatal encephalopathy, dominant optic atrophy, Leigh syndrome, Parkinson's disease, and Barth syndrome.
    Keywords:  MICOS; cristae membranes; human disease; mitochondria; mitochondriopathies; oxidative phosphorylation
  15. Cell Death Dis. 2020 Feb 07. 11(2): 110
    Hubackova S, Davidova E, Boukalova S, Kovarova J, Bajzikova M, Coelho A, Terp MG, Ditzel HJ, Rohlena J, Neuzil J.
      p53-mutated tumors often exhibit increased resistance to standard chemotherapy and enhanced metastatic potential. Here we demonstrate that inhibition of dihydroorotate dehydrogenase (DHODH), a key enzyme of the de novo pyrimidine synthesis pathway, effectively decreases proliferation of cancer cells via induction of replication and ribosomal stress in a p53- and checkpoint kinase 1 (Chk1)-dependent manner. Mechanistically, a block in replication and ribosomal biogenesis result in p53 activation paralleled by accumulation of replication forks that activate the ataxia telangiectasia and Rad3-related kinase/Chk1 pathway, both of which lead to cell cycle arrest. Since in the absence of functional p53 the cell cycle arrest fully depends on Chk1, combined DHODH/Chk1 inhibition in p53-dysfunctional cancer cells induces aberrant cell cycle re-entry and erroneous mitosis, resulting in massive cell death. Combined DHODH/Chk1 inhibition effectively suppresses p53-mutated tumors and their metastasis, and therefore presents a promising therapeutic strategy for p53-mutated cancers.
  16. mBio. 2020 Feb 04. pii: e03171-19. [Epub ahead of print]11(1):
    Carvalho F, Spier A, Chaze T, Matondo M, Cossart P, Stavru F.
      Mitochondrial function adapts to cellular demands and is affected by the ability of the organelle to undergo fusion and fission in response to physiological and nonphysiological cues. We previously showed that infection with the human bacterial pathogen Listeria monocytogenes elicits transient mitochondrial fission and a drop in mitochondrion-dependent energy production through a mechanism requiring the bacterial pore-forming toxin listeriolysin O (LLO). Here, we performed quantitative mitochondrial proteomics to search for host factors involved in L. monocytogenes-induced mitochondrial fission. We found that Mic10, a critical component of the mitochondrial contact site and cristae organizing system (MICOS) complex, is significantly enriched in mitochondria isolated from cells infected with wild-type but not with LLO-deficient L. monocytogenes Increased mitochondrial Mic10 levels did not correlate with upregulated transcription, suggesting a posttranscriptional mechanism. We then showed that Mic10 is necessary for L. monocytogenes-induced mitochondrial network fragmentation and that it contributes to L. monocytogenes cellular infection independently of MICOS proteins Mic13, Mic26, and Mic27. In conclusion, investigation of L. monocytogenes infection allowed us to uncover a role for Mic10 in mitochondrial fission.IMPORTANCE Pathogenic bacteria can target host cell organelles to take control of key cellular processes and promote their intracellular survival, growth, and persistence. Mitochondria are essential, highly dynamic organelles with pivotal roles in a wide variety of cell functions. Mitochondrial dynamics and function are intimately linked. Our previous research showed that Listeria monocytogenes infection impairs mitochondrial function and triggers fission of the mitochondrial network at an early infection stage, in a process that is independent of the presence of the main mitochondrial fission protein Drp1. Here, we analyzed how mitochondrial proteins change in response to L. monocytogenes infection and found that infection raises the levels of Mic10, a mitochondrial inner membrane protein involved in formation of cristae. We show that Mic10 is important for L. monocytogenes-dependent mitochondrial fission and infection of host cells. Our findings thus offer new insight into the mechanisms used by L. monocytogenes to hijack mitochondria to optimize host infection.
    Keywords:  Listeria monocytogenes ; MICOS complex; Mic10; mitochondrial fission; proteomics
  17. Cell Metab. 2020 Feb 04. pii: S1550-4131(20)30007-3. [Epub ahead of print]31(2): 211-212
    Tang S, Li X, Locasale JW.
      Dietary methionine and its subsequent metabolism have profound effects on metabolic disease, cancer, and healthspan. In this issue of Cell Metabolism, Roy et al. (2020) report methionine as a nutritional factor for activated T cells that maintains H3K4 methylation and mediates functions that affect autoimmune disease.
  18. Cell Metab. 2020 Feb 04. pii: S1550-4131(20)30005-X. [Epub ahead of print]31(2): 217-218
    Zhang CS, Hardie DG, Lin SC.
      Deficiency of glucose, even under sufficient amino acid supply, turns off translation and promotes catabolic processes to aid cell survival. A recent report by Yoon et al. (2020) shows that glucose is required for the full activity of the leucyl-tRNA synthetase LARS1 and maintains mTORC1 function via LARS1 to enhance translation. Glucose starvation abolishes both effects via phosphorylation of LARS1 by the AMPK-ULK1 signaling pathway. This study supports the idea that glucose starvation inhibits translation at multiple levels.
  19. Biochem Biophys Res Commun. 2020 Feb 03. pii: S0006-291X(20)30220-5. [Epub ahead of print]
    Fujimura R, Yamamoto T, Takabatake Y, Takahashi A, Namba-Hamano T, Minami S, Sakai S, Matsuda J, Hesaka A, Yonishi H, Nakamura J, Matsui I, Matsusaka T, Niimura F, Yanagita M, Isaka Y.
      Hyperphosphatemia is a common complication in patients with advanced chronic kidney disease (CKD) as well as an increased risk of cardiovascular mortality; however, the molecular mechanisms of phosphate-mediated kidney injury are largely unknown. Autophagy is a lysosomal degradation system, which plays protective roles against kidney diseases. Here, we studied the role of autophagy in kidney proximal tubular cells (PTECs) during phosphate overload. Temporal cessation of autophagy in drug-induced PTEC-specific autophagy-deficient mice that were fed high phosphate diet induced mild cytosolic swelling and an accumulation of SQSTM1/p62-and ubiquitin-positive protein aggregates in PTECs, indicating that phosphate overload requires enhanced autophagic activity for the degradation of increasing substrate. Morphological and biochemical analysis demonstrated that high phosphate activates mitophagy in PTECs in response to oxidative stress. PTEC-specific autophagy-deficient mice receiving heminephrectomy and autophagy-deficient cultured PTECs exhibited mitochondrial dysfunction, increased reactive oxygen species production, and reduced ATP production in response to phosphate overload, suggesting that high phosphate-induced autophagy counteracts mitochondrial injury and maintains cellular bioenergetics in PTECs. Thus, potentiating autophagic activity could be a therapeutic option for suppressing CKD progression during phosphate overload.
    Keywords:  Autophagic flux; Autophagy; Mitochondria; Mitophagy; Phosphate
  20. Nat Genet. 2020 Feb 05.
    Yuan Y, Ju YS, Kim Y, Li J, Wang Y, Yoon CJ, Yang Y, Martincorena I, Creighton CJ, Weinstein JN, Xu Y, Han L, Kim HL, Nakagawa H, Park K, Campbell PJ, Liang H, .
      Mitochondria are essential cellular organelles that play critical roles in cancer. Here, as part of the International Cancer Genome Consortium/The Cancer Genome Atlas Pan-Cancer Analysis of Whole Genomes Consortium, which aggregated whole-genome sequencing data from 2,658 cancers across 38 tumor types, we performed a multidimensional, integrated characterization of mitochondrial genomes and related RNA sequencing data. Our analysis presents the most definitive mutational landscape of mitochondrial genomes and identifies several hypermutated cases. Truncating mutations are markedly enriched in kidney, colorectal and thyroid cancers, suggesting oncogenic effects with the activation of signaling pathways. We find frequent somatic nuclear transfers of mitochondrial DNA, some of which disrupt therapeutic target genes. Mitochondrial copy number varies greatly within and across cancers and correlates with clinical variables. Co-expression analysis highlights the function of mitochondrial genes in oxidative phosphorylation, DNA repair and the cell cycle, and shows their connections with clinically actionable genes. Our study lays a foundation for translating mitochondrial biology into clinical applications.
  21. Int J Biochem Cell Biol. 2020 Feb 02. pii: S1357-2725(20)30021-2. [Epub ahead of print] 105704
    Kalpage HA, Wan J, Morse PT, Zurek MP, Turner AA, Khobeir A, Yazdi N, Hakim L, Liu J, Vaishnav A, Sanderson TH, Recanati MA, Grossman LI, Lee I, Edwards BFP, Hüttemann M.
      Cytochrome c (Cytc)1is a cellular life and death decision molecule that regulates cellular energy supply and apoptosis through tissue specific post-translational modifications. Cytc is an electron carrier in the mitochondrial electron transport chain (ETC) and thus central for aerobic energy production. Under conditions of cellular stress, Cytc release from the mitochondria is a committing step for apoptosis, leading to apoptosome formation, caspase activation, and cell death. Recently, Cytc was shown to be a target of cellular signaling pathways that regulate the functions of Cytc by tissue-specific phosphorylations. So far five phosphorylations sites of Cytc have been mapped and functionally characterized, Tyr97, Tyr48, Thr28, Ser47, and Thr58. All five phosphorylations partially inhibit respiration, which we propose results in optimal intermediate mitochondrial membrane potentials and low ROS production under normal conditions. Four of the phosphorylations result in inhibition of the apoptotic functions of Cytc, suggesting a cytoprotective role for phosphorylated Cytc. Interestingly, these phosphorylations are lost during stress conditions such as ischemia. This results in maximal ETC flux during reperfusion, mitochondrial membrane potential hyperpolarization, excessive ROS generation, and apoptosis. We here present a new model proposing that the electron transfer from Cytc to cytochrome c oxidase is the rate-limiting step of the ETC, which is regulated via post-translational modifications of Cytc. This regulation may be dysfunctional in disease conditions such as ischemia-reperfusion injury and neurodegenerative disorders through increased ROS, or cancer where post-translational modifications on Cytc may provide a mechanism to evade apoptosis.
    Keywords:  Cytochrome c; apoptosis; cell signaling; phosphorylation; reactive oxygen species; respiration
  22. Antioxid Redox Signal. 2020 Feb 01.
    Erlich J, To E, Liong S, Brooks RD, Vlahos R, O'Leary JJ, Brooks DA, Selemidis S.
      SIGNIFICANCE: Up until recently, metabolism has scarcely been referenced in terms of immunology. However, emerging evidence has shown that immune cells undergo an adaptation of metabolic processes, known as the metabolic switch. This switch is key to the activation, and sustained inflammatory phenotype in immune cells, which includes the production of cytokines and reactive oxygen species (ROS) that underpin infectious diseases, respiratory and cardiovascular disease, neurodegenerative disease as well as cancer. Recent Advances: There is a burgeoning body of evidence that immunometabolism and redox biology drive infectious diseases. For example, influenza A virus (IAV) utilise endogenous ROS production via NOX2-containing NADPH oxidases and mitochondria to circumvent antiviral responses. These evolutionary conserved processes are promoted by glycolysis, the pentose phosphate pathway and the tricarboxylic acid cycle that drive inflammation. Such metabolic products involve succinate, which stimulates inflammation through ROS-dependent stabilisation of HIF-1α, promoting IL-1β production by the inflammasome. In addition, itaconate has recently gained significant attention for its role as an anti-inflammatory and antioxidant metabolite of the TCA cycle. Critical Issues and Future directions: The molecular mechanisms by which immunometabolism and ROS promote viral and bacterial pathology are largely unknown. This review will provide an overview of the current paradigms with an emphasis on the roles of immunometabolism and ROS in the context of IAV infection and secondary complications due to bacterial infection such as streptococcus pneumoniae. Molecular targets based on metabolic cell processes and ROS generation may provide novel and effective therapeutic strategies for IAV and associated bacterial superinfections.
  23. Cell Rep. 2020 Feb 04. pii: S2211-1247(20)30022-X. [Epub ahead of print]30(5): 1417-1433.e7
    Dubreuil MM, Morgens DW, Okumoto K, Honsho M, Contrepois K, Lee-McMullen B, Traber GM, Sood RS, Dixon SJ, Snyder MP, Fujiki Y, Bassik MC.
      Reactive oxygen species (ROS) play critical roles in metabolism and disease, yet a comprehensive analysis of the cellular response to oxidative stress is lacking. To systematically identify regulators of oxidative stress, we conducted genome-wide Cas9/CRISPR and shRNA screens. This revealed a detailed picture of diverse pathways that control oxidative stress response, ranging from the TCA cycle and DNA repair machineries to iron transport, trafficking, and metabolism. Paradoxically, disrupting the pentose phosphate pathway (PPP) at the level of phosphogluconate dehydrogenase (PGD) protects cells against ROS. This dramatically alters metabolites in the PPP, consistent with rewiring of upper glycolysis to promote antioxidant production. In addition, disruption of peroxisomal import unexpectedly increases resistance to oxidative stress by altering the localization of catalase. Together, these studies provide insights into the roles of peroxisomal matrix import and the PPP in redox biology and represent a rich resource for understanding the cellular response to oxidative stress.
    Keywords:  CRISPR; catalase; genome-wide screen; oxidative stress; pentose phosphate pathway; peroxisomal import pathway; phosphogluconate dehydrogenase; reactive oxygen species; shRNA
  24. Oncogene. 2020 Feb 07.
    Yang R, Li X, Wu Y, Zhang G, Liu X, Li Y, Bao Y, Yang W, Cui H.
      Cancer metabolism research has recently been revived and its focus expanded from glucose and the Warburg's effects on other nutrients, such as glutamine. The underlying mechanism of oncogenic alterations of glutaminolysis remains unclear. Genetic alterations of EGFR are observed in ~50% of glioblastoma (GBM) patients, and have been found to play important roles in the metabolic abnormalities of GBM. In this study, we found that glutamine metabolism was upregulated after EGFR activation in a GDH1 (glutamate dehydrogenase 1)-dependent manner. Knockdown of GDH1 significantly reduced the cell proliferation, colony formation and tumorigenesis abilities of glioblastoma cells. Furthermore, we showed that GDH1-mediated glutaminolysis was involved in EGF-promoted cell proliferation. EGFR triggered the phosphorylation of ELK1 at Ser 383 through activating MEK/ERK signaling. Phosphorylated ELK1 enriched in the promoter of GDH1 to activate the transcription of GDH1, which then promoted glutamine metabolism. In addition, EGFR activation did not accelerate glutaminolysis in ELK1 knockdown or ELK1 Ser383-mutated cells. Collectively, our findings indicate that EGFR phosphorylates ELK1 to activate GDH1 transcription and glutaminolysis through MEK/ERK pathway, providing new insight into oncogenic alterations of glutamine metabolism.
  25. Cell Chem Biol. 2020 Jan 28. pii: S2451-9456(20)30034-9. [Epub ahead of print]
    Yao S, Nguyen TV, Rolfe A, Agrawal AA, Ke J, Peng S, Colombo F, Yu S, Bouchard P, Wu J, Huang KC, Bao X, Omoto K, Selvaraj A, Yu L, Ioannidis S, Vaillancourt FH, Zhu P, Larsen NA, Bolduc DM.
      Carbamoyl phosphate synthetase 1 (CPS1) catalyzes the first step in the ammonia-detoxifying urea cycle, converting ammonia to carbamoyl phosphate under physiologic conditions. In cancer, CPS1 overexpression supports pyrimidine synthesis to promote tumor growth in some cancer types, while in others CPS1 activity prevents the buildup of toxic levels of intratumoral ammonia to allow for sustained tumor growth. Targeted CPS1 inhibitors may, therefore, provide a therapeutic benefit for cancer patients with tumors overexpressing CPS1. Herein, we describe the discovery of small-molecule CPS1 inhibitors that bind to a previously unknown allosteric pocket to block ATP hydrolysis in the first step of carbamoyl phosphate synthesis. CPS1 inhibitors are active in cellular assays, blocking both urea synthesis and CPS1 support of the pyrimidine biosynthetic pathway, while having no activity against CPS2. These newly discovered CPS1 inhibitors are a first step toward providing researchers with valuable tools for probing CPS1 cancer biology.
    Keywords:  CPS1; carbamoyl phosphate synthetase 1; chemical probe; high-throughput screen; inhibitor; pyrimidine synthesis; urea cycle
  26. Front Cardiovasc Med. 2019 ;6 193
    Arrieta A, Blackwood EA, Stauffer WT, Glembotski CC.
      The integrity of the proteome in cardiac myocytes is critical for robust heart function. Proteome integrity in all cells is managed by protein homeostasis or proteostasis, which encompasses processes that maintain the balance of protein synthesis, folding, and degradation in ways that allow cells to adapt to conditions that present a potential challenge to viability (1). While there are processes in various cellular locations in cardiac myocytes that contribute to proteostasis, those in the cytosol, mitochondria and endoplasmic reticulum (ER) have dominant roles in maintaining cardiac contractile function. Cytosolic proteostasis has been reviewed elsewhere (2, 3); accordingly, this review focuses on proteostasis in the ER and mitochondria, and how they might influence each other and, thus, impact heart function in the settings of cardiac physiology and disease.
    Keywords:  UPR; endoplasmic reticulum; mitochondria; protein folding; proteostasis
  27. Cell Metab. 2020 Jan 31. pii: S1550-4131(20)30009-7. [Epub ahead of print]
    He M, Chiang HH, Luo H, Zheng Z, Qiao Q, Wang L, Tan M, Ohkubo R, Mu WC, Zhao S, Wu H, Chen D.
      It is well documented that the rate of aging can be slowed, but it remains unclear to which extent aging-associated conditions can be reversed. How the interface of immunity and metabolism impinges upon the diabetes pandemic is largely unknown. Here, we show that NLRP3, a pattern recognition receptor, is modified by acetylation in macrophages and is deacetylated by SIRT2, an NAD+-dependent deacetylase and a metabolic sensor. We have developed a cell-based system that models aging-associated inflammation, a defined co-culture system that simulates the effects of inflammatory milieu on insulin resistance in metabolic tissues during aging, and aging mouse models; and demonstrate that SIRT2 and NLRP3 deacetylation prevent, and can be targeted to reverse, aging-associated inflammation and insulin resistance. These results establish the dysregulation of the acetylation switch of the NLRP3 inflammasome as an origin of aging-associated chronic inflammation and highlight the reversibility of aging-associated chronic inflammation and insulin resistance.
    Keywords:  NLRP3; SIRT1; SIRT2; SIRT3; SIRT4; SIRT5; SIRT6; SIRT7; caspase 1; inflammasome
  28. Nat Rev Immunol. 2020 Feb 05.
    Garner H, de Visser KE.
      Metastatic disease is responsible for approximately 90% of cancer deaths. For successful dissemination and metastasis, cancer cells must evade detection and destruction by the immune system. This process is enabled by factors secreted by the primary tumour that shape both the intratumoural microenvironment and the systemic immune landscape. Here, we review the evidence of aberrant immune cell crosstalk in metastasis formation and the role that primary tumours play in hijacking these interactions in order to enhance their metastatic potential. Moreover, we highlight the intriguing parallels between the inflammatory pathways underlying inflammatory disorders and cancer progression.
  29. Nature. 2020 Feb 05.
    Fujioka Y, Alam JM, Noshiro D, Mouri K, Ando T, Okada Y, May AI, Knorr RL, Suzuki K, Ohsumi Y, Noda NN.
      Many biomolecules undergo liquid-liquid phase separation to form liquid-like condensates that mediate diverse cellular functions1,2. Autophagy is able to degrade such condensates using autophagosomes-double-membrane structures that are synthesized de novo at the pre-autophagosomal structure (PAS) in yeast3-5. Whereas Atg proteins that associate with the PAS have been characterized, the physicochemical and functional properties of the PAS remain unclear owing to its small size and fragility. Here we show that the PAS is in fact a liquid-like condensate of Atg proteins. The autophagy-initiating Atg1 complex undergoes phase separation to form liquid droplets in vitro, and point mutations or phosphorylation that inhibit phase separation impair PAS formation in vivo. In vitro experiments show that Atg1-complex droplets can be tethered to membranes via specific protein-protein interactions, explaining the vacuolar membrane localization of the PAS in vivo. We propose that phase separation has a critical, active role in autophagy, whereby it organizes the autophagy machinery at the PAS.
  30. Front Oncol. 2019 ;9 1514
    Heske CM.
      Tumor cells have increased requirements for NAD+. Thus, many cancers exhibit an increased reliance on NAD+ production pathways. This dependence may be exploited therapeutically through pharmacological targeting of NAMPT, the rate-limiting enzyme in the NAD+ salvage pathway. Despite promising preclinical data using NAMPT inhibitors in cancer models, early NAMPT inhibitors showed limited efficacy in several early phase clinical trials, necessitating the identification of strategies, such as drug combinations, to enhance their efficacy. While the effect of NAMPT inhibitors on impairment of energy metabolism in cancer cells has been well-described, more recent insights have uncovered a number of additional targetable cellular processes that are impacted by inhibition of NAMPT. These include sirtuin function, DNA repair machinery, redox homeostasis, molecular signaling, cellular stemness, and immune processes. This review highlights the recent findings describing the effects of NAMPT inhibitors on the non-metabolic functions of malignant cells, with a focus on how this information can be leveraged clinically. Combining NAMPT inhibitors with other therapies that target NAD+-dependent processes or selecting tumors with specific vulnerabilities that can be co-targeted with NAMPT inhibitors may represent opportunities to exploit the multiple functions of this enzyme for greater therapeutic benefit.
    Keywords:  NAD+; NAMPT; PARP; ROS; cancer; sirtuins
  31. Cell Death Differ. 2020 Feb 03.
    Haschka MD, Karbon G, Soratroi C, O'Neill KL, Luo X, Villunger A.
      Cells experiencing delays in mitotic progression are prone to undergo apoptosis unless they can exit mitosis before proapoptotic factors reach a critical threshold. Microtubule targeting agents (MTAs) arrest cells in mitosis and induce apoptotic cell death engaging the BCL2 network. Degradation of the antiapoptotic BCL2 family member MCL-1 is considered to set the time until onset of apoptosis upon MTA treatment. MCL1 degradation involves its interaction with one of its key binding partners, the proapoptotic BH3-only protein NOXA. Here, we report that the mitochondria-associated E3-ligase MARCH5, best known for its role in mitochondrial quality control and regulation of components of the mitochondrial fission machinery, controls the levels of MCL1/NOXA protein complexes in steady state as well as during mitotic arrest. Inhibition of MARCH5 function sensitizes cancer cells to the proapoptotic effects of MTAs by the accumulation of NOXA and primes cancer cells that may undergo slippage to escape death in mitosis to cell death in the next G1 phase. We propose that inhibition of MARCH5 may be a suitable strategy to sensitize cancer cells to antimitotic drug treatment.
  32. Oncogenesis. 2020 Feb 07. 9(2): 14
    Zhao E, Hou J, Cui H.
      In a recent study published in Cancer Research, Xia and colleagues reported that, in cancer, constituents in serine-glycine-one-carbon (SGOC) metabolism exhibit enhanced transcriptional activation and are increasingly utilised, which results in more glucose-derived carbon to serine-glycine biosynthesis. The current work identifies an MYCN-dependent metabolic vulnerability and shows a variety of associations between metabolic reprogramming and enhanced sensitivity to metabolic stress, which may lead the way to unlocking new anticancer therapies. Here, we summarised new insights into the role of SGOC metabolism in the progression of neuroblastoma (NB) with highly activated SGOC metabolism.
  33. Proc Natl Acad Sci U S A. 2020 Feb 05. pii: 201918215. [Epub ahead of print]
    Mondanelli G, Coletti A, Greco FA, Pallotta MT, Orabona C, Iacono A, Belladonna ML, Albini E, Panfili E, Fallarino F, Gargaro M, Manni G, Matino D, Carvalho A, Cunha C, Maciel P, Di Filippo M, Gaetani L, Bianchi R, Vacca C, Iamandii IM, Proietti E, Boscia F, Annunziato L, Peppelenbosch M, Puccetti P, Calabresi P, Macchiarulo A, Santambrogio L, Volpi C, Grohmann U.
      l-tryptophan (Trp), an essential amino acid for mammals, is the precursor of a wide array of immunomodulatory metabolites produced by the kynurenine and serotonin pathways. The kynurenine pathway is a paramount source of several immunoregulatory metabolites, including l-kynurenine (Kyn), the main product of indoleamine 2,3-dioxygenase 1 (IDO1) that catalyzes the rate-limiting step of the pathway. In the serotonin pathway, the metabolite N-acetylserotonin (NAS) has been shown to possess antioxidant, antiinflammatory, and neuroprotective properties in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). However, little is known about the exact mode of action of the serotonin metabolite and the possible interplay between the 2 Trp metabolic pathways. Prompted by the discovery that NAS neuroprotective effects in EAE are abrogated in mice lacking IDO1 expression, we investigated the NAS mode of action in neuroinflammation. We found that NAS directly binds IDO1 and acts as a positive allosteric modulator (PAM) of the IDO1 enzyme in vitro and in vivo. As a result, increased Kyn will activate the ligand-activated transcription factor aryl hydrocarbon receptor and, consequently, antiinflammatory and immunoregulatory effects. Because NAS also increased IDO1 activity in peripheral blood mononuclear cells of a significant proportion of MS patients, our data may set the basis for the development of IDO1 PAMs as first-in-class drugs in autoimmune/neuroinflammatory diseases.
    Keywords:  N-acetylserotonin (NAS); aryl hydrocarbon receptor (AhR); dendritic cells; indoleamine 2,3-dioxygenase 1 (IDO1); neuroinflammation
  34. EMBO Rep. 2020 Feb 06. e48804
    Ost M, Igual Gil C, Coleman V, Keipert S, Efstathiou S, Vidic V, Weyers M, Klaus S.
      Mitochondrial dysfunction promotes metabolic stress responses in a cell-autonomous as well as organismal manner. The wasting hormone growth differentiation factor 15 (GDF15) is recognized as a biomarker of mitochondrial disorders, but its pathophysiological function remains elusive. To test the hypothesis that GDF15 is fundamental to the metabolic stress response during mitochondrial dysfunction, we investigated transgenic mice (Ucp1-TG) with compromised muscle-specific mitochondrial OXPHOS capacity via respiratory uncoupling. Ucp1-TG mice show a skeletal muscle-specific induction and diurnal variation of GDF15 as a myokine. Remarkably, genetic loss of GDF15 in Ucp1-TG mice does not affect muscle wasting or transcriptional cell-autonomous stress response but promotes a progressive increase in body fat mass. Furthermore, muscle mitochondrial stress-induced systemic metabolic flexibility, insulin sensitivity, and white adipose tissue browning are fully abolished in the absence of GDF15. Mechanistically, we uncovered a GDF15-dependent daytime-restricted anorexia, whereas GDF15 is unable to suppress food intake at night. Altogether, our evidence suggests a novel diurnal action and key pathophysiological role of mitochondrial stress-induced GDF15 in the regulation of systemic energy metabolism.
    Keywords:  GDF15; anorexia; integrated stress response; mitochondrial dysfunction; muscle wasting
  35. Oncogene. 2020 Feb 05.
    NavaneethaKrishnan S, Rosales JL, Lee KY.
      We previously demonstrated that loss of Cdk5 in breast cancer cells promotes ROS-mediated cell death by inducing mitochondrial permeability transition pore (mPTP) opening (Oncogene 37, 1788-1804). However, the molecular mechanism by which Cdk5 loss causes mPTP opening remains to be investigated. Using primary mouse embryonic fibroblasts (MEFs) isolated from Cdk5-/- mouse embryos, we show that absence of Cdk5 causes a significant increase in both mPTP opening and mitochondrial Ca2+ level. Analysis of subcellular fractions of MEFs demonstrates that Cdk5 localizes in the mitochondria-associated endoplasmic reticulum (ER) membrane (MAM) and Cdk5 loss in MAMs causes increased ER-mitochondria tethering, a process required for Ca2+ transfer from the ER to the mitochondria. Loss of Cdk5 also causes increased ATP-mediated mitochondrial Ca2+ uptake from the ER. Inhibition of ER Ca2+ release or mitochondrial Ca2+ uptake in Cdk5-/- MEFs prevents mPTP opening, indicating that mPTP opening in Cdk5-/- MEFs is due to increased Ca2+ transfer from the ER to the mitochondria. Altogether, our findings suggest that Cdk5 in MAMs regulates mitochondrial Ca2+ homeostasis that is disturbed upon Cdk5 loss, which leads to mPTP opening.
  36. Nat Commun. 2020 Feb 07. 11(1): 796
    Viscarra JA, Wang Y, Nguyen HP, Choi YG, Sul HS.
      Fatty acid and triglyceride synthesis increases greatly in response to feeding and insulin. This lipogenic induction involves coordinate transcriptional activation of various enzymes in lipogenic pathway, including fatty acid synthase and glycerol-3-phosphate acyltransferase. Here, we show that JMJD1C is a specific histone demethylase for lipogenic gene transcription in liver. In response to feeding/insulin, JMJD1C is phosphorylated at T505 by mTOR complex to allow direct interaction with USF-1 for recruitment to lipogenic promoter regions. Thus, by demethylating H3K9me2, JMJD1C alters chromatin accessibility to allow transcription. Consequently, JMJD1C promotes lipogenesis in vivo to increase hepatic and plasma triglyceride levels, showing its role in metabolic adaption for activation of the lipogenic program in response to feeding/insulin, and its contribution to development of hepatosteatosis resulting in insulin resistance.
  37. Cancer Res. 2020 Feb 03. pii: canres.2994.2019. [Epub ahead of print]
    Su P, Wang Q, Bi E, Ma X, Liu L, Yang M, Qian J, Yi Q.
      Tumor-associated macrophages (TAMs) are important tumor-promoting cells. However, the mechanism underlying how tumor and its microenvironment reprogram these cells remains elusive. Here we report that lipids play a crucial role in TAM generation in tumor microenvironment. Macrophages from both human and murine tumor tissues are enriched with lipids as a result of increased lipid uptake by macrophages. TAMs expressed elevated levels of the scavenger receptor CD36, accumulated lipids, and used fatty acid oxidation (FAO) instead of glycolysis for energy. High levels of FAO promoted mitochondrial oxidative phosphorylation, production of reactive oxygen species, phosphorylation of JAK1 and dephosphorylation of SHP1, leading to STAT6 activation and transcription of genes regulating TAM generation and function. These processes were critical for TAM polarization and activity in vitro and in vivo. In summary, we describe a novel mechanism underlying lipid metabolism-initiated process that promotes the differentiation and function of the protumor TAMs in TME.
  38. Biotechnol Bioeng. 2020 Feb 05.
    Ramos JRC, Rath AG, Genzel Y, Sandig V, Reichl U.
      Mathematical modeling of animal cell growth and metabolism is essential for the understanding and improvement of the production of biopharmaceuticals. Models can explain the dynamic behavior of cell growth and product formation, support the identification of the most relevant parameters for process design, and significantly reduce the number of experiments to be performed for process optimization. Few dynamic models have been established that describe both extracellular and intracellular dynamics of growth and metabolism of animal cells. In this study, a model was developed, which comprises a set of 33 ODEs to describe batch cultivations of suspension AGE1.HN.AAT cells considered for the production of alpha1-antitrypsin. This model combines a segregated cell growth model with a structured model of intracellular metabolism. Overall, it considers the viable cell concentration, mean cell diameter, viable cell volume, concentration of extracellular substrates, and intracellular concentrations of key metabolites from the central carbon metabolism. Furthermore, the release of metabolic by-products such as lactate and ammonium was estimated directly from the intracellular reactions. Based on the same set of parameters, this model simulates well the dynamics of four independent batch cultivations. Analysis of the simulated intracellular rates revealed at least two distinct cellular physiological states. The first physiological state was characterized by a high glycolytic rate and high lactate production. Whereas the second state was characterized by efficient ATP production, a low glycolytic rate, and reactions of the TCA cycle running in the reverse direction from alpha-ketoglutarate to citrate. Finally, we show possible applications of the model for cell line engineering and media optimization with two case studies. This article is protected by copyright. All rights reserved.
    Keywords:  Dynamic model; TCA cycle; animal cell; glycolysis; kinetic; metabolism
  39. Oncogene. 2020 Feb 07.
    Saliakoura M, Reynoso-Moreno I, Pozzato C, Rossi Sebastiano M, Galié M, Gertsch J, Konstantinidou G.
      Enhanced prostaglandin production promotes the development and progression of cancer. Prostaglandins are generated from arachidonic acid (AA) by the action of cyclooxygenase (COX) isoenzymes. However, how cancer cells are able to maintain an elevated supply of AA for prostaglandin production remains unclear. Here, by using lung cancer cell lines and clinically relevant KrasG12D-driven mouse models, we show that the long-chain acyl-CoA synthetase (ACSL3) channels AA into phosphatidylinositols to provide the lysophosphatidylinositol-acyltransferase 1 (LPIAT1) with a pool of AA to sustain high prostaglandin synthesis. LPIAT1 knockdown suppresses proliferation and anchorage-independent growth of lung cancer cell lines, and hinders in vivo tumorigenesis. In primary human lung tumors, the expression of LPIAT1 is elevated compared with healthy tissue, and predicts poor patient survival. This study uncovers the ACSL3-LPIAT1 axis as a requirement for the sustained prostaglandin synthesis in lung cancer with potential therapeutic value.
  40. Cell Rep. 2020 Feb 04. pii: S2211-1247(20)30021-8. [Epub ahead of print]30(5): 1400-1416.e6
    Bellier J, Nokin MJ, Caprasse M, Tiamiou A, Blomme A, Scheijen JL, Koopmansch B, MacKay GM, Chiavarina B, Costanza B, Rademaker G, Durieux F, Agirman F, Maloujahmoum N, Cusumano PG, Lovinfosse P, Leung HY, Lambert F, Bours V, Schalkwijk CG, Hustinx R, Peulen O, Castronovo V, Bellahcène A.
      The use of cetuximab anti-epidermal growth factor receptor (anti-EGFR) antibodies has opened the era of targeted and personalized therapy in colorectal cancer (CRC). Poor response rates have been unequivocally shown in mutant KRAS and are even observed in a majority of wild-type KRAS tumors. Therefore, patient selection based on mutational profiling remains problematic. We previously identified methylglyoxal (MGO), a by-product of glycolysis, as a metabolite promoting tumor growth and metastasis. Mutant KRAS cells under MGO stress show AKT-dependent survival when compared with wild-type KRAS isogenic CRC cells. MGO induces AKT activation through phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin 2 (mTORC2) and Hsp27 regulation. Importantly, the sole induction of MGO stress in sensitive wild-type KRAS cells renders them resistant to cetuximab. MGO scavengers inhibit AKT and resensitize KRAS-mutated CRC cells to cetuximab in vivo. This study establishes a link between MGO and AKT activation and pinpoints this oncometabolite as a potential target to tackle EGFR-targeted therapy resistance in CRC.
    Keywords:  AKT signaling; EGFR-targeted therapy; Hsp27; KRAS mutation; aminoguanidine; carnosine; cetuximab; colorectal cancer; methylglyoxal
  41. Proc Natl Acad Sci U S A. 2020 Feb 04. pii: 201914153. [Epub ahead of print]
    Brandt AC, McNally L, Lorimer EL, Unger B, Koehn OJ, Suazo KF, Rein L, Szabo A, Tsaih SW, Distefano MD, Flister MJ, Rigo F, McNally MT, Williams CL.
      The chaperone protein SmgGDS promotes cell-cycle progression and tumorigenesis in human breast and nonsmall cell lung cancer. Splice variants of SmgGDS, named SmgGDS-607 and SmgGDS-558, facilitate the activation of oncogenic members of the Ras and Rho families of small GTPases through membrane trafficking via regulation of the prenylation pathway. SmgGDS-607 interacts with newly synthesized preprenylated small GTPases, while SmgGDS-558 interacts with prenylated small GTPases. We determined that cancer cells have a high ratio of SmgGDS-607:SmgGDS-558 (607:558 ratio), and this elevated ratio is associated with reduced survival of breast cancer patients. These discoveries suggest that targeting SmgGDS splicing to lower the 607:558 ratio may be an effective strategy to inhibit the malignant phenotype generated by small GTPases. Here we report the development of a splice-switching oligonucleotide, named SSO Ex5, that lowers the 607:558 ratio by altering exon 5 inclusion in SmgGDS pre-mRNA (messenger RNA). Our results indicate that SSO Ex5 suppresses the prenylation of multiple small GTPases in the Ras, Rho, and Rab families and inhibits ERK activity, resulting in endoplasmic reticulum (ER) stress, the unfolded protein response, and ultimately apoptotic cell death in breast and lung cancer cell lines. Furthermore, intraperitoneal (i.p.) delivery of SSO Ex5 in MMTV-PyMT mice redirects SmgGDS splicing in the mammary gland and slows tumorigenesis in this aggressive model of breast cancer. Taken together, our results suggest that the high 607:558 ratio is required for optimal small GTPase prenylation, and validate this innovative approach of targeting SmgGDS splicing to diminish malignancy in breast and lung cancer.
    Keywords:  RAP1GDS1; SmgGDS; alternative splicing; prenylation; small GTPases
  42. Cell Death Dis. 2020 Feb 06. 11(2): 102
    Li Y, Gruber JJ, Litzenburger UM, Zhou Y, Miao YR, LaGory EL, Li AM, Hu Z, Yip M, Hart LS, Maris JM, Chang HY, Giaccia AJ, Ye J.
      Despite the fact that Otto H. Warburg discovered the Warburg effect almost one hundred years ago, why cancer cells waste most of the glucose carbon as lactate remains an enigma. Warburg proposed a connection between the Warburg effect and cell dedifferentiation. Hypoxia is a common tumor microenvironmental stress that induces the Warburg effect and blocks tumor cell differentiation. The underlying mechanism by which this occurs is poorly understood, and no effective therapeutic strategy has been developed to overcome this resistance to differentiation. Using a neuroblastoma differentiation model, we discovered that hypoxia repressed cell differentiation through reducing cellular acetyl-CoA levels, leading to reduction of global histone acetylation and chromatin accessibility. The metabolic switch triggering this global histone hypoacetylation was the induction of pyruvate dehydrogenase kinases (PDK1 and PDK3). Inhibition of PDKs using dichloroacetate (DCA) restored acetyl-CoA generation and histone acetylation under hypoxia. Knocking down PDK1 induced neuroblastoma cell differentiation, highlighting the critical role of PDK1 in cell fate control. Importantly, acetate or glycerol triacetate (GTA) supplementation restored differentiation markers expression and neuron differentiation under hypoxia. Moreover, ATAC-Seq analysis demonstrated that hypoxia treatment significantly reduced chromatin accessibility at RAR/RXR binding sites, which can be restored by acetate supplementation. In addition, hypoxia-induced histone hypermethylation by increasing 2-hydroxyglutarate (2HG) and reducing α-ketoglutarate (αKG). αKG supplementation reduced histone hypermethylation upon hypoxia, but did not restore histone acetylation or differentiation markers expression. Together, these findings suggest that diverting pyruvate flux away from acetyl-CoA generation to lactate production is the key mechanism that Warburg effect drives dedifferentiation and tumorigenesis. We propose that combining differentiation therapy with acetate/GTA supplementation might represent an effective therapy against neuroblastoma.
  43. Nat Microbiol. 2020 Feb 03.
    Geier B, Sogin EM, Michellod D, Janda M, Kompauer M, Spengler B, Dubilier N, Liebeke M.
      Spatial metabolomics describes the location and chemistry of small molecules involved in metabolic phenotypes, defence molecules and chemical interactions in natural communities. Most current techniques are unable to spatially link the genotype and metabolic phenotype of microorganisms in situ at a scale relevant to microbial interactions. Here, we present a spatial metabolomics pipeline (metaFISH) that combines fluorescence in situ hybridization (FISH) microscopy and high-resolution atmospheric-pressure matrix-assisted laser desorption/ionization mass spectrometry to image host-microbe symbioses and their metabolic interactions. The metaFISH pipeline aligns and integrates metabolite and fluorescent images at the micrometre scale to provide a spatial assignment of host and symbiont metabolites on the same tissue section. To illustrate the advantages of metaFISH, we mapped the spatial metabolome of a deep-sea mussel and its intracellular symbiotic bacteria at the scale of individual epithelial host cells. Our analytical pipeline revealed metabolic adaptations of the epithelial cells to the intracellular symbionts and variation in metabolic phenotypes within a single symbiont 16S rRNA phylotype, and enabled the discovery of specialized metabolites from the host-microbe interface. metaFISH provides a culture-independent approach to link metabolic phenotypes to community members in situ and is a powerful tool for microbiologists across fields.
  44. Proc Natl Acad Sci U S A. 2020 Feb 06. pii: 201919403. [Epub ahead of print]
    Li X, Wang J, Wang L, Feng G, Li G, Yu M, Li Y, Liu C, Yuan X, Zang G, Li Z, Zhao L, Ouyang H, Quan Q, Wang G, Zhang C, Li O, Xiang J, Zhu JK, Li W, Zhou Q, Zhang K.
      Epigenetic alterations and metabolic dysfunction are two hallmarks of aging. However, the mechanism of how their interaction regulates aging, particularly in mammals, remains largely unknown. Here we show ELOVL fatty acid elongase 2 (Elovl2), a gene whose epigenetic alterations are most highly correlated with age prediction, contributes to aging by regulating lipid metabolism. Impaired Elovl2 function disturbs lipid synthesis with increased endoplasmic reticulum stress and mitochondrial dysfunction, leading to key accelerated aging phenotypes. Restoration of mitochondrial activity can rescue age-related macular degeneration (AMD) phenotypes induced by Elovl2 deficiency in human retinal pigmental epithelial (RPE) cells. We revealed an epigenetic-metabolism axis contributing to aging and potentially to antiaging therapy.
    Keywords:  ER stress; aging; epigenetic alteration; lipid metabolism; mitochondrial dysfunction