bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2019‒05‒05
53 papers selected by
Christian Frezza,

  1. Coupling Krebs cycle metabolites to signalling in immunity and cancer.
  2. Regulation of succinate dehydrogenase and role of succinate in cancer.
  3. Comprehensive Genetic Characterization of Mitochondrial Ca2+ Uniporter Components Reveals Their Different Physiological Requirements In Vivo.
  4. Critical role of mitochondrial dysfunction and impaired mitophagy in diabetic nephropathy.
  5. Exploring the In Vivo Role of the Mitochondrial Calcium Uniporter in Brown Fat Bioenergetics.
  6. Mitochondrial metabolism and the maintenance of hematopoietic stem cell quiescence.
  7. Mutations in ELAC2 associated with hypertrophic cardiomyopathy impair mitochondrial tRNA 3'-end processing.
  8. Loss of MCU prevents mitochondrial fusion in G1-S phase and blocks cell cycle progression and proliferation.
  9. Inferring cancer dependencies on metabolic genes from large-scale genetic screens.
  10. Proteolytic regulation of mitochondrial dynamics.
  11. RB constrains lineage fidelity and multiple stages of tumour progression and metastasis.
  12. Anaerobic Glycolysis Maintains the Glomerular Filtration Barrier Independent of Mitochondrial Metabolism and Dynamics.
  13. Teriflunomide treatment for multiple sclerosis modulates T cell mitochondrial respiration with affinity-dependent effects.
  14. TEFM regulates both transcription elongation and RNA processing in mitochondria.
  15. Hydrogen Sulfide Inhibits Ca2+-induced Mitochondrial Permeability Transition Pore (MPTP) Opening in Type-1 Diabetes.
  16. Mechanisms and roles of mitophagy in neurodegenerative diseases.
  17. Redox-dependent loss of flavin by mitochondrial complex I in brain ischemia/reperfusion injury.
  18. The mitochondrial metabolic function of DJ-1 is modulated by 14-3-3β.
  19. Essential role of O-GlcNAcylation in stabilization of oncogenic factors.
  20. STX17 dynamically regulated by Fis1 induces mitophagy via hierarchical macroautophagic mechanism.
  21. Versatility of Preprotein Transfer from the Cytosol to Mitochondria.
  22. Quantitative Proteomics of Presynaptic Mitochondria Reveal an Overexpression and Biological Relevance of Neuronal MitoNEET in Postnatal Brain Development.
  23. Acute psychological stress increases serum circulating cell-free mitochondrial DNA.
  24. Non-canonical HIF-1 stabilization contributes to intestinal tumorigenesis.
  25. Circadian clock regulation of the glycogen synthase (gsn) gene by WCC is critical for rhythmic glycogen metabolism in Neurospora crassa.
  26. Short-term high salt intake impairs hepatic mitochondrial bioenergetics and biosynthesis in SIRT3 knockout mice.
  27. Short-chain fatty acids: Bacterial messengers modulating the immunometabolism of T cells.
  28. Disease-Associated Genetic Variation in Human Mitochondrial Protein Import.
  29. Functional Assessment of Lipoyltransferase-1 Deficiency in Cells, Mice, and Humans.
  30. Targeting cancer cell metabolism in glioblastoma.
  31. Secreted parasite Pin1 isomerase stabilizes host PKM2 to reprogram host cell metabolism.
  32. LKB1 and KEAP1/NRF2 pathways cooperatively promote metabolic reprogramming with enhanced glutamine dependence in KRAS-mutant lung adenocarcinoma.
  33. MEK1/2 inhibitor withdrawal reverses acquired resistance driven by BRAFV600E amplification whereas KRASG13D amplification promotes EMT-chemoresistance.
  34. Metabolic constraints of swelling-activated glutamate release in astrocytes and their implication for ischemic tissue damage.
  35. Dual inhibition of glutaminase and carnitine palmitoyltransferase decreases growth and migration of glutaminase inhibition-resistant triple-negative breast cancer cells.
  36. An old medicine as a new drug to prevent mitochondrial complex I from producing oxygen radicals.
  37. An aerobic eukaryotic parasite with functional mitochondria that likely lacks a mitochondrial genome.
  38. Slc25a36 modulates pluripotency of mouse embryonic stem cells by regulating mitochondrial function and glutathione level.
  39. Identification of Kinases Responsible for p53-Dependent Autophagy.
  40. The mitochondrial R-loop.
  41. Structural changes in the transport cycle of the mitochondrial ADP/ATP carrier.
  42. Editorial: Mitochondrial Communication in Physiology, Disease and Aging.
  43. NAD Metabolic Dependency Determines Therapeutic Sensitivity in Cancer.
  44. Mitochondrial calcium uniporter complex modulation in cancerogenesis.
  45. The quantitative relationship between isotopic and net contributions of lactate and glucose to the TCA cycle.
  46. Protein O-GlcNAcylation Is Essential for the Maintenance of Renal Energy Homeostasis and Function via Lipolysis during Fasting and Diabetes.
  47. Tyrosine aminotransferase is involved in the oxidative stress response by metabolizing meta-tyrosine in Caenorhabditis elegans.
  48. Spectral tracing of deuterium for imaging glucose metabolism.
  49. nNOS/GSNOR interaction contributes to skeletal muscle differentiation and homeostasis.
  50. Akt and STAT5 mediate naïve human CD4+ T-cell early metabolic response to TCR stimulation.
  51. The histone demethylase JMJD2B is critical for p53-mediated autophagy and survival in nutlin-treated cancer cells.
  52. cAMP/PKA signaling compartmentalization in cardiomyocytes: Lessons from FRET-based biosensors.
  53. Deficient Endoplasmic Reticulum-Mitochondrial Phosphatidylserine Transfer Causes Liver Disease.
  1. Nat Metab. 2019 Jan;1 16-33
    Coupling Krebs cycle metabolites to signalling in immunity and cancer.
    Dylan G Ryan, Michael P Murphy, Christian Frezza, Hiran A Prag, Edward T Chouchani, Luke A O'Neill, Evanna L Mills.
      Metabolic reprogramming has become a key focus for both immunologists and cancer biologists, with exciting advances providing new insights into underlying mechanisms of disease. Metabolites traditionally associated with bioenergetics or biosynthesis have been implicated in immunity and malignancy in transformed cells, with a particular focus on intermediates of the mitochondrial pathway known as the Krebs cycle. Among these, the intermediates succinate, fumarate, itaconate, 2-hydroxyglutarate isomers (D-2-hydroxyglutarate and L-2-hydroxyglutarate) and acetyl-CoA now have extensive evidence for "non-metabolic" signalling functions in both physiological immune contexts and in disease contexts, such as the initiation of carcinogenesis. This review will describe how metabolic reprogramming, with emphasis placed on these metabolites, leads to altered immune cell and transformed cell function. The latest findings are informative for new therapeutic approaches which could be transformative for a range of diseases.
    DOI:  https://doi.org/10.1038/s42255-018-0014-7
  2. Semin Cell Dev Biol. 2019 Apr 27. pii: S1084-9521(19)30056-4. [Epub ahead of print]
    Regulation of succinate dehydrogenase and role of succinate in cancer.
    Elisa Dalla Pozza, Ilaria Dando, Raffaella Pacchiana, Elio Liboi, Maria Teresa Scupoli, Massimo Donadelli, Marta Palmieri.
      Succinate dehydrogenase (SDH) has been classically considered a mitochondrial enzyme with the unique property to participate in both the citric acid cycle and the electron transport chain. However, in recent years, several studies have highlighted the role of the SDH substrate, i.e. succinate, in biological processes other than metabolism, tumorigenesis being the most remarkable. For this reason, SDH has now been defined a tumor suppressor and succinate an oncometabolite. In this review, we discuss recent findings regarding alterations in SDH activity leading to succinate accumulation, which include SDH mutations, regulation of mRNA expression, post-translational modifications and endogenous SDH inhibitors. Further, we report an extensive examination of the role of succinate in cancer development through the induction of epigenetic and metabolic alterations and the effects on epithelial to mesenchymal transition, cell migration and invasion, and angiogenesis. Finally, we have focused on succinate and SDH as diagnostic markers for cancers having altered SDH expression/activity.
    Keywords:  SDH; cancer; metabolism; oncometabolites; succinate
    DOI:  https://doi.org/10.1016/j.semcdb.2019.04.013
  3. Cell Rep. 2019 Apr 30. pii: S2211-1247(19)30498-X. [Epub ahead of print]27(5): 1541-1550.e5
    Comprehensive Genetic Characterization of Mitochondrial Ca2+ Uniporter Components Reveals Their Different Physiological Requirements In Vivo.
    Roberta Tufi, Thomas P Gleeson, Sophia von Stockum, Victoria L Hewitt, Juliette J Lee, Ana Terriente-Felix, Alvaro Sanchez-Martinez, Elena Ziviani, Alexander J Whitworth.
      Mitochondrial Ca2+ uptake is an important mediator of metabolism and cell death. Identification of components of the highly conserved mitochondrial Ca2+ uniporter has opened it up to genetic analysis in model organisms. Here, we report a comprehensive genetic characterization of all known uniporter components conserved in Drosophila. While loss of pore-forming MCU or EMRE abolishes fast mitochondrial Ca2+ uptake, this results in only mild phenotypes when young, despite shortened lifespans. In contrast, loss of the MICU1 gatekeeper is developmentally lethal, consistent with unregulated Ca2+ uptake. Mutants for the neuronally restricted regulator MICU3 are viable with mild neurological impairment. Genetic interaction analyses reveal that MICU1 and MICU3 are not functionally interchangeable. More surprisingly, loss of MCU or EMRE does not suppress MICU1 mutant lethality, suggesting that this results from uniporter-independent functions. Our data reveal the interplay among components of the mitochondrial Ca2+ uniporter and shed light on their physiological requirements in vivo.
    Keywords:  Drosophila; EMRE; MCU; MICU1; MICU3; calcium; genetic interaction; genetics; mitochondria
    DOI:  https://doi.org/10.1016/j.celrep.2019.04.033
  4. J Cell Physiol. 2019 Apr 29.
    Critical role of mitochondrial dysfunction and impaired mitophagy in diabetic nephropathy.
    Sugandh Saxena, Alpana Mathur, Poonam Kakkar.
      Mitochondrial dynamics play a critical role in deciding the fate of a cell under normal and diseased condition. Recent surge of studies indicate their regulatory role in meeting energy demands in renal cells making them critical entities in the progression of diabetic nephropathy. Diabetes is remarkably associated with abnormal fuel metabolism, a basis for free radical generation, which if left unchecked may devastate the mitochondria structurally and functionally. Impaired mitochondrial function and their aberrant accumulation have been known to be involved in the manifestation of diabetic nephropathy, indicating perturbed balance of mitochondrial dynamics, and mitochondrial turnover. Mitochondrial dynamics emphasize the critical role of mitochondrial fission proteins such as mitochondrial fission 1, dynamin-related protein 1 and mitochondrial fission factor and fusion proteins including mitofusin-1, mitofusin-2 and optic atrophy 1. Clearance of dysfunctional mitochondria is aided by translocation of autophagy machinery to the impaired mitochondria and subsequent activation of mitophagy regulating proteins PTEN-induced putative kinase 1 and Parkin, for which mitochondrial fission is a prior event. In this review, we discuss recent progression in our understanding of the molecular mechanisms targeting reactive oxygen species mediated alterations in mitochondrial energetics, mitophagy related disorders, impaired glucose transport, tubular atrophy, and renal cell death. The molecular cross talks linking autophagy and renoprotection through an intervention of 5'-AMP-activated protein kinase, mammalian target of rapamycin, and SIRT1 factors are also highlighted here, as in-depth exploration of these pathways may help in deriving therapeutic strategies for managing diabetes provoked end-stage renal disease.
    Keywords:  diabetic nephropathy; free radicals; mitochondrial dysfunction; mitophagy; renal dysfunction
    DOI:  https://doi.org/10.1002/jcp.28712
  5. Cell Rep. 2019 Apr 30. pii: S2211-1247(19)30468-1. [Epub ahead of print]27(5): 1364-1375.e5
    Exploring the In Vivo Role of the Mitochondrial Calcium Uniporter in Brown Fat Bioenergetics.
    Daniel Flicker, Yasemin Sancak, Eran Mick, Olga Goldberger, Vamsi K Mootha.
      The mitochondrial calcium uniporter has been proposed to coordinate the organelle's energetics with calcium signaling. Uniporter current has previously been reported to be extremely high in brown adipose tissue (BAT), yet it remains unknown how the uniporter contributes to BAT physiology. Here, we report the generation and characterization of a mouse model lacking Mcu, the pore forming subunit of the uniporter, specifically in BAT (BAT-Mcu-KO). BAT-Mcu-KO mice lack uniporter-based calcium uptake in BAT mitochondria but exhibit unaffected cold tolerance, diet-induced obesity, and transcriptional response to cold in BAT. Unexpectedly, we found in wild-type animals that cold powerfully activates the ATF4-dependent integrated stress response (ISR) in BAT and upregulates circulating FGF21 and GDF15, raising the hypothesis that the ISR partly underlies the pleiotropic effects of BAT on systemic metabolism. Our study demonstrates that the uniporter is largely dispensable for BAT thermogenesis and demonstrates activation of the ISR in BAT in response to cold.
    Keywords:  ATF4; FGF21; GDF15; MCU; brown fat; calcium; integrated stress response; mitochondria; thermogenesis; uniporter
    DOI:  https://doi.org/10.1016/j.celrep.2019.04.013
  6. Curr Opin Hematol. 2019 Apr 30.
    Mitochondrial metabolism and the maintenance of hematopoietic stem cell quiescence.
    Mengjia Hu, Junping Wang.
      PURPOSE OF REVIEW: Hematopoietic stem cells (HSCs) are characterized by a potent multilineage regenerative capability that is dependent on their quiescence property. In the past few decades, researchers have found many intrinsic and niche-derived factors that can regulate HSCs, whereas how to precisely control HSC behaviors remains elusive. Recently, mitochondrial metabolism has been shown to be involved in the regulation of HSC biology. The purpose of this review is to overview recent advances in the relationship between mitochondrial metabolism and maintenance of HSC quiescence.RECENT FINDINGS: On the basis of fact that HSCs are heterogeneous populations that have their unique metabolic characteristics, increasing studies have demonstrated that the quiescence and function of HSCs are closely correlated with the mitochondrial mass and activity, as well as the levels of mitochondria-derived reactive oxygen species and metabolites. Apart from that, mitochondria have been reported to undergo internal protective programs, including mitochondrial unfolded protein response, autophagy and mitochondrial dynamics, which are beneficial to maintaining HSC homeostasis.
    SUMMARY: The maintenance of HSC quiescence needs a metabolic balance in mitochondria, and unraveling the metabolic complexity may provide deep understanding of the functional heterogeneity of HSCs.
    DOI:  https://doi.org/10.1097/MOH.0000000000000507
  7. Hum Mutat. 2019 May 02.
    Mutations in ELAC2 associated with hypertrophic cardiomyopathy impair mitochondrial tRNA 3'-end processing.
    Makenzie Saoura, Christopher A Powell, Robert Kopajtich, Ahmad Alahmad, Haya H Al-Balool, Buthaina Albash, Majid Alfadhel, Charlotte L Alston, Enrico Bertini, Penelope Bonnen, Drago Bratkovic, Rosalba Carrozzo, Maria A Donati, Michela Di Nottia, Daniele Ghezzi, Amy Goldstein, Eric Haan, Rita Horvath, Joanne Hughes, Federica Invernizzi, Eleonora Lamantea, Benjamin Lucas, Kyla-Gaye Pinnock, Maria Pujantell, Shamima Rahman, Pedro Rebelo-Guiomar, Saikat Santra, Daniela Verrigni, Robert McFarland, Holger Prokisch, Robert W Taylor, Louis Levinger, Michal Minczuk.
      Mutations in either the mitochondrial or nuclear genomes are associated with a diverse group of human disorders characterized by impaired mitochondrial respiration. Within this group, an increasing number of mutations have been identified in nuclear genes involved in mitochondrial RNA metabolism, including ELAC2. The ELAC2 gene codes for the mitochondrial RNase Z, responsible for endonucleolytic cleavage of the 3' ends of mitochondrial pre-tRNAs. Here, we report the identification of sixteen novel ELAC2 variants in individuals presenting with mitochondrial respiratory chain deficiency, hypertrophic cardiomyopathy and lactic acidosis. We provide evidence for the pathogenicity of the novel missense variants by studying the RNase Z activity in an in vitro system. We also modelled the residues affected by missense mutation in solved RNase Z structures, providing insight into enzyme structure and function. Finally, we show that primary fibroblasts from the affected individuals have elevated levels of unprocessed mitochondrial RNA precursors. Our study thus broadly confirms the correlation of ELAC2 variants with severe infantile-onset forms of hypertrophic cardiomyopathy and mitochondrial respiratory chain dysfunction. One rare missense variant associated with the occurrence of prostate cancer (p.Arg781His) impairs the mitochondrial RNase Z activity of ELAC2, suggesting a functional link between tumorigenesis and mitochondrial RNA metabolism This article is protected by copyright. All rights reserved.
    Keywords:  Mitochondria; RNA; RNase Z; cardiomyopathy; mitochondrial disease
    DOI:  https://doi.org/10.1002/humu.23777
  8. Sci Signal. 2019 Apr 30. pii: eaav1439. [Epub ahead of print]12(579):
    Loss of MCU prevents mitochondrial fusion in G1-S phase and blocks cell cycle progression and proliferation.
    Olha M Koval, Emily K Nguyen, Velarchana Santhana, Trevor P Fidler, Sara C Sebag, Tyler P Rasmussen, Dylan J Mittauer, Stefan Strack, Prabhat C Goswami, E Dale Abel, Isabella M Grumbach.
      The role of the mitochondrial Ca2+ uniporter (MCU) in physiologic cell proliferation remains to be defined. Here, we demonstrated that the MCU was required to match mitochondrial function to metabolic demands during the cell cycle. During the G1-S transition (the cycle phase with the highest mitochondrial ATP output), mitochondrial fusion, oxygen consumption, and Ca2+ uptake increased in wild-type cells but not in cells lacking MCU. In proliferating wild-type control cells, the addition of the growth factors promoted the activation of the Ca2+/calmodulin-dependent kinase II (CaMKII) and the phosphorylation of the mitochondrial fission factor Drp1 at Ser616 The lack of the MCU was associated with baseline activation of CaMKII, mitochondrial fragmentation due to increased Drp1 phosphorylation, and impaired mitochondrial respiration and glycolysis. The mitochondrial fission/fusion ratio and proliferation in MCU-deficient cells recovered after MCU restoration or inhibition of mitochondrial fragmentation or of CaMKII in the cytosol. Our data highlight a key function for the MCU in mitochondrial adaptation to the metabolic demands during cell cycle progression. Cytosolic CaMKII and the MCU participate in a regulatory circuit, whereby mitochondrial Ca2+ uptake affects cell proliferation through Drp1.
    DOI:  https://doi.org/10.1126/scisignal.aav1439
  9. BMC Biol. 2019 Apr 30. 17(1): 37
    Inferring cancer dependencies on metabolic genes from large-scale genetic screens.
    Shoval Lagziel, Won Dong Lee, Tomer Shlomi.
      BACKGROUND: Cancer cells reprogram their metabolism to survive and propagate. Thus, targeting metabolic rewiring in tumors is a promising therapeutic strategy. Genome-wide RNAi and CRISPR screens are powerful tools for identifying genes essential for cancer cell proliferation and survival. Integrating loss-of-function genetic screens with genomics and transcriptomics datasets reveals molecular mechanisms that underlie cancer cell dependence on specific genes; though explaining cell line-specific essentiality of metabolic genes was recently shown to be especially challenging.RESULTS: We find that variability in tissue culture medium between cell lines in a genetic screen is a major confounding factor affecting cell line-specific essentiality of metabolic genes-while, quite surprisingly, not being previously accounted for. Additionally, we find that altered expression level of a metabolic gene in a certain cell line is less indicative of its essentiality than for other genes. However, cell line-specific essentiality of metabolic genes is significantly correlated with changes in the expression of neighboring enzymes in the metabolic network. Utilizing a machine learning method that accounts for tissue culture media and functional association between neighboring enzymes, we generated predictive models for cancer cell line-specific dependence on 162 metabolic genes (representing a ~ 2.2-fold increase compared to previous studies). The generated predictive models reveal numerous novel associations between molecular features and cell line-specific dependency on metabolic genes. Specifically, we demonstrate how cancer cell dependence on one-carbon metabolic enzymes is explained based on cancer lineage, oncogenic mutations, and RNA expression of neighboring enzymes.
    CONCLUSIONS: Considering culture media as well as accounting for molecular features of functionally related metabolic enzymes in a metabolic network significantly improves our understanding of cancer cell line-specific dependence on metabolic genes. We expect our approach and predictive models of metabolic gene essentiality to be a useful tool for investigating metabolic abnormalities in cancer.
    Keywords:  CRISPR; Cancer metabolism; Gene-silencing screens; Metabolic networks; RNAi; Tissue culture medium; Tumor microenvironment
    DOI:  https://doi.org/10.1186/s12915-019-0654-4
  10. Mitochondrion. 2019 Apr 25. pii: S1567-7249(19)30047-9. [Epub ahead of print]
    Proteolytic regulation of mitochondrial dynamics.
    Jonathan V Dietz, Iryna Bohovych, Martonio Ponte Viana, Oleh Khalimonchuk.
      Spatiotemporal changes in the abundance, shape, and cellular localization of the mitochondrial network, also known as mitochondrial dynamics, are now widely recognized to play a key role in mitochondrial and cellular physiology as well as disease states. This process involves coordinated remodeling of the outer and inner mitochondrial membranes by conserved dynamin-like guanosine triphosphatases and their partner molecules in response to various physiological and stress stimuli. Although the core machineries that mediate fusion and partitioning of the mitochondrial network have been extensively characterized, many aspects of their function and regulation are incompletely understood and only beginning to emerge. In the present review we briefly summarize current knowledge about how the key mitochondrial dynamics-mediating factors are regulated via selective proteolysis by mitochondrial and cellular proteolytic machineries.
    Keywords:  GTPases; Mitochondria; Mitochondrial dynamics; Proteolysis
    DOI:  https://doi.org/10.1016/j.mito.2019.04.008
  11. Nature. 2019 May 01.
    RB constrains lineage fidelity and multiple stages of tumour progression and metastasis.
    David M Walter, Travis J Yates, Miguel Ruiz-Torres, Caroline Kim-Kiselak, A Andrea Gudiel, Charuhas Deshpande, Walter Z Wang, Michelle Cicchini, Kate L Stokes, John W Tobias, Elizabeth Buza, David M Feldser.
      Mutations in the retinoblastoma (RB) tumour suppressor pathway are a hallmark of cancer and a prevalent feature of lung adenocarcinoma1-3. Although RB was the first tumour suppressor to be identified, the molecular and cellular basis that underlies selection for persistent RB loss in cancer remains unclear4-6. Methods that reactivate the RB pathway using inhibitors of cyclin-dependent kinases CDK4 and CDK6 are effective in some cancer types and are currently under evaluation for the treatment of lung adenocarcinoma7-9. Whether RB pathway reactivation will have therapeutic effects and whether targeting CDK4 and CDK6 is sufficient to reactivate RB pathway activity in lung cancer remains unknown. Here we model RB loss during lung adenocarcinoma progression and pathway reactivation in established oncogenic KRAS-driven tumours in mice. We show that RB loss enables cancer cells to bypass two distinct barriers during tumour progression. First, RB loss abrogates the requirement for amplification of the MAPK signal during malignant progression. We identify CDK2-dependent phosphorylation of RB as an effector of MAPK signalling and critical mediator of resistance to inhibition of CDK4 and CDK6. Second, RB inactivation deregulates the expression of cell-state-determining factors, facilitates lineage infidelity and accelerates the acquisition of metastatic competency. By contrast, reactivation of RB reprograms advanced tumours towards a less metastatic cell state, but is nevertheless unable to halt cancer cell proliferation and tumour growth due to adaptive rewiring of MAPK pathway signalling, which restores a CDK-dependent suppression of RB. Our study demonstrates the power of reversible gene perturbation approaches to identify molecular mechanisms of tumour progression, causal relationships between genes and the tumour suppressive programs that they control and critical determinants of successful cancer therapy.
    DOI:  https://doi.org/10.1038/s41586-019-1172-9
  12. Cell Rep. 2019 Apr 30. pii: S2211-1247(19)30467-X. [Epub ahead of print]27(5): 1551-1566.e5
    Anaerobic Glycolysis Maintains the Glomerular Filtration Barrier Independent of Mitochondrial Metabolism and Dynamics.
    Paul T Brinkkoetter, Tillmann Bork, Sarah Salou, Wei Liang, Athanasia Mizi, Cem Özel, Sybille Koehler, H Henning Hagmann, Christina Ising, Alexander Kuczkowski, Svenia Schnyder, Ahmed Abed, Bernhard Schermer, Thomas Benzing, Oliver Kretz, Victor G Puelles, Simon Lagies, Manuel Schlimpert, Bernd Kammerer, Christoph Handschin, Christoph Schell, Tobias B Huber.
      The cellular responses induced by mitochondrial dysfunction remain elusive. Intrigued by the lack of almost any glomerular phenotype in patients with profound renal ischemia, we comprehensively investigated the primary sources of energy of glomerular podocytes. Combining functional measurements of oxygen consumption rates, glomerular metabolite analysis, and determination of mitochondrial density of podocytes in vivo, we demonstrate that anaerobic glycolysis and fermentation of glucose to lactate represent the key energy source of podocytes. Under physiological conditions, we could detect neither a developmental nor late-onset pathological phenotype in podocytes with impaired mitochondrial biogenesis machinery, defective mitochondrial fusion-fission apparatus, or reduced mtDNA stability and transcription caused by podocyte-specific deletion of Pgc-1α, Drp1, or Tfam, respectively. Anaerobic glycolysis represents the predominant metabolic pathway of podocytes. These findings offer a strategy to therapeutically interfere with the enhanced podocyte metabolism in various progressive kidney diseases, such as diabetic nephropathy or focal segmental glomerulosclerosis (FSGS).
    Keywords:  anaerobic glycolysis; glomerular filtration barrier; metabolomics; podocytes
    DOI:  https://doi.org/10.1016/j.celrep.2019.04.012
  13. Sci Transl Med. 2019 May 01. pii: eaao5563. [Epub ahead of print]11(490):
    Teriflunomide treatment for multiple sclerosis modulates T cell mitochondrial respiration with affinity-dependent effects.
    Luisa Klotz, Melanie Eschborn, Maren Lindner, Marie Liebmann, Martin Herold, Claudia Janoschka, Belén Torres Garrido, Andreas Schulte-Mecklenbeck, Catharina C Gross, Johanna Breuer, Petra Hundehege, Vilmos Posevitz, Béatrice Pignolet, Giulia Nebel, Shirin Glander, Nicole Freise, Judith Austermann, Timo Wirth, Graham R Campbell, Tilman Schneider-Hohendorf, Maria Eveslage, David Brassat, Nicholas Schwab, Karin Loser, Johannes Roth, Karin B Busch, Monika Stoll, Don J Mahad, Sven G Meuth, Timothy Turner, Amit Bar-Or, Heinz Wiendl.
      Interference with immune cell proliferation represents a successful treatment strategy in T cell-mediated autoimmune diseases such as rheumatoid arthritis and multiple sclerosis (MS). One prominent example is pharmacological inhibition of dihydroorotate dehydrogenase (DHODH), which mediates de novo pyrimidine synthesis in actively proliferating T and B lymphocytes. Within the TERIDYNAMIC clinical study, we observed that the DHODH inhibitor teriflunomide caused selective changes in T cell subset composition and T cell receptor repertoire diversity in patients with relapsing-remitting MS (RRMS). In a preclinical antigen-specific setup, DHODH inhibition preferentially suppressed the proliferation of high-affinity T cells. Mechanistically, DHODH inhibition interferes with oxidative phosphorylation (OXPHOS) and aerobic glycolysis in activated T cells via functional inhibition of complex III of the respiratory chain. The affinity-dependent effects of DHODH inhibition were closely linked to differences in T cell metabolism. High-affinity T cells preferentially use OXPHOS during early activation, which explains their increased susceptibility toward DHODH inhibition. In a mouse model of MS, DHODH inhibitory treatment resulted in preferential inhibition of high-affinity autoreactive T cell clones. Compared to T cells from healthy controls, T cells from patients with RRMS exhibited increased OXPHOS and glycolysis, which were reduced with teriflunomide treatment. Together, these data point to a mechanism of action where DHODH inhibition corrects metabolic disturbances in T cells, which primarily affects profoundly metabolically active high-affinity T cell clones. Hence, DHODH inhibition may promote recovery of an altered T cell receptor repertoire in autoimmunity.
    DOI:  https://doi.org/10.1126/scitranslmed.aao5563
  14. EMBO Rep. 2019 Apr 29. pii: e48101. [Epub ahead of print]
    TEFM regulates both transcription elongation and RNA processing in mitochondria.
    Shan Jiang, Camilla Koolmeister, Jelena Misic, Stefan Siira, Inge Kühl, Eduardo Silva Ramos, Maria Miranda, Min Jiang, Viktor Posse, Oleksandr Lytovchenko, Ilian Atanassov, Florian A Schober, Rolf Wibom, Kjell Hultenby, Dusanka Milenkovic, Claes M Gustafsson, Aleksandra Filipovska, Nils-Göran Larsson.
      Regulation of replication and expression of mitochondrial DNA (mtDNA) is essential for cellular energy conversion via oxidative phosphorylation. The mitochondrial transcription elongation factor (TEFM) has been proposed to regulate the switch between transcription termination for replication primer formation and processive, near genome-length transcription for mtDNA gene expression. Here, we report that Tefm is essential for mouse embryogenesis and that levels of promoter-distal mitochondrial transcripts are drastically reduced in conditional Tefm-knockout hearts. In contrast, the promoter-proximal transcripts are much increased in Tefm knockout mice, but they mostly terminate before the region where the switch from transcription to replication occurs, and consequently, de novo mtDNA replication is profoundly reduced. Unexpectedly, deep sequencing of RNA from Tefm knockouts revealed accumulation of unprocessed transcripts in addition to defective transcription elongation. Furthermore, a proximity-labeling (BioID) assay showed that TEFM interacts with multiple RNA processing factors. Our data demonstrate that TEFM acts as a general transcription elongation factor, necessary for both gene transcription and replication primer formation, and loss of TEFM affects RNA processing in mammalian mitochondria.
    Keywords:  RNA processing; mtDNA replication; transcription elongation
    DOI:  https://doi.org/10.15252/embr.201948101
  15. Am J Physiol Endocrinol Metab. 2019 Apr 30.
    Hydrogen Sulfide Inhibits Ca2+-induced Mitochondrial Permeability Transition Pore (MPTP) Opening in Type-1 Diabetes.
    Am Sashi Papu John, Sourav Kundu, Sathnur Pushpakumar, Matthew Amin, Suresh C Tyagi, Utpal Sen.
      Hydrogen sulfide (H2S) attenuates N-Methyl-D-Aspartate receptor-R1 (NMDA-R1) and mitigates diabetic renal damage; however, the molecular mechanism is not well known. While NMDA-R1 facilitates Ca2+ permeability, H2S is known to inhibit L-type Ca2+ channel. High Ca2+ activates cyclophilin D (CypD), a gatekeeper protein of mitochondrial permeability transition pore (MPTP), thus facilitating molecular exchange between matrix and cytoplasm causing oxidative outburst and cell death. We tested the hypothesis whether NMDA-R1 mediates Ca2+ influx causing CypD activation and MPTP opening leading to oxidative stress and renal injury in diabetes. Also, whether H2S treatment blocks Ca2+ channel and thus inhibits CypD and MPTP opening and prevents renal damage. C57BL/6J and Akita (C57BL/6J-Ins2Akita) mice were treated without or with H2S donor GYY (GYY4137, 0.25 mg/Kg/day) intra-peritoneally for 8 weeks. In vitro studies were performed using mouse glomerular endothelial cells (MGECs). Results indicated that low levels of H2S and increased expression of NMDA-R1 in diabetes induced Ca2+ permeability, which was ameliorated by H2S treatment. We observed cytosolic Ca2+ influx in hyperglycemic (HG) condition along with mitochondrial (mt)-CypD activation, increased MPTP opening and oxidative outburst, which were mitigated with H2S treatment. Renal injury biomarker, KIM-1 was upregulated in HG condition and normalized following H2S treatment. Inhibition of NMDA-R1 by pharmacological blocker, MK-801 revealed similar results. We conclude that NMDA-R1-mediated Ca2+ influx in diabetes induces MPTP opening via CypD activation leading to increased oxidative stress and renal injury, and H2S protects diabetic kidney from injury by blocking mitochondrial Ca2+ permeability through NMDA-R1 pathway.
    Keywords:  CypD; H2S; KIM-1; NMDA-R1; ROS
    DOI:  https://doi.org/10.1152/ajpendo.00251.2018
  16. CNS Neurosci Ther. 2019 May 02.
    Mechanisms and roles of mitophagy in neurodegenerative diseases.
    Yan Wang, Na Liu, Bingwei Lu.
      Mitochondria are double-membrane-encircled organelles existing in most eukaryotic cells and playing important roles in energy production, metabolism, Ca2+ buffering, and cell signaling. Mitophagy is the selective degradation of mitochondria by autophagy. Mitophagy can effectively remove damaged or stressed mitochondria, which is essential for cellular health. Thanks to the implementation of genetics, cell biology, and proteomics approaches, we are beginning to understand the mechanisms of mitophagy, including the roles of ubiquitin-dependent and receptor-dependent signals on damaged mitochondria in triggering mitophagy. Mitochondrial dysfunction and defective mitophagy have been broadly associated with neurodegenerative diseases. This review is aimed at summarizing the mechanisms of mitophagy in higher organisms and the roles of mitophagy in the pathogenesis of neurodegenerative diseases. Although many studies have been devoted to elucidating the mitophagy process, a deeper understanding of the mechanisms leading to mitophagy defects in neurodegenerative diseases is required for the development of new therapeutic interventions, taking into account the multifactorial nature of diseases and the phenotypic heterogeneity of patients.
    Keywords:  LC3 adapters; PINK1; Parkin; mitochondria; mitophagy; mitophagy receptors; neurodegenerative diseases; ubiquitin
    DOI:  https://doi.org/10.1111/cns.13140
  17. Antioxid Redox Signal. 2019 Apr 30.
    Redox-dependent loss of flavin by mitochondrial complex I in brain ischemia/reperfusion injury.
    Anna Stepanova, Sergei Sosunov, Zoya Niatsetskaya, Csaba Konrad, Anatoly A Starkov, Giovanni Manfredi, Ilka Wittig, Vadim Ten, Alexander Galkin.
      AIMS: Brain ischemia/reperfusion (I/R) is associated with impairment of mitochondrial function. However, the mechanisms of mitochondrial failure are not fully understood. This work was undertaken to determine the mechanisms and time course of mitochondrial energy dysfunction after reperfusion following neonatal brain hypoxia-ischemia (HI) in mice.RESULTS: HI/reperfusion decreased the activity of mitochondrial complex I, which was recovered after 30 min of reperfusion and then declined again after 1 h. Decreased complex I activity occurred in parallel with a loss in the content of non-covalently-bound membrane flavin mononucleotide (FMN). FMN dissociation from the enzyme is caused by succinate-supported reverse electron transfer. Administration of FMN precursor riboflavin prior to HI/reperfusion was associated with decreased infarct volume, attenuation of neurological deficit and preserved complex I activity compared to vehicle-treated mice. In vitro, the rate of FMN release during oxidation of succinate was not affected by the oxygen level and amount of endogenously produced ROS.
    INNOVATION: Our data suggest that dissociation of FMN from mitochondrial complex I may represent a novel mechanism of enzyme inhibition defining respiratory chain failure in I/R. Strategies preventing FMN release during HI and reperfusion may limit the extent of energy failure and cerebral HI injury. The proposed mechanism of acute I/R-induced complex I impairment is distinct from the generally accepted mechanism of oxidative stress-mediated I/R injury.
    CONCLUSION: Our study is the first to highlight a critical role of mitochondrial complex I-FMN dissociation in the development of HI-reperfusion injury of the neonatal brain.
    DOI:  https://doi.org/10.1089/ars.2018.7693
  18. FASEB J. 2019 Apr 29. fj201802754R
    The mitochondrial metabolic function of DJ-1 is modulated by 14-3-3β.
    Maria Weinert, Aurelie Millet, Elizabeth A Jonas, Kambiz N Alavian.
      Mitochondrial metabolic plasticity is a key adaptive mechanism in response to changes in cellular metabolic demand. Changes in mitochondrial metabolic efficiency have been linked to pathophysiological conditions, including cancer, neurodegeneration, and obesity. The ubiquitously expressed DJ-1 (Parkinsonism-associated deglycase) is known as a Parkinson's disease gene and an oncogene. The pleiotropic functions of DJ-1 include reactive oxygen species scavenging, RNA binding, chaperone activity, endocytosis, and modulation of major signaling pathways involved in cell survival and metabolism. Nevertheless, how these functions are linked to the role of DJ-1 in mitochondrial plasticity is not fully understood. In this study, we describe an interaction between DJ-1 and 14-3-3β that regulates the localization of DJ-1, in a hypoxia-dependent manner, either to the cytosol or to mitochondria. This interaction acts as a modulator of mitochondrial metabolic efficiency and a switch between glycolysis and oxidative phosphorylation. Modulation of this novel molecular mechanism of mitochondrial metabolic efficiency is potentially involved in the neuroprotective function of DJ-1 as well as its role in proliferation of cancer cells.-Weinert, M., Millet, A., Jonas, E. A., Alavian, K. N. The mitochondrial metabolic function of DJ-1 is modulated by 14-3-3β.
    Keywords:  metabolic plasticity; mitochondrial efficiency; neuroprotective oncogenes
    DOI:  https://doi.org/10.1096/fj.201802754R
  19. Biochim Biophys Acta Gen Subj. 2019 Apr 26. pii: S0304-4165(19)30079-0. [Epub ahead of print]
    Essential role of O-GlcNAcylation in stabilization of oncogenic factors.
    Vivek Makwana, Philip Ryan, Bhautikkumar Patel, Matt Alteen, Shailendra-Anoopkumar Dukie, David J Vocadlo, Santosh Rudrawar.
      A reversible post-translational protein modification which involves addition of N-acetylglucosamine (GlcNAc) onto hydroxyl groups of serine and/or threonine residues which is known as O-GlcNAcylation, has emerged as a potent competitor of phosphorylation. This glycosyltransfer reaction is catalyzed by the enzyme O-linked β-N-acetylglucosamine transferase (OGT). This enzyme uses uridine diphosphate N-acetylglucosamine (UDP-GlcNAc), the end product of hexosamine biosynthetic pathway, to modify numerous nuclear and cytosolic proteins. O-GlcNAcylation influences cancer cell metabolism in such a way that hyper-O-GlcNAcylation is considered as a prominent trait of many cancers, and is proposed as a major factor enabling cancer cell proliferation and progression. Growing evidence supports a connection between O-GlcNAcylation and major oncogenic factors, including for example, c-MYC, HIF-1α, and NF-κB. A comprehensive study of the roles of O-GlcNAc modification of oncogenic factors is warranted as a thorough understanding may help drive advances in cancer diagnosis and therapy. The focus of this article is to highlight the interplay between oncogenic factors and O-GlcNAcylation along with OGT in cancer cell proliferation and survival. The prospects for OGT inhibitors will also be discussed.
    Keywords:  O-GlcNAcylation; OGT enzyme; OGT inhibitors; Oncogenic factors
    DOI:  https://doi.org/10.1016/j.bbagen.2019.04.002
  20. Nat Commun. 2019 May 03. 10(1): 2059
    STX17 dynamically regulated by Fis1 induces mitophagy via hierarchical macroautophagic mechanism.
    Hongxu Xian, Qiaoyun Yang, Lin Xiao, Han-Ming Shen, Yih-Cherng Liou.
      Mitophagy is the selective autophagic targeting and removal of dysfunctional mitochondria. While PINK1/Parkin-dependent mitophagy is well-characterized, PINK1/Parkin-independent route is poorly understood. Using structure illumination microscopy (SR-SIM), we demonstrate that the SNARE protein Syntaxin 17 (STX17) initiates mitophagy upon depletion of outer mitochondrial membrane protein Fis1. With proteomics analysis, we identify the STX17-Fis1 interaction, which controls the dynamic shuffling of STX17 between ER and mitochondria. Fis1 loss results in aberrant STX17 accumulation on mitochondria, which exposes the N terminus and promotes self-oligomerization to trigger mitophagy. Mitochondrial STX17 interacts with ATG14 and recruits core autophagy proteins to form mitophagosome, followed by Rab7-dependent mitophagosome-lysosome fusion. Furthermore, Fis1 loss impairs mitochondrial respiration and potentially sensitizes cells to mitochondrial clearance, which is mediated through canonical autophagy machinery, closely linking non-selective macroautophagy to mitochondrial turnover. Our findings uncover a PINK1/Parkin-independent mitophagic mechanism in which outer mitochondrial membrane protein Fis1 regulates mitochondrial quality control.
    DOI:  https://doi.org/10.1038/s41467-019-10096-1
  21. Trends Cell Biol. 2019 Apr 25. pii: S0962-8924(19)30050-9. [Epub ahead of print]
    Versatility of Preprotein Transfer from the Cytosol to Mitochondria.
    Thomas Becker, Jiyao Song, Nikolaus Pfanner.
      Mitochondrial biogenesis requires the import of a large number of precursor proteins from the cytosol. Although specific membrane-bound preprotein translocases have been characterized in detail, it was assumed that protein transfer from the cytosol to mitochondria mainly involved unselective binding to molecular chaperones. Recent findings suggest an unexpected versatility of protein transfer to mitochondria. Cytosolic factors have been identified that bind to selected subsets of preproteins and guide them to mitochondrial receptors in a post-translational manner. Cotranslational import processes are emerging. Mechanisms for crosstalk between protein targeting to mitochondria and other cell organelles, in particular the endoplasmic reticulum (ER) and peroxisomes, have been uncovered. We discuss how a network of cytosolic machineries and targeting pathways promote and regulate preprotein transfer into mitochondria.
    Keywords:  Hsp70; J-protein; TOM complex; cotranslational protein import; protein targeting
    DOI:  https://doi.org/10.1016/j.tcb.2019.03.007
  22. Dev Neurobiol. 2019 May 02.
    Quantitative Proteomics of Presynaptic Mitochondria Reveal an Overexpression and Biological Relevance of Neuronal MitoNEET in Postnatal Brain Development.
    Kelly L Stauch, Lance M Villeneuve, Steven Totusek, Benjamin Lamberty, Pawel Ciborowski, Howard S Fox.
      Although it has been recognized that energy metabolism and mitochondrial structure and functional activity in the immature brain differs from that of the adult, few studies have examined mitochondria specifically at the neuronal synapse during postnatal brain development. In this study, we examined the presynaptic mitochondrial proteome in mice at postnatal day 7 and 42, a period that involves the formation and maturation of synapses. Application of two independent quantitative proteomics approaches - SWATH-MS and super-SILAC - revealed a total of 40 proteins as significantly differentially expressed in the presynaptic mitochondria. In addition to elevated levels of proteins known to be involved in ATP metabolic processes, our results identified increased levels of mitoNEET (Cisd1), an iron-sulfur containing protein that regulates mitochondrial bioenergetics. We found that mitoNEET overexpression plays a cell-type specific role in ATP synthesis and in neuronal cells promotes ATP generation. The elevated ATP levels in SH-SY5Y neuroblastoma cells were associated with increased mitochondrial membrane potential and a fragmented mitochondrial network, further supporting a role for mitoNEET as a key regulator of mitochondrial function. This article is protected by copyright. All rights reserved.
    Keywords:  MitoNEET; Mitochondria; Proteomics; Synaptic
    DOI:  https://doi.org/10.1002/dneu.22684
  23. Psychoneuroendocrinology. 2019 Mar 28. pii: S0306-4530(18)31214-9. [Epub ahead of print]106 268-276
    Acute psychological stress increases serum circulating cell-free mitochondrial DNA.
    Caroline Trumpff, Anna L Marsland, Carla Basualto-Alarcón, James L Martin, Judith E Carroll, Gabriel Sturm, Amy E Vincent, Eugene V Mosharov, Zhenglong Gu, Brett A Kaufman, Martin Picard.
      Intrinsic biological mechanisms transduce psychological stress into physiological adaptation that requires energy, but the role of mitochondria and mitochondrial DNA (mtDNA) in this process has not been defined in humans. Here, we show that similar to physical injury, exposure to psychological stress increases serum circulating cell-free mtDNA (ccf-mtDNA) levels. Healthy midlife adults exposed on two separate occasions to a brief psychological challenge exhibited a 2-3-fold increase in ccf-mtDNA, with no change in ccf-nuclear DNA levels, establishing the magnitude and specificity for ccf-mtDNA reactivity. In cell-based studies, we show that glucocorticoid signaling - a consequence of psychological stress in humans - is sufficient to induce mtDNA extrusion in a time frame consistent with stress-induced ccf-mtDNA increase. Collectively, these findings provide evidence that acute psychological stress induces ccf-mtDNA and implicate neuroendocrine signaling as a potential trigger for ccf-mtDNA release. Further controlled work is needed to confirm that observed increases in ccf-mtDNA result from stress exposure and to determine the functional significance of this effect.
    Keywords:  Cell-free DNA; Mitochondria; Mitokine; Neuroendocrine; Psychobiology; Psychosocial stress
    DOI:  https://doi.org/10.1016/j.psyneuen.2019.03.026
  24. Oncogene. 2019 May 01.
    Non-canonical HIF-1 stabilization contributes to intestinal tumorigenesis.
    Nadine Rohwer, Sandra Jumpertz, Merve Erdem, Antje Egners, Klaudia T Warzecha, Athanassios Fragoulis, Anja A Kühl, Rafael Kramann, Sabine Neuss, Ines Rudolph, Tobias Endermann, Christin Zasada, Ivayla Apostolova, Marco Gerling, Stefan Kempa, Russell Hughes, Claire E Lewis, Winfried Brenner, Maciej B Malinowski, Martin Stockmann, Lutz Schomburg, William Faller, Owen J Sansom, Frank Tacke, Markus Morkel, Thorsten Cramer.
      The hypoxia-inducible transcription factor HIF-1 is appreciated as a promising target for cancer therapy. However, conditional deletion of HIF-1 and HIF-1 target genes in cells of the tumor microenvironment can result in accelerated tumor growth, calling for a detailed characterization of the cellular context to fully comprehend HIF-1's role in tumorigenesis. We dissected cell type-specific functions of HIF-1 for intestinal tumorigenesis by lineage-restricted deletion of the Hif1a locus. Intestinal epithelial cell-specific Hif1a loss reduced activation of Wnt/β-catenin, tumor-specific metabolism and inflammation, significantly inhibiting tumor growth. Deletion of Hif1a in myeloid cells reduced the expression of fibroblast-activating factors in tumor-associated macrophages resulting in decreased abundance of tumor-associated fibroblasts (TAF) and robustly reduced tumor formation. Interestingly, hypoxia was detectable only sparsely and without spatial association with HIF-1α, arguing for an importance of hypoxia-independent, i.e., non-canonical, HIF-1 stabilization for intestinal tumorigenesis that has not been previously appreciated. This adds a further layer of complexity to the regulation of HIF-1 and suggests that hypoxia and HIF-1α stabilization can be uncoupled in cancer. Collectively, our data show that HIF-1 is a pivotal pro-tumorigenic factor for intestinal tumor formation, controlling key oncogenic programs in both the epithelial tumor compartment and the tumor microenvironment.
    DOI:  https://doi.org/10.1038/s41388-019-0816-4
  25. Proc Natl Acad Sci U S A. 2019 May 02. pii: 201815360. [Epub ahead of print]
    Circadian clock regulation of the glycogen synthase (gsn) gene by WCC is critical for rhythmic glycogen metabolism in Neurospora crassa.
    Mokryun Baek, Stela Virgilio, Teresa M Lamb, Oneida Ibarra, Juvana Moreira Andrade, Rodrigo Duarte Gonçalves, Andrey Dovzhenok, Sookkyung Lim, Deborah Bell-Pedersen, Maria Celia Bertolini, Christian I Hong.
      Circadian clocks generate rhythms in cellular functions, including metabolism, to align biological processes with the 24-hour environment. Disruption of this alignment by shift work alters glucose homeostasis. Glucose homeostasis depends on signaling and allosteric control; however, the molecular mechanisms linking the clock to glucose homeostasis remain largely unknown. We investigated the molecular links between the clock and glycogen metabolism, a conserved glucose homeostatic process, in Neurospora crassa We find that glycogen synthase (gsn) mRNA, glycogen phosphorylase (gpn) mRNA, and glycogen levels, accumulate with a daily rhythm controlled by the circadian clock. Because the synthase and phosphorylase are critical to homeostasis, their roles in generating glycogen rhythms were investigated. We demonstrate that while gsn was necessary for glycogen production, constitutive gsn expression resulted in high and arrhythmic glycogen levels, and deletion of gpn abolished gsn mRNA rhythms and rhythmic glycogen accumulation. Furthermore, we show that gsn promoter activity is rhythmic and is directly controlled by core clock component white collar complex (WCC). We also discovered that WCC-regulated transcription factors, VOS-1 and CSP-1, modulate the phase and amplitude of rhythmic gsn mRNA, and these changes are similarly reflected in glycogen oscillations. Together, these data indicate the importance of clock-regulated gsn transcription over signaling or allosteric control of glycogen rhythms, a mechanism that is potentially conserved in mammals and critical to metabolic homeostasis.
    Keywords:  Neurospora crassa; circadian rhythms; glycogen metabolism; glycogen phosphorylase; glycogen synthase
    DOI:  https://doi.org/10.1073/pnas.1815360116
  26. Free Radic Res. 2019 May 02. 1-10
    Short-term high salt intake impairs hepatic mitochondrial bioenergetics and biosynthesis in SIRT3 knockout mice.
    Lihan Jiang, Qinghua Chen, Meiling Wu, Tingting Ji, Shanlin Liu, Fengge Zhu, Dongyun Shi.
      High salt intake (HS) is an important factor in the development of many metabolic diseases. The liver is the metabolic center in the body. However, the effect of short-term HS on the liver mitochondria and its mechanism are still unclear. In this study, we investigated the effects of short-term HS on liver mitochondrial function. We found that HS reduced Sirtuin3 (SIRT3) protein level, increasing protein carbonylation in mice liver. HS intake decreased ATP production, mitochondrial transcription factor A (TFAM), and complex I level. SIRT3 knockout (SKO) mice exhibited similar results with HS-treated wild-type mice but with a less extent of carbonylation and ATP reduction. Our study shows that short-term HS led to increased hepatic oxidative state, impaired mitochondrial biosynthesis, and bioenergetics. HS-treated mice could still maintain hepatic glucose homeostasis by compensatory activation of Adenosine 5'-monophosphate-activated protein kinase (AMPK). However, in HS-treated SKO mice, AMPK was not activated, instead, the glycogen synthase activity increased, which caused an exceptionally increased glycogen accumulation. This study provides evidence that short-term HS intake could cause the early hepatic metabolic changes, highlighting the importance of controlling salt intake especially in those patients with defects in SIRT3. Highlights High salt intake down-regulates SIRT3 protein level and increases oxidation. High salt intake activates AMPK via AMP-dependent pathway. High salt intake impairs energy metabolism. High salt combined with SIRT3 knockout results in glycogen accumulation.
    Keywords:  AMPK; ROS; SIRT3; glucose metabolism; high salt; mitochondria
    DOI:  https://doi.org/10.1080/10715762.2019.1580499
  27. Eur J Immunol. 2019 May 03.
    Short-chain fatty acids: Bacterial messengers modulating the immunometabolism of T cells.
    Maik Luu, Alexander Visekruna.
      Short-chain fatty acids (SCFAs) are mainly generated by bacterial fermentation of non-digestible carbohydrates such as dietary fiber. In the last decade, new investigations have revealed that SCFAs have a very specific function and serve as active microbial metabolites, which are able to modulate the function of immune cells in the intestine and other tissues. Recent studies have highlighted the immunomodulatory potential of SCFAs in several autoimmune and inflammatory disorders such as multiple sclerosis, colitis, type 1 diabetes and rheumatoid arthritis. While the SCFA-mediated activation of GPR41/GPR43 signalling pathways and their inhibitory activity on histone deacetylases have been extensively investigated, the impact of SCFAs on the T cell metabolism is poorly understood. SCFAs induce metabolic alterations in T cells by enhancing the activity of the mTOR complex and by regulating their glucose metabolism. Once taken up into T lymphocytes, SCFA-derived acetyl groups contribute to the cellular acetyl-CoA pool, which influences the histone acetylation and cytokine gene expression. This article reviews how SCFAs modulate the metabolic status of T cells, thereby impacting on epigenetic modifications and T cell function. We will also discuss how the recent findings from SCFA biology might be utilized for potential immune therapies of various autoimmune diseases. This article is protected by copyright. All rights reserved.
    Keywords:  CD4+ T cells; immunometabolism; microbiota-host interaction; short-chain fatty acids; therapeutic modulation
    DOI:  https://doi.org/10.1002/eji.201848009
  28. Am J Hum Genet. 2019 May 02. pii: S0002-9297(19)30115-6. [Epub ahead of print]104(5): 784-801
    Disease-Associated Genetic Variation in Human Mitochondrial Protein Import.
    Emmanuelle Nicolas, Rossella Tricarico, Michelle Savage, Erica A Golemis, Michael J Hall.
      Mitochondrial dysfunction has consequences not only for cellular energy output but also for cellular signaling pathways. Mitochondrial dysfunction, often based on inherited gene variants, plays a role in devastating human conditions such as mitochondrial neuropathies, myopathies, cardiovascular disorders, and Parkinson and Alzheimer diseases. Of the proteins essential for mitochondrial function, more than 98% are encoded in the cell nucleus, translated in the cytoplasm, sorted based on the presence of encoded mitochondrial targeting sequences (MTSs), and imported to specific mitochondrial sub-compartments based on the integrated activity of a series of mitochondrial translocases, proteinases, and chaperones. This import process is typically dynamic; as cellular homeostasis is coordinated through communication between the mitochondria and the nucleus, many of the adaptive responses to stress depend on modulation of mitochondrial import. We here describe an emerging class of disease-linked gene variants that are found to impact the mitochondrial import machinery itself or to affect the proteins during their import into mitochondria. As a whole, this class of rare defects highlights the importance of correct trafficking of mitochondrial proteins in the cell and the potential implications of failed targeting on metabolism and energy production. The existence of this variant class could have importance beyond rare neuromuscular disorders, given an increasing body of evidence suggesting that aberrant mitochondrial function may impact cancer risk and therapeutic response.
    DOI:  https://doi.org/10.1016/j.ajhg.2019.03.019
  29. Cell Rep. 2019 Apr 30. pii: S2211-1247(19)30460-7. [Epub ahead of print]27(5): 1376-1386.e6
    Functional Assessment of Lipoyltransferase-1 Deficiency in Cells, Mice, and Humans.
    Min Ni, Ashley Solmonson, Chunxiao Pan, Chendong Yang, Dan Li, Ashley Notzon, Ling Cai, Gerardo Guevara, Lauren G Zacharias, Brandon Faubert, Hieu S Vu, Lei Jiang, Bookyung Ko, Noriko Merida Morales, Jimin Pei, Gonçalo Vale, Dinesh Rakheja, Nick V Grishin, Jeffrey G McDonald, Garrett K Gotway, Markey C McNutt, Juan M Pascual, Ralph J DeBerardinis.
      Inborn errors of metabolism (IEMs) link metabolic defects to human phenotypes. Modern genomics has accelerated IEM discovery, but assessing the impact of genomic variants is still challenging. Here, we integrate genomics and metabolomics to identify a cause of lactic acidosis and epilepsy. The proband is a compound heterozygote for variants in LIPT1, which encodes the lipoyltransferase required for 2-ketoacid dehydrogenase (2KDH) function. Metabolomics reveals abnormalities in lipids, amino acids, and 2-hydroxyglutarate consistent with loss of multiple 2KDHs. Homozygous knockin of a LIPT1 mutation reduces 2KDH lipoylation in utero and results in embryonic demise. In patient fibroblasts, defective 2KDH lipoylation and function are corrected by wild-type, but not mutant, LIPT1 alleles. Isotope tracing reveals that LIPT1 supports lipogenesis and balances oxidative and reductive glutamine metabolism. Altogether, the data extend the role of LIPT1 in metabolic regulation and demonstrate how integrating genomics and metabolomics can uncover broader aspects of IEM pathophysiology.
    Keywords:  2-ketoacid dehydrogenase; epilepsy,developmental delay; fatty acid oxidation; genomics; inborn errors of metabolism; lactic acidosis; lipogenesis; lipoylation; metabolomics
    DOI:  https://doi.org/10.1016/j.celrep.2019.04.005
  30. Nat Rev Drug Discov. 2019 Mar 27.
    Targeting cancer cell metabolism in glioblastoma.
    Sarah Crunkhorn.
      
    DOI:  https://doi.org/10.1038/d41573-019-00054-3
  31. Commun Biol. 2019 ;2 152
    Secreted parasite Pin1 isomerase stabilizes host PKM2 to reprogram host cell metabolism.
    Justine Marsolier, Martine Perichon, Jonathan B Weitzman, Souhila Medjkane.
      Metabolic reprogramming is an important feature of host-pathogen interactions and a hallmark of tumorigenesis. The intracellular apicomplexa parasite Theileria induces a Warburg-like effect in host leukocytes by hijacking signaling machineries, epigenetic regulators and transcriptional programs to create a transformed cell state. The molecular mechanisms underlying host cell transformation are unclear. Here we show that a parasite-encoded prolyl-isomerase, TaPin1, stabilizes host pyruvate kinase isoform M2 (PKM2) leading to HIF-1α-dependent regulation of metabolic enzymes, glucose uptake and transformed phenotypes in parasite-infected cells. Our results provide a direct molecular link between the secreted parasite TaPin1 protein and host gene expression programs. This study demonstrates the importance of prolyl isomerization in the parasite manipulation of host metabolism.
    Keywords:  Cancer metabolism; Cell signalling
    DOI:  https://doi.org/10.1038/s42003-019-0386-6
  32. Cancer Res. 2019 Apr 30. pii: canres.3527.2018. [Epub ahead of print]
    LKB1 and KEAP1/NRF2 pathways cooperatively promote metabolic reprogramming with enhanced glutamine dependence in KRAS-mutant lung adenocarcinoma.
    Ana Galan-Cobo, Piyada Sitthideatphaiboon, Xiao Qu, Alissa Poteete, Marlese A Pisegna, Pan Tong, Pei-Hsuan Chen, Lindsey K Boroughs, Mirna L M Rodriguez, Winter Zhang, Francesco Parlati, Jing Wang, Varsha Gandhi, Ferdinandos Skoulidis, Ralph J DeBerardinis, John D Minna, John V Heymach.
      In KRAS-mutant lung adenocarcinoma, tumors with LKB1 loss (KL) are highly enriched for concurrent KEAP1 mutations, which activate the KEAP1/NRF2 pathway (KLK). Here we investigated the biological consequences of these co-occurring alterations and explored whether they conferred specific therapeutic vulnerabilities. Compared with KL tumors, KLK tumors exhibited increased expression of genes involved in glutamine metabolism, the tricarboxylic acid cycle, and the redox homeostasis signature. Using isogenic pairs with knockdown or overexpression of LKB1, KEAP1, and NRF2, we found that LKB1 loss results in increased energetic and redox stress marked by increased levels of intracellular ROS and decreased levels of ATP, NADPH/NADP+ ratio, and glutathione. Activation of the KEAP1/NRF2 axis in LKB1-deficient cells enhanced cell survival and played a critical role in the maintenance of energetic and redox homeostasis in a glutamine-dependent manner. LKB1 and the KEAP1/NRF2 pathways cooperatively drove metabolic reprogramming and enhanced sensitivity to the glutaminase inhibitor CB-839 in vitro and in vivo. Overall, these findings elucidate the adaptive advantage provided by KEAP1/NRF2 pathway activation in KL tumors and support clinical testing of glutaminase inhibitor in subsets of KRAS-mutant lung adenocarcinoma.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-18-3527
  33. Nat Commun. 2019 May 02. 10(1): 2030
    MEK1/2 inhibitor withdrawal reverses acquired resistance driven by BRAFV600E amplification whereas KRASG13D amplification promotes EMT-chemoresistance.
    Matthew J Sale, Kathryn Balmanno, Jayeta Saxena, Eiko Ozono, Katarzyna Wojdyla, Rebecca E McIntyre, Rebecca Gilley, Anna Woroniuk, Karen D Howarth, Gareth Hughes, Jonathan R Dry, Mark J Arends, Pilar Caro, David Oxley, Susan Ashton, David J Adams, Julio Saez-Rodriguez, Paul D Smith, Simon J Cook.
      Acquired resistance to MEK1/2 inhibitors (MEKi) arises through amplification of BRAFV600E or KRASG13D to reinstate ERK1/2 signalling. Here we show that BRAFV600E amplification and MEKi resistance are reversible following drug withdrawal. Cells with BRAFV600E amplification are addicted to MEKi to maintain a precise level of ERK1/2 signalling that is optimal for cell proliferation and survival, and tumour growth in vivo. Robust ERK1/2 activation following MEKi withdrawal drives a p57KIP2-dependent G1 cell cycle arrest and senescence or expression of NOXA and cell death, selecting against those cells with amplified BRAFV600E. p57KIP2 expression is required for loss of BRAFV600E amplification and reversal of MEKi resistance. Thus, BRAFV600E amplification confers a selective disadvantage during drug withdrawal, validating intermittent dosing to forestall resistance. In contrast, resistance driven by KRASG13D amplification is not reversible; rather ERK1/2 hyperactivation drives ZEB1-dependent epithelial-to-mesenchymal transition and chemoresistance, arguing strongly against the use of drug holidays in cases of KRASG13D amplification.
    DOI:  https://doi.org/10.1038/s41467-019-09438-w
  34. J Neurochem. 2019 Apr 29.
    Metabolic constraints of swelling-activated glutamate release in astrocytes and their implication for ischemic tissue damage.
    Corinne S Wilson, Martin D Bach, Zahra Ashkavand, Kenneth R Norman, Nina Martino, Alejandro P Adam, Alexander A Mongin.
      Volume-regulated anion channel (VRAC) is a glutamate-permeable channel that is activated by physiological and pathological cell swelling and promotes ischemic brain damage. However, because VRAC opening requires cytosolic ATP, it is not clear if and how its activity is sustained in the metabolically compromised CNS. In the present study, we used cultured astrocytes - the cell type which shows prominent swelling in stroke - to model how metabolic stress and changes in gene expression may impact VRAC function in the ischemic and post-ischemic brain. The metabolic state of primary rat astrocytes was modified with chemical inhibitors and examined using luciferin-luciferase ATP assays and a Seahorse analyzer. Swelling-activated glutamate release was quantified with the radiotracer D-[3 H]aspartate. The specific contribution of VRAC to swelling-activated glutamate efflux was validated by RNAi knockdown of the essential subunit, leucine-rich repeat-containing 8A (LRRC8A); expression levels of VRAC components were measured with qRT-PCR. Using this methodology, we found that complete metabolic inhibition with the glycolysis blocker 2-deoxy-D-glucose and the mitochondrial poison sodium cyanide reduced astrocytic ATP levels by >90% and abolished glutamate release from swollen cells (via VRAC). When only mitochondrial respiration was inhibited by cyanide or rotenone, the intracellular ATP levels and VRAC activity were largely preserved. Bypassing glycolysis by providing the mitochondrial substrates pyruvate and/or glutamine led to partial recovery of ATP levels and VRAC activity. Unexpectedly, the metabolic block of VRAC was overridden when ATP-depleted cells were exposed to extreme cell swelling (≥50% reduction in medium osmolarity). 24-h anoxic adaptation caused a moderate reduction in the expression levels of the VRAC component LRRC8A, but no significant changes in VRAC activity. Overall, our findings suggest that (1) astrocytic VRAC activity metabolism can be sustained by low levels of glucose and (2) the inhibitory influence of diminishing ATP levels and the stimulatory effect of cellular swelling are the two major factors that govern VRAC activity in the ischemic brain. This article is protected by copyright. All rights reserved.
    Keywords:  LRRC8; metabolic inhibition, cerebral ischemia; stroke; volume-regulated anion channel
    DOI:  https://doi.org/10.1111/jnc.14711
  35. J Biol Chem. 2019 Apr 30. pii: jbc.RA119.008180. [Epub ahead of print]
    Dual inhibition of glutaminase and carnitine palmitoyltransferase decreases growth and migration of glutaminase inhibition-resistant triple-negative breast cancer cells.
    Larissa Menezes Dos Reis, Douglas Adamoski, Rodolpho Ornitz Oliveira Souza, Carolline Fernanda Rodrigues Ascenção, Krishina Ratna Sousa de Oliveira, Felipe Corrêa-da-Silva, Fábio Malta de Sá Patroni, Marília Meira Dias, Sílvio Roberto Consonni, Pedro Manoel Mendes de Moraes-Vieira, Ariel Mariano Silber, Sandra Martha Gomes Dias.
      Triple-negative breast cancers (TNBCs) lack progesterone and estrogen receptors and do not have amplified human epidermal growth factor receptor 2, the main therapeutic targets for managing breast cancer. TNBCs have an altered metabolism, including an increased Warburg effect and glutamine dependence, making the glutaminase inhibitor CB-839 therapeutically promising for this tumor type. Accordingly, CB-839 is currently in phase I/II clinical trials. However, not all TNBCs respond to CB-839 treatment, with the tumor resistance mechanism not fully understood yet. Here, we classified cell lines as CB-839 sensitive or resistant according to their growth responses to CB-839. Compared with sensitive cells, resistant cells were less glutaminolytic and, upon CB-839 treatment, exhibited a smaller decrease in ATP content and less mitochondrial fragmentation, an indicator of poor mitochondrial health. Transcriptional analyses revealed that the expression levels of genes linked to lipid metabolism were altered between the sensitive and resistant cells and between breast cancer tissues (available from The Cancer Genome Atlas project) with low versus high glutaminase (GLS) gene expression. Of note, CB-839-resistant TNBC cells had increased carnitine palmitoyltransferase 2 (CPT2) protein and CPT1 activity levels. In agreement, CB-839-resistant TNBC cells mobilized more fatty acid into mitochondria for oxidation, which responded to AMP-activated protein kinase and acetyl-CoA carboxylase signaling. Moreover, chemical inhibition of both glutaminase and CPT1 decreased cell proliferation and migration of CB-839-resistant cells compared with single inhibition of each enzyme. We propose that dual targeting of glutaminase and CPT1 activities may have therapeutic relevance for managing CB-839-resistant tumors.
    Keywords:  CB-839; CPT1; CPT2; beta-oxidation; breast cancer; cancer therapy; energy metabolism; etomoxir; glutaminase
    DOI:  https://doi.org/10.1074/jbc.RA119.008180
  36. PLoS One. 2019 ;14(5): e0216385
    An old medicine as a new drug to prevent mitochondrial complex I from producing oxygen radicals.
    Dominique Detaille, Philippe Pasdois, Audrey Sémont, Pierre Dos Santos, Philippe Diolez.
      FINDINGS: Here, we demonstrate that OP2113 (5-(4-Methoxyphenyl)-3H-1,2-dithiole-3-thione, CAS 532-11-6), synthesized and used as a drug since 1696, does not act as an unspecific antioxidant molecule (i.e., as a radical scavenger) but unexpectedly decreases mitochondrial reactive oxygen species (ROS/H2O2) production by acting as a specific inhibitor of ROS production at the IQ site of complex I of the mitochondrial respiratory chain. Studies performed on isolated rat heart mitochondria also showed that OP2113 does not affect oxidative phosphorylation driven by complex I or complex II substrates. We assessed the effect of OP2113 on an infarct model of ex vivo rat heart in which mitochondrial ROS production is highly involved and showed that OP2113 protects heart tissue as well as the recovery of heart contractile activity.CONCLUSION / SIGNIFICANCE: This work represents the first demonstration of a drug authorized for use in humans that can prevent mitochondria from producing ROS/H2O2. OP2113 therefore appears to be a member of the new class of mitochondrial ROS blockers (S1QELs) and could protect mitochondrial function in numerous diseases in which ROS-induced mitochondrial dysfunction occurs. These applications include but are not limited to aging, Parkinson's and Alzheimer's diseases, cardiac atrial fibrillation, and ischemia-reperfusion injury.
    DOI:  https://doi.org/10.1371/journal.pone.0216385
  37. Sci Adv. 2019 Apr;5(4): eaav1110
    An aerobic eukaryotic parasite with functional mitochondria that likely lacks a mitochondrial genome.
    Uwe John, Yameng Lu, Sylke Wohlrab, Marco Groth, Jan Janouškovec, Gurjeet S Kohli, Felix C Mark, Ulf Bickmeyer, Sarah Farhat, Marius Felder, Stephan Frickenhaus, Laure Guillou, Patrick J Keeling, Ahmed Moustafa, Betina M Porcel, Klaus Valentin, Gernot Glöckner.
      Dinoflagellates are microbial eukaryotes that have exceptionally large nuclear genomes; however, their organelle genomes are small and fragmented and contain fewer genes than those of other eukaryotes. The genus Amoebophrya (Syndiniales) comprises endoparasites with high genetic diversity that can infect other dinoflagellates, such as those forming harmful algal blooms (e.g., Alexandrium). We sequenced the genome (~100 Mb) of Amoebophrya ceratii to investigate the early evolution of genomic characters in dinoflagellates. The A. ceratii genome encodes almost all essential biosynthetic pathways for self-sustaining cellular metabolism, suggesting a limited dependency on its host. Although dinoflagellates are thought to have descended from a photosynthetic ancestor, A. ceratii appears to have completely lost its plastid and nearly all genes of plastid origin. Functional mitochondria persist in all life stages of A. ceratii, but we found no evidence for the presence of a mitochondrial genome. Instead, all mitochondrial proteins appear to be lost or encoded in the A. ceratii nucleus.
    DOI:  https://doi.org/10.1126/sciadv.aav1110
  38. Biochem J. 2019 Apr 29. pii: BCJ20190057. [Epub ahead of print]
    Slc25a36 modulates pluripotency of mouse embryonic stem cells by regulating mitochondrial function and glutathione level.
    Yanli Xin, Yanliang Wang, Liang Zhong, Bingbo Shi, Hui Liang, Jianyong Han.
      Mitochondria play a central role in the maintenance of the naïve state of embryonic stem cells. Many details of the mechanism remain to be fully elucidate. Solute carrier family 25 member 36 ( Slc25a36 ) might regulate mitochondrial function through transporting pyrimidine nucleotides for mtDNA/RNA synthesis. Its physical role in this process remains unknown; however, Slc25a36 was recently found to be highly expressed in naïve mouse embryonic stem cells (mESCs). Here, the function of Slc25a36 was characterized as a maintenance factor of mESCs pluripotency. Slc25a36 deficiency (via knockdown) has been demonstrated to result in mitochondrial dysfunction, which induces the differentiation of mESCs. The expression of key pluripotency markers ( Pou5f1 , Sox2 , Nanog and Utf1 ) decreased, while that of key TE genes ( Cdx2 , Gata3 , and Hand1 ) increased. Cdx2 positive cells emerged in Slc25a3 6 deficient colonies under trophoblast stem cell culture conditions. As a result of Slc25a3 6 deficiency, mtDNA of knockdown cells declined, leading to impaired mitochondria with swollen morphology, decreased mitochondrial membrane potential and low numbers. The key transcription regulators of mitochondrial biogenesis also decreased. These results indicate that mitochondrial dysfunction leads to an inability to support the pluripotency maintenance. Moreover, down-regulated glutathione metabolism and up-regulated focal adhesion reinforced and stabilized the process of differentiation by separately enhancing OCT4 degradation and promoting cell spread. This study improves the understanding of the function of Slc25a36 , as well as the relationship of mitochondrial function with naïve pluripotency maintenance and stem cell fate decision.
    Keywords:  Focal adhesion; Glutathione metabolism; Mitochondria membrane potential; Murine embryonic stem cell; Pluripotency; Slc25a36
    DOI:  https://doi.org/10.1042/BCJ20190057
  39. iScience. 2019 Apr 23. pii: S2589-0042(19)30120-8. [Epub ahead of print]15 109-118
    Identification of Kinases Responsible for p53-Dependent Autophagy.
    Stephanie L Celano, Lisette P Yco, Matthew G Kortus, Abigail R Solitro, Hakan Gunaydin, Mark Scott, Edward Spooner, Ronan C O'Hagan, Peter Fuller, Katie R Martin, Stuart D Shumway, Jeffrey P MacKeigan.
      In cancer, autophagy is upregulated to promote cell survival and tumor growth during times of nutrient stress and can confer resistance to drug treatments. Several major signaling networks control autophagy induction, including the p53 tumor suppressor pathway. In response to DNA damage and other cellular stresses, p53 is stabilized and activated, while HDM2 binds to and ubiquitinates p53 for proteasome degradation. Thus blocking the HDM2-p53 interaction is a promising therapeutic strategy in cancer; however, the potential survival advantage conferred by autophagy induction may limit therapeutic efficacy. In this study, we leveraged an HDM2 inhibitor to identify kinases required for p53-dependent autophagy. Interestingly, we discovered that p53-dependent autophagy requires several kinases, including the myotonic dystrophy protein kinase-like alpha (MRCKα). MRCKα is a CDC42 effector reported to activate actin-myosin cytoskeletal reorganization. Overall, this study provides evidence linking MRCKα to autophagy and reveals additional insights into the role of kinases in p53-dependent autophagy.
    Keywords:  Biological Sciences; Cell Biology; Functional Aspects of Cell Biology
    DOI:  https://doi.org/10.1016/j.isci.2019.04.023
  40. Nucleic Acids Res. 2019 May 02. pii: gkz277. [Epub ahead of print]
    The mitochondrial R-loop.
    Ian J Holt.
      The DNA in mitochondria contributes essential components of the organelle's energy producing machinery that is essential for life. In 1971, many mitochondrial DNA molecules were found to have a third strand of DNA that maps to a region containing critical regulatory elements for transcription and replication. Forty-five years later, a third strand of RNA in the same region has been reported. This mitochondrial R-loop is present on thousands of copies of mitochondrial DNA per cell making it potentially the most abundant R-loop in nature. Here, I assess the discovery of the mitochondrial R-loop, discuss why it remained unrecognized for almost half a century and propose for it central roles in the replication, organization and expression of mitochondrial DNA, which if compromised can lead to disease states.
    DOI:  https://doi.org/10.1093/nar/gkz277
  41. Curr Opin Struct Biol. 2019 Apr 27. pii: S0959-440X(18)30131-3. [Epub ahead of print]57 135-144
    Structural changes in the transport cycle of the mitochondrial ADP/ATP carrier.
    Jonathan J Ruprecht, Edmund Rs Kunji.
      The mitochondrial ADP/ATP carrier, also called adenine nucleotide translocase, accomplishes one of the most important transport activities in eukaryotic cells, importing ADP into the mitochondrial matrix for ATP synthesis, and exporting ATP to fuel cellular activities. In the transport cycle, the carrier changes between a cytoplasmic and matrix state, in which the central substrate binding site is alternately accessible to these compartments. A structure of a cytoplasmic state was known, but recently, a structure of a matrix-state in complex with bongkrekic acid was solved. Comparison of the two states explains the function of highly conserved sequence features and reveals that the transport mechanism is unique, involving the coordinated movement of six dynamic elements around a central translocation pathway.
    DOI:  https://doi.org/10.1016/j.sbi.2019.03.029
  42. Front Cell Dev Biol. 2019 ;7 54
    Editorial: Mitochondrial Communication in Physiology, Disease and Aging.
    Nuno Raimundo, Anita Krisko.
      
    Keywords:  age-related disease; aging; endoplasmic reticulum; lysosome; mitochondria
    DOI:  https://doi.org/10.3389/fcell.2019.00054
  43. Cancer Discov. 2019 May 03.
    NAD Metabolic Dependency Determines Therapeutic Sensitivity in Cancer.
      Cancer cells exhibit tissue-specific dependencies on various NAD biosynthetic pathways for survival.
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2019-067
  44. Cell Cycle. 2019 Apr 28.
    Mitochondrial calcium uniporter complex modulation in cancerogenesis.
    Saverio Marchi, Veronica Angela Maria Vitto, Alberto Danese, Mariusz R Wieckowski, Carlotta Giorgi, Paolo Pinton.
      Aberrations in mitochondrial Ca2+ homeostasis have been associated with different pathological conditions, including neurological defects, cardiovascular diseases, and, in the last years, cancer. With the recent molecular identification of the mitochondrial calcium uniporter (MCU) complex, the channel that allows Ca2+ accumulation into the mitochondrial matrix, alterations in the expression levels or functioning in one or more MCU complex members have been linked to different cancers and cancer-related phenotypes. In this review, we will analyze the role of the uniporter and mitochondrial Ca2+ derangements in modulating cancer cell sensitivity to death, invasiveness and migratory capacity, as well as cancer progression in vivo. We will also discuss some critical points and contradictory results to highlight the consequence of MCU complex modulation in tumor development. Mitochondrial calcium and cancer.
    DOI:  https://doi.org/10.1080/15384101.2019.1612698
  45. J Biol Chem. 2019 Apr 30. pii: jbc.RA119.007841. [Epub ahead of print]
    The quantitative relationship between isotopic and net contributions of lactate and glucose to the TCA cycle.
    Minfeng Ying, Cheng Guo, Xun Hu.
      Whether growing cancer cells prefer lactate as a fuel over glucose or vice versa is an important yet controversial issue. Labeling of tricarboxylic acid (TCA) cycle intermediates with glucose or lactate isotope tracers is often used to report the relative contributions of these two metabolites to the TCA cycle. However, this approach may not yield accurate results, as isotopic labeling may not accurately reflect net contributions of each metabolite. This may be due to isotopic exchange occurring during the conversion between pyruvate and lactate. To evaluate this quantitatively, we used an equation (CG - CG' = CL' - CL) assessing the relationship between isotopic labeling and net consumption measurements in vitro. CG and CL refer to the contributions of glucose and lactate to the TCA cycle as measured by their net consumption, whereas CG' and CL' refer to glucose and lactate's contributions determined with isotopic labeling. We found that the isotopic labeling data overestimate the net contribution of lactate to the TCA cycle and underestimate that of glucose. The overestimated amount is equal to the isotopic exchange amount between pyruvate and lactate. After excluding the interference of isotopic exchange, the major carbon contribution (i.e. acetyl-CoA) to the TCA cycle comes from glucose rather than lactate in vitro. We propose that these relative contributions of glucose and lactate may also be present in cancer cells in vivo.
    Keywords:  13C-labeling; glucose; isotope exchange; isotopic tracer; lactic acid; metabolic flux; net contribution; tricarboxylic acid cycle (TCA cycle) (Krebs cycle); tumor metabolism
    DOI:  https://doi.org/10.1074/jbc.RA119.007841
  46. J Am Soc Nephrol. 2019 May 01. pii: ASN.2018090950. [Epub ahead of print]
    Protein O-GlcNAcylation Is Essential for the Maintenance of Renal Energy Homeostasis and Function via Lipolysis during Fasting and Diabetes.
    Sho Sugahara, Shinji Kume, Masami Chin-Kanasaki, Issei Tomita, Mako Yasuda-Yamahara, Kosuke Yamahara, Naoko Takeda, Norihisa Osawa, Motoko Yanagita, Shin-Ichi Araki, Hiroshi Maegawa.
      BACKGROUND: Energy metabolism in proximal tubular epithelial cells (PTECs) is unique, because ATP production largely depends on lipolysis in both the fed and fasting states. Furthermore, disruption of renal lipolysis is involved in the pathogenesis of diabetic tubulopathy. Emerging evidence suggests that protein O-GlcNAcylation, an intracellular nutrient-sensing system, may regulate a number of metabolic pathways according to changes in nutritional status. Although O-GlcNAcylation in PTECs has been demonstrated experimentally, its precise role in lipolysis in PTECs is unclear.METHODS: To investigate the mechanism of renal lipolysis in PTECs-specifically, the role played by protein O-GlcNAcylation-we generated mice with PTECs deficient in O-GlcNAc transferase (Ogt). We analyzed their renal phenotypes during ad libitum feeding, after prolonged fasting, and after mice were fed a high-fat diet for 16 weeks to induce obesity and diabetes.
    RESULTS: Although PTEC-specific Ogt-deficient mice lacked a marked renal phenotype during ad libitum feeding, after fasting 48 hours, they developed Fanconi syndrome-like abnormalities, PTEC apoptosis, and lower rates of renal lipolysis and ATP production. Proteomic analysis suggested that farnesoid X receptor-dependent upregulation of carboxylesterase-1 is involved in O-GlcNAcylation's regulation of lipolysis in fasted PTECs. PTEC-specific Ogt-deficient mice with diabetes induced by a high-fat diet developed severe tubular cell damage and enhanced lipotoxicity.
    CONCLUSIONS: Protein O-GlcNAcylation is essential for renal lipolysis during prolonged fasting and offers PTECs significant protection against lipotoxicity in diabetes.
    Keywords:  diabetes mellitus; lipids; obesity; renal proximal tubule cell
    DOI:  https://doi.org/10.1681/ASN.2018090950
  47. J Biol Chem. 2019 May 01. pii: jbc.RA118.004426. [Epub ahead of print]
    Tyrosine aminotransferase is involved in the oxidative stress response by metabolizing meta-tyrosine in Caenorhabditis elegans.
    Brett R Ipson, Rebecca A Green, John T Wilson, Jacob N Watson, Kym F Faull, Alfred L Fisher.
      Under oxidative stress conditions, hydroxyl radicals can oxidize the phenyl ring of phenylalanine producing the abnormal tyrosine isomer meta-tyrosine (m-tyrosine). m-Tyrosine levels are commonly used as a biomarker of oxidative stress, and its accumulation has recently been reported to adversely affect cells, suggesting a direct role for m-tyrosine in oxidative stress effects. We found that the Caenorhabditis elegans ortholog of tyrosine aminotransferase (TATN-1)-the first enzyme involved in the metabolic degradation of tyrosine-is up-regulated in response to oxidative stress and directly activated by the oxidative stress-responsive transcription factor SKN-1. Worms deficient in tyrosine aminotransferase activity displayed increased sensitivity to multiple sources of oxidative stress. Biochemical assays revealed that m-tyrosine is a substrate for TATN-1-mediated deamination, suggesting that TATN-1 also metabolizes m-tyrosine. Consistent with a toxic effect of m-tyrosine and a protective function of TATN-1, tatn-1 mutant worms exhibited delayed development, marked reduction in fertility, and shortened lifespan when exposed to m-tyrosine. A forward genetic screen identified a mutation in the previously uncharacterized gene F01D4.5-homologous with human transcription factor 20 (TCF20) and retinoic acid induced 1 (RAI1)-that suppresses the adverse phenotypes observed in m-tyrosine-treated tatn-1 mutant worms. RNA-Seq analysis of F01D4.5 mutant worms disclosed a significant reduction in the expression of specific isoforms of genes encoding ribosomal proteins, suggesting that alterations in protein synthesis or ribosome structure could diminish the adverse effects of m-tyrosine. Our findings uncover a critical role for tyrosine aminotransferase in the oxidative stress response via m-tyrosine metabolism.
    Keywords:  aging; amino acid; gene expression; meta-tyrosine; oxidative stress; ribosome; tyrosine; tyrosine aminotransferase
    DOI:  https://doi.org/10.1074/jbc.RA118.004426
  48. Nat Biomed Eng. 2019 Apr 29.
    Spectral tracing of deuterium for imaging glucose metabolism.
    Luyuan Zhang, Lingyan Shi, Yihui Shen, Yupeng Miao, Mian Wei, Naixin Qian, Yinong Liu, Wei Min.
      Cells and tissues often display pronounced spatial and dynamical metabolic heterogeneity. Common glucose-imaging techniques report glucose uptake or catabolism activity, yet do not trace the functional utilization of glucose-derived anabolic products. Here we report a microscopy technique for the optical imaging, via the spectral tracing of deuterium (STRIDE), of diverse macromolecules derived from glucose. Based on stimulated Raman-scattering imaging, STRIDE visualizes the metabolic dynamics of newly synthesized macromolecules, such as DNA, protein, lipids and glycogen, via the enrichment and distinct spectra of carbon-deuterium bonds transferred from the deuterated glucose precursor. STRIDE can also use spectral differences derived from different glucose isotopologues to visualize temporally separated glucose populations using a pulse-chase protocol. We also show that STRIDE can be used to image glucose metabolism in many mouse tissues, including tumours, brain, intestine and liver, at a detection limit of 10 mM of carbon-deuterium bonds. STRIDE provides a high-resolution and chemically informative assessment of glucose anabolic utilization.
    DOI:  https://doi.org/10.1038/s41551-019-0393-4
  49. Cell Death Dis. 2019 May 01. 10(5): 354
    nNOS/GSNOR interaction contributes to skeletal muscle differentiation and homeostasis.
    Costanza Montagna, Salvatore Rizza, Claudia Cirotti, Emiliano Maiani, Maurizio Muscaritoli, Antonio Musarò, Maria Teresa Carrí, Elisabetta Ferraro, Francesco Cecconi, Giuseppe Filomeni.
      Neuronal nitric oxide synthase (nNOS) plays a crucial role in the maintenance of correct skeletal muscle function due, at least in part, to S-nitrosylation of specific protein targets. Similarly, we recently provided evidence for a muscular phenotype in mice lacking the denitrosylase S-nitrosoglutathione reductase (GSNOR). Here, we demonstrate that nNOS and GSNOR are concomitantly expressed during differentiation of C2C12. They colocalizes at the sarcolemma and co-immunoprecipitate in cells and in myofibers. We also provide evidence that GSNOR expression decreases in mouse models of muscular dystrophies and of muscle atrophy and wasting, i.e., aging and amyotrophic lateral sclerosis, suggesting a more general regulatory role of GSNOR in skeletal muscle homeostasis.
    DOI:  https://doi.org/10.1038/s41419-019-1584-3
  50. Nat Commun. 2019 May 03. 10(1): 2042
    Akt and STAT5 mediate naïve human CD4+ T-cell early metabolic response to TCR stimulation.
    Nicholas Jones, Emma E Vincent, James G Cronin, Silvia Panetti, Megan Chambers, Sean R Holm, Sian E Owens, Nigel J Francis, David K Finlay, Catherine A Thornton.
      Metabolic pathways that regulate T-cell function show promise as therapeutic targets in diverse diseases. Here, we show that at rest cultured human effector memory and central memory CD4+ T-cells have elevated levels of glycolysis and oxidative phosphorylation (OXPHOS), in comparison to naïve T-cells. Despite having low resting metabolic rates, naive T-cells respond to TCR stimulation with robust and rapid increases in glycolysis and OXPHOS. This early metabolic switch requires Akt activity to support increased rates of glycolysis and STAT5 activity for amino acid biosynthesis and TCA cycle anaplerosis. Importantly, both STAT5 inhibition and disruption of TCA cycle anaplerosis are associated with reduced IL-2 production, demonstrating the functional importance of this early metabolic program. Our results define STAT5 as a key node in modulating the early metabolic program following activation in naive CD4+ T-cells and in turn provide greater understanding of how cellular metabolism shapes T-cell responses.
    DOI:  https://doi.org/10.1038/s41467-019-10023-4
  51. J Biol Chem. 2019 Apr 29. pii: jbc.RA118.007122. [Epub ahead of print]
    The histone demethylase JMJD2B is critical for p53-mediated autophagy and survival in nutlin-treated cancer cells.
    Lei Duan, Ricardo E Perez, Xin Lai, Ling Chen, Carl G Maki.
      Autophagy promotes cancer cell survival in response to p53 activation by the anticancer agent Nutlin-3a (Nutlin). We previously reported that Nutlin kills MDM2-amplified cancer cells and that this killing is associated with an inhibition of glucose metabolism, reduced alpha-ketoglutarate (α-KG) levels, and reduced autophagy. In the current report, using SJSA1, U2OS, A549, and MHM cells, we found that Nutlin alters histone methylation in an MDM2 proto-oncogene (MDM2)-dependent manner and that this, in turn, regulates autophagy-related gene (ATG) expression and cell death. In MDM2-amplified cells, Nutlin increased histone (H) 3 lysine (K) 9 and K36 trimethylation (me3) coincident with reduced autophagy and increased apoptosis. Blocking histone methylation restored autophagy and rescued these cells from Nutlin-induced killing. In MDM2-nonamplified cells, H3K9me3 and H3K36me3 levels were either reduced or not changed by the Nutlin treatment, and this coincided with increased autophagy and cell survival. Blocking histone demethylation reduced autophagy and sensitized these cells to Nutlin-induced killing. Further experiments suggested that MDM2 amplification increases histone methylation in Nutlin-treated cells by causing depletion of the histone demethylase Jumonji domain-containing protein 2B (JMJD2B). Finally, JMJD2B knockdown or inhibition increased H3K9/K36me3 levels, decreased ATG gene expression and autophagy, and sensitized MDM2-nonamplified cells to apoptosis. Together, these results support a model in which MDM2- and JMJD2B-regulated histone methylation levels modulate ATG gene expression, autophagy, and cell fate in response to the MDM2 antagonist Nutlin-3a.
    Keywords:  ATG16L1; ULK1; autophagy; histone demethylase; histone methylation; mouse double minute 2 homolog (MDM2); p53
    DOI:  https://doi.org/10.1074/jbc.RA118.007122
  52. J Mol Cell Cardiol. 2019 Apr 24. pii: S0022-2828(18)31228-8. [Epub ahead of print]
    cAMP/PKA signaling compartmentalization in cardiomyocytes: Lessons from FRET-based biosensors.
    Alessandra Ghigo, Delphine Mika.
      3',5'-cyclic adenosine monophosphate (cAMP) is a ubiquitous second messenger produced in response to the stimulation of G protein-coupled receptors (GPCRs). It regulates a plethora of pathophysiological processes in different organs, including the cardiovascular system. It is now clear that cAMP is not uniformly distributed within cardiac myocytes but confined in specific subcellular compartments where it modulates key players of the excitation-contraction coupling as well as other processes including gene transcription, mitochondrial homeostasis and cell death. This review will cover the major cAMP microdomains in cardiac myocytes. We will describe recent work using pioneering tools developed for investigating the organization and the function of the major cAMP microdomains in cardiomyocytes, including the plasma membrane, the sarcoplasmic reticulum, the myofilaments, the nucleus and the mitochondria.
    Keywords:  Biosensor; Compartmentalization; Cyclic AMP; FRET; Microdomain
    DOI:  https://doi.org/10.1016/j.yjmcc.2019.04.020
  53. Cell. 2019 May 02. pii: S0092-8674(19)30396-4. [Epub ahead of print]177(4): 881-895.e17
    Deficient Endoplasmic Reticulum-Mitochondrial Phosphatidylserine Transfer Causes Liver Disease.
    María Isabel Hernández-Alvarez, David Sebastián, Sara Vives, Saška Ivanova, Paola Bartoccioni, Pamela Kakimoto, Natalia Plana, Sónia R Veiga, Vanessa Hernández, Nuno Vasconcelos, Gopal Peddinti, Anna Adrover, Mariona Jové, Reinald Pamplona, Isabel Gordaliza-Alaguero, Enrique Calvo, Noemí Cabré, Rui Castro, Antonija Kuzmanic, Marie Boutant, David Sala, Tuulia Hyotylainen, Matej Orešič, Joana Fort, Ekaitz Errasti-Murugarren, Cecilia M P Rodrígues, Modesto Orozco, Jorge Joven, Carles Cantó, Manuel Palacin, Sonia Fernández-Veledo, Joan Vendrell, Antonio Zorzano.
      Non-alcoholic fatty liver is the most common liver disease worldwide. Here, we show that the mitochondrial protein mitofusin 2 (Mfn2) protects against liver disease. Reduced Mfn2 expression was detected in liver biopsies from patients with non-alcoholic steatohepatitis (NASH). Moreover, reduced Mfn2 levels were detected in mouse models of steatosis or NASH, and its re-expression in a NASH mouse model ameliorated the disease. Liver-specific ablation of Mfn2 in mice provoked inflammation, triglyceride accumulation, fibrosis, and liver cancer. We demonstrate that Mfn2 binds phosphatidylserine (PS) and can specifically extract PS into membrane domains, favoring PS transfer to mitochondria and mitochondrial phosphatidylethanolamine (PE) synthesis. Consequently, hepatic Mfn2 deficiency reduces PS transfer and phospholipid synthesis, leading to endoplasmic reticulum (ER) stress and the development of a NASH-like phenotype and liver cancer. Ablation of Mfn2 in liver reveals that disruption of ER-mitochondrial PS transfer is a new mechanism involved in the development of liver disease.
    Keywords:  MAMs; Mfn2; NASH; mitochondria; phosphatidylserine; phospholipid transfer
    DOI:  https://doi.org/10.1016/j.cell.2019.04.010
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