bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2020‒05‒10
53 papers selected by
Christian Frezza,

  1. Hexokinase 2 displacement from mitochondria-associated membranes prompts Ca2+ -dependent death of cancer cells.
  2. A Nutrient-Sensing Transition at Birth Triggers Glucose-Responsive Insulin Secretion.
  3. Succinate Can Shuttle Reducing Power from the Hypoxic Retina to the O2-Rich Pigment Epithelium.
  4. Mitochondrial cross-compartmental signalling to maintain proteostasis and longevity.
  5. OPA1-Exon4b Binds to mtDNA D-Loop for Transcriptional and Metabolic Modulation, Independent of Mitochondrial Fusion.
  6. The RNA helicase DDX5 supports mitochondrial function in small cell lung cancer.
  7. FBP1 loss disrupts liver metabolism and promotes tumorigenesis through a hepatic stellate cell senescence secretome.
  8. Sirt4: A Multifaceted Enzyme at the Crossroads of Mitochondrial Metabolism and Cancer.
  9. Formate induces a metabolic switch in nucleotide and energy metabolism.
  10. Autophagy promotes immune evasion of pancreatic cancer by degrading MHC-I.
  11. Mitochondrial DNA segregation and replication restrict the transmission of detrimental mutation.
  12. SHMT inhibition is effective and synergizes with methotrexate in T-cell acute lymphoblastic leukemia.
  13. The Role of Mitochondrial-related Nuclear Genes in Age-related Common Disease.
  14. Warburg and Beyond: The Power of Mitochondrial Metabolism to Collaborate or Replace Fermentative Glycolysis in Cancer.
  15. Mechanisms governing autophagosome biogenesis.
  16. Linking mitochondrial and chloroplast retrograde signalling in plants.
  17. Cardiac metabolism as a driver and therapeutic target of myocardial infarction.
  18. Mendelian neurodegenerative disease genes involved in autophagy.
  19. OPA1 and Angiogenesis: Beyond the Fusion Function.
  20. Vitamin K2 promotes PI3K/AKT/HIF-1α-mediated glycolysis that leads to AMPK-dependent autophagic cell death in bladder cancer cells.
  21. MCL-1Matrix maintains neuronal survival by enhancing mitochondrial integrity and bioenergetic capacity under stress conditions.
  22. SnapShot: Lysosomal Functions.
  23. Mitochondrial retrograde signalling in neurological disease.
  24. The tumor microenvironment as a metabolic barrier to effector T cells and immunotherapy.
  25. Entry of glucose- and glutamine-derived carbons into the citric acid cycle supports early steps of HIV-1 infection in CD4 T cells.
  26. MitophAging: Mitophagy in Aging and Disease.
  27. EWS-FLI1-regulated serine synthesis and exogenous serine are necessary for Ewing sarcoma cellular proliferation and tumor growth.
  28. Regulated repression governs the cell fate promoter controlling yeast meiosis.
  29. Maintaining Myocardial Glucose Utilization in Diabetic Cardiomyopathy Accelerates Mitochondrial Dysfunction.
  30. Extracellular Acidosis and mTOR Inhibition Drive the Differentiation of Human Monocyte-Derived Dendritic Cells.
  31. Distinct Roles of Mitochondrial HIGD1A and HIGD2A in Respiratory Complex and Supercomplex Biogenesis.
  32. Reductive amination of α-Ketoglutarate in metabolite extracts results in glutamate overestimation.
  33. Nuclear encoded mitochondrial ribosomal proteins are required to initiate gastrulation.
  34. Fructose-1,6-Bisphosphatase 2 Inhibits Sarcoma Progression by Restraining Mitochondrial Biogenesis.
  35. Metabolism and Immune Modulation in Patients with Solid Tumors: Systematic Review of Preclinical and Clinical Evidence.
  36. Tissue metabolic profiling shows that saccharopine accumulates during renal ischemic-reperfusion injury, while kynurenine and itaconate accumulate in renal allograft rejection.
  37. Retrograde signals from endosymbiotic organelles: a common control principle in eukaryotic cells.
  38. A biallelic pathogenic variant in the OGDH gene results in a neurological disorder with features of a mitochondrial disease.
  39. Metabolic Regulation of Tissue Stem Cells.
  40. Chromatin Regulator, CHD1, Remodels the Immunosuppressive Tumor Microenvironment in PTEN-Deficient Prostate Cancer.
  41. NAD+ Controls Circadian Reprogramming through PER2 Nuclear Translocation to Counter Aging.
  42. Emerging Role of Cell Competition in Cancer.
  43. GCN2 regulates pancreatic β cell mass by sensing intracellular amino acid levels.
  44. Succinate induces skeletal muscle fiber remodeling via SUCNR1 signaling.
  45. CRY1-CBS binding regulates circadian clock function and metabolism.
  46. TALPID3 and ANKRD26 selectively orchestrate FBF1 localization and cilia gating.
  47. Metabolic Pathways That Control Skin Homeostasis and Inflammation.
  48. Stable and temporary enzyme complexes and metabolons involved in energy and redox metabolism.
  49. Mitochondria regulate intestinal stem cell proliferation and epithelial homeostasis through FOXO.
  50. Structural insights into G domain dimerization and pathogenic mutation of OPA1.
  51. Autophagy Suppresses TRP53/p53 and Oxidative Stress to Enable Mammalian Survival.
  52. Metabolic cost of rapid adaptation of single yeast cells.
  53. CHCHD10-regulated OPA1-mitofilin complex mediates TDP-43-induced mitochondrial phenotypes associated with frontotemporal dementia.
  1. EMBO Rep. 2020 May 08. e49117
    Hexokinase 2 displacement from mitochondria-associated membranes prompts Ca2+ -dependent death of cancer cells.
    Francesco Ciscato, Riccardo Filadi, Ionica Masgras, Marco Pizzi, Oriano Marin, Nunzio Damiano, Paola Pizzo, Alessandro Gori, Federica Frezzato, Federica Chiara, Livio Trentin, Paolo Bernardi, Andrea Rasola.
      Cancer cells undergo changes in metabolic and survival pathways that increase their malignancy. Isoform 2 of the glycolytic enzyme hexokinase (HK2) enhances both glucose metabolism and resistance to death stimuli in many neoplastic cell types. Here, we observe that HK2 locates at mitochondria-endoplasmic reticulum (ER) contact sites called MAMs (mitochondria-associated membranes). HK2 displacement from MAMs with a selective peptide triggers mitochondrial Ca2+ overload caused by Ca2+ release from ER via inositol-3-phosphate receptors (IP3Rs) and by Ca2+ entry through plasma membrane. This results in Ca2+ -dependent calpain activation, mitochondrial depolarization and cell death. The HK2-targeting peptide causes massive death of chronic lymphocytic leukemia B cells freshly isolated from patients, and an actionable form of the peptide reduces growth of breast and colon cancer cells allografted in mice without noxious effects on healthy tissues. These results identify a signaling pathway primed by HK2 displacement from MAMs that can be activated as anti-neoplastic strategy.
    Keywords:  Hexokinase 2; anti-neoplastic strategy; cancer; cell penetrating peptide; mitochondria-associated membranes
    DOI:  https://doi.org/10.15252/embr.201949117
  2. Cell Metab. 2020 Apr 23. pii: S1550-4131(20)30186-8. [Epub ahead of print]
    A Nutrient-Sensing Transition at Birth Triggers Glucose-Responsive Insulin Secretion.
    Aharon Helman, Andrew L Cangelosi, Jeffrey C Davis, Quan Pham, Arielle Rothman, Aubrey L Faust, Juerg R Straubhaar, David M Sabatini, Douglas A Melton.
      A drastic transition at birth, from constant maternal nutrient supply in utero to intermittent postnatal feeding, requires changes in the metabolic system of the neonate. Despite their central role in metabolic homeostasis, little is known about how pancreatic β cells adjust to the new nutritional challenge. Here, we find that after birth β cell function shifts from amino acid- to glucose-stimulated insulin secretion in correlation with the change in the nutritional environment. This adaptation is mediated by a transition in nutrient sensitivity of the mTORC1 pathway, which leads to intermittent mTORC1 activity. Disrupting nutrient sensitivity of mTORC1 in mature β cells reverts insulin secretion to a functionally immature state. Finally, manipulating nutrient sensitivity of mTORC1 in stem cell-derived β cells in vitro strongly enhances their glucose-responsive insulin secretion. These results reveal a mechanism by which nutrients regulate β cell function, thereby enabling a metabolic adaptation for the newborn.
    Keywords:  embryo; in vitro differentiation; insulin secretion; mTORC1; maturation; nutrient sensing; pancreas; stem cell-derived β cells; β cells
    DOI:  https://doi.org/10.1016/j.cmet.2020.04.004
  3. Cell Rep. 2020 May 05. pii: S2211-1247(20)30555-6. [Epub ahead of print]31(5): 107606
    Succinate Can Shuttle Reducing Power from the Hypoxic Retina to the O2-Rich Pigment Epithelium.
    Celia M Bisbach, Daniel T Hass, Brian M Robbings, Austin M Rountree, Martin Sadilek, Ian R Sweet, James B Hurley.
      When O2 is plentiful, the mitochondrial electron transport chain uses it as a terminal electron acceptor. However, the mammalian retina thrives in a hypoxic niche in the eye. We find that mitochondria in retinas adapt to their hypoxic environment by reversing the succinate dehydrogenase reaction to use fumarate to accept electrons instead of O2. Reverse succinate dehydrogenase activity produces succinate and is enhanced by hypoxia-induced downregulation of cytochrome oxidase. Retinas can export the succinate they produce to the neighboring O2-rich retinal pigment epithelium-choroid complex. There, succinate enhances O2 consumption by severalfold. Malate made from succinate in the pigment epithelium can then be imported into the retina, where it is converted to fumarate to again accept electrons in the reverse succinate dehydrogenase reaction. This malate-succinate shuttle can sustain these two tissues by transferring reducing power from an O2-poor tissue (retina) to an O2-rich one (retinal pigment epithelium-choroid).
    Keywords:  ecosystem; hypoxia; metabolic flux; metabolism; mitochondria; oxygen; retina; retinal pigment epithelium; succinate; succinate dehydrogenase
    DOI:  https://doi.org/10.1016/j.celrep.2020.107606
  4. Philos Trans R Soc Lond B Biol Sci. 2020 Jun 22. 375(1801): 20190414
    Mitochondrial cross-compartmental signalling to maintain proteostasis and longevity.
    Marte Molenaars, Eileen G Daniels, Amber Meurs, Georges E Janssens, Riekelt H Houtkooper.
      Lifespan in eukaryotic species can be prolonged by shifting from cellular states favouring growth to those favouring maintenance and stress resistance. For instance, perturbations in mitochondrial oxidative phosphorylation (OXPHOS) can shift cells into this latter state and extend lifespan. Because mitochondria rely on proteins synthesized from nuclear as well as mitochondrial DNA, they need to constantly send and receive messages from other compartments of the cell in order to function properly and maintain homeostasis, and lifespan extension is often dependent on this cross-compartmental signalling. Here, we describe the mechanisms of bi-directional mitochondrial cross-compartmental signalling resulting in proteostasis and longevity. These proteostasis mechanisms are highly context-dependent, governed by the origin and extent of stress. Furthermore, we discuss the translatability of these mechanisms and explore therapeutic developments, such as the antibiotic studies targeting mitochondria or mitochondria-derived peptides as therapies for age-related diseases such as neurodegeneration and cancer. This article is part of the theme issue 'Retrograde signalling from endosymbiotic organelles'.
    Keywords:  longevity; mitochondria; proteostasis; retrograde signalling
    DOI:  https://doi.org/10.1098/rstb.2019.0414
  5. Front Cell Dev Biol. 2020 ;8 180
    OPA1-Exon4b Binds to mtDNA D-Loop for Transcriptional and Metabolic Modulation, Independent of Mitochondrial Fusion.
    Liang Yang, Haite Tang, Xiaobing Lin, Yi Wu, Sheng Zeng, Yongzhang Pan, Yukun Li, Ge Xiang, Yi-Fang Lin, Shi-Mei Zhuang, Zhiyin Song, Yiguo Jiang, Xingguo Liu.
      Optic Atrophy 1 (OPA1) has well-established roles in both mitochondrial fusion and apoptotic crista remodeling and is required for the maintenance and distribution of mitochondrial DNA (mtDNA), which are essential for energy metabolism. However, the relationship between OPA1 and mitochondrial metabolism and the underlying mechanisms remain unclear. Here, we show that OPA1-Exon4b modulates mitochondrial respiration and rescues inner mitochondrial membrane potential (Δψm), independent of mitochondrial fusion. OPA1-Exon4b is required for the maintenance of normal TFAM distribution and enhances mtDNA transcription by binding the D-loop of mtDNA. Finally, we show that mRNA levels of OPA1 isoforms containing Exon4b are specifically downregulated in hepatocellular carcinoma (HCC), leading to a reduction in Δψm. Thus, our study demonstrates a novel mitochondrial functional self-recovery pathway involving enhanced mtDNA transcription-mediated recovery of mitochondrial respiratory chain proteins. This mitochondrial fusion-independent pathway may contribute to mitochondrial multi-functional switches in tumorigenesis.
    Keywords:  Optic Atrophy 1 (OPA1); hepatocellular carcinoma; mitochondrial DNA; mitochondrial fusion; mtDNA D-loop
    DOI:  https://doi.org/10.3389/fcell.2020.00180
  6. J Biol Chem. 2020 May 06. pii: jbc.RA120.012600. [Epub ahead of print]
    The RNA helicase DDX5 supports mitochondrial function in small cell lung cancer.
    Zheng Xing, Matthew P Russon, Sagar M Utturkar, Elizabeth J Tran.
      DEAD-box helicase 5 (DDX5) is a founding member of the DEAD-box RNA helicase family, a group of enzymes that regulate ribonucleoprotein (RNP) formation and function in every aspect of RNA metabolism, ranging from synthesis to decay. Our lab previously found that DDX5 is involved in energy homeostasis, a process that is altered in many cancers. Small cell lung cancer (SCLC) is an understudied cancer type for which effective treatments are currently unavailable. Using an array of methods, including shRNA-mediated gene silencing, RNA-Seq and ChIP-Seq analyses, and metabolite profiling, we show here that DDX5 is overexpressed in SCLC cell lines and that its down-regulation results in various metabolic and cellular alterations. Depletion of DDX5 resulted in reduced growth and mitochondrial dysfunction in the chemoresistant SCLC cell line H69AR. The latter was evidenced by downregulation of genes involved in oxidative phosphorylation and by impaired oxygen consumption. Interestingly, DDX5 depletion specifically reduced intracellular succinate, a tricarboxcylic acid (TCA) cycle intermediate that serves as a direct electron donor to mitochondrial complex II. We propose that the oncogenic role of DDX5, at least in part, manifests as upregulation of respiration supporting the energy demands of cancer cells.
    Keywords:  DEAD-box helicase 5 (DDX5); RNA helicase; bioenergetics; cell proliferation; gene expression; mitochondrial metabolism; respiration; small cell lung cancer; tricarboxylic acid cycle (TCA cycle) (Krebs cycle)
    DOI:  https://doi.org/10.1074/jbc.RA120.012600
  7. Nat Cell Biol. 2020 May 04.
    FBP1 loss disrupts liver metabolism and promotes tumorigenesis through a hepatic stellate cell senescence secretome.
    Fuming Li, Peiwei Huangyang, Michelle Burrows, Kathy Guo, Romain Riscal, Jason Godfrey, Kyoung Eun Lee, Nan Lin, Pearl Lee, Ian A Blair, Brian Keith, Bo Li, M Celeste Simon.
      The crosstalk between deregulated hepatocyte metabolism and cells within the tumour microenvironment, as well as the consequent effects on liver tumorigenesis, are not completely understood. We show here that hepatocyte-specific loss of the gluconeogenic enzyme fructose 1,6-bisphosphatase 1 (FBP1) disrupts liver metabolic homeostasis and promotes tumour progression. FBP1 is universally silenced in both human and murine liver tumours. Hepatocyte-specific Fbp1 deletion results in steatosis, concomitant with activation and senescence of hepatic stellate cells (HSCs), exhibiting a senescence-associated secretory phenotype. Depleting senescent HSCs by 'senolytic' treatment with dasatinib/quercetin or ABT-263 inhibits tumour progression. We further demonstrate that FBP1-deficient hepatocytes promote HSC activation by releasing HMGB1; blocking its release with the small molecule inflachromene limits FBP1-dependent HSC activation, the subsequent development of the senescence-associated secretory phenotype and tumour progression. Collectively, these findings provide genetic evidence for FBP1 as a metabolic tumour suppressor in liver cancer and establish a critical crosstalk between hepatocyte metabolism and HSC senescence that promotes tumour growth.
    DOI:  https://doi.org/10.1038/s41556-020-0511-2
  8. Front Oncol. 2020 ;10 474
    Sirt4: A Multifaceted Enzyme at the Crossroads of Mitochondrial Metabolism and Cancer.
    Daniela Tomaselli, Clemens Steegborn, Antonello Mai, Dante Rotili.
      Sirtuins are NAD+-dependent deacylases that play crucial roles in the regulation of cellular metabolism, and as a result, are implicated in several diseases. The mitochondrial sirtuin Sirt4, for a long time considered as mainly a mono-ADP-ribosyltransferase, recently has shown a robust deacylase activity in addition to the already accepted substrate-dependent lipoamidase and deacetylase properties. Through these and likely other enzymatic and non-enzymatic activities, Sirt4 closely controls various metabolic events, and its dysregulation is linked to various aging-related disorders, including type 2 diabetes, cardiac hypertrophy, non-alcoholic fatty liver disease, obesity, and cancer. For its capability to inhibit glutamine catabolism and for the modulation of genome stability in cancer cells in response to different DNA-damaging conditions, Sirt4 is proposed as either a mitochondrial tumor suppressor or a tumor-promoting protein in a context-dependent manner. In addition to what is already known about the roles of Sirt4 in different biological settings, further studies are certainly still needed in order to validate this enzyme as a new potential target for various aging diseases.
    Keywords:  cancer; metabolism; mitochondria; protein deacylation; sirtuins
    DOI:  https://doi.org/10.3389/fonc.2020.00474
  9. Cell Death Dis. 2020 May 04. 11(5): 310
    Formate induces a metabolic switch in nucleotide and energy metabolism.
    Kristell Oizel, Jacqueline Tait-Mulder, Jorge Fernandez-de-Cossio-Diaz, Matthias Pietzke, Holly Brunton, Sergio Lilla, Sandeep Dhayade, Dimitri Athineos, Giovanny Rodriguez Blanco, David Sumpton, Gillian M Mackay, Karen Blyth, Sara R Zanivan, Johannes Meiser, Alexei Vazquez.
      Formate is a precursor for the de novo synthesis of purine and deoxythymidine nucleotides. Formate also interacts with energy metabolism by promoting the synthesis of adenine nucleotides. Here we use theoretical modelling together with metabolomics analysis to investigate the link between formate, nucleotide and energy metabolism. We uncover that endogenous or exogenous formate induces a metabolic switch from low to high adenine nucleotide levels, increasing the rate of glycolysis and repressing the AMPK activity. Formate also induces an increase in the pyrimidine precursor orotate and the urea cycle intermediate argininosuccinate, in agreement with the ATP-dependent activities of carbamoyl-phosphate and argininosuccinate synthetase. In vivo data for mouse and human cancers confirms the association between increased formate production, nucleotide and energy metabolism. Finally, the in vitro observations are recapitulated in mice following and intraperitoneal injection of formate. We conclude that formate is a potent regulator of purine, pyrimidine and energy metabolism.
    DOI:  https://doi.org/10.1038/s41419-020-2523-z
  10. Nature. 2020 May;581(7806): 100-105
    Autophagy promotes immune evasion of pancreatic cancer by degrading MHC-I.
    Keisuke Yamamoto, Anthony Venida, Julian Yano, Douglas E Biancur, Miwako Kakiuchi, Suprit Gupta, Albert S W Sohn, Subhadip Mukhopadhyay, Elaine Y Lin, Seth J Parker, Robert S Banh, Joao A Paulo, Kwun Wah Wen, Jayanta Debnath, Grace E Kim, Joseph D Mancias, Douglas T Fearon, Rushika M Perera, Alec C Kimmelman.
      Immune evasion is a major obstacle for cancer treatment. Common mechanisms of evasion include impaired antigen presentation caused by mutations or loss of heterozygosity of the major histocompatibility complex class I (MHC-I), which has been implicated in resistance to immune checkpoint blockade (ICB) therapy1-3. However, in pancreatic ductal adenocarcinoma (PDAC), which is resistant to most therapies including ICB4, mutations that cause loss of MHC-I are rarely found5 despite the frequent downregulation of MHC-I expression6-8. Here we show that, in PDAC, MHC-I molecules are selectively targeted for lysosomal degradation by an autophagy-dependent mechanism that involves the autophagy cargo receptor NBR1. PDAC cells display reduced expression of MHC-I at the cell surface and instead demonstrate predominant localization within autophagosomes and lysosomes. Notably, inhibition of autophagy restores surface levels of MHC-I and leads to improved antigen presentation, enhanced anti-tumour T cell responses and reduced tumour growth in syngeneic host mice. Accordingly, the anti-tumour effects of autophagy inhibition are reversed by depleting CD8+ T cells or reducing surface expression of MHC-I. Inhibition of autophagy, either genetically or pharmacologically with chloroquine, synergizes with dual ICB therapy (anti-PD1 and anti-CTLA4 antibodies), and leads to an enhanced anti-tumour immune response. Our findings demonstrate a role for enhanced autophagy or lysosome function in immune evasion by selective targeting of MHC-I molecules for degradation, and provide a rationale for the combination of autophagy inhibition and dual ICB therapy as a therapeutic strategy against PDAC.
    DOI:  https://doi.org/10.1038/s41586-020-2229-5
  11. J Cell Biol. 2020 Jul 06. pii: e201905160. [Epub ahead of print]219(7):
    Mitochondrial DNA segregation and replication restrict the transmission of detrimental mutation.
    Zhe Chen, Zong-Heng Wang, Guofeng Zhang, Christopher K E Bleck, Dillon J Chung, Grey P Madison, Eric Lindberg, Christian Combs, Robert S Balaban, Hong Xu.
      Although mitochondrial DNA (mtDNA) is prone to accumulate mutations and lacks conventional DNA repair mechanisms, deleterious mutations are exceedingly rare. How the transmission of detrimental mtDNA mutations is restricted through the maternal lineage is debated. Here, we demonstrate that mitochondrial fission, together with the lack of mtDNA replication, segregate mtDNA into individual organelles in the Drosophila early germarium. After mtDNA segregation, mtDNA transcription begins, which activates respiration. Mitochondria harboring wild-type genomes have functional electron transport chains and propagate more vigorously than mitochondria containing deleterious mutations in hetreoplasmic cells. Therefore, mtDNA expression acts as a stress test for the integrity of mitochondrial genomes and sets the stage for replication competition. Our observations support selective inheritance at the organelle level through a series of developmentally orchestrated mitochondrial processes. We also show that the Balbiani body has a minor role in mtDNA selective inheritance by supplying healthy mitochondria to the pole plasm. These two mechanisms may act synergistically to secure the transmission of functional mtDNA through Drosophila oogenesis.
    DOI:  https://doi.org/10.1083/jcb.201905160
  12. Leukemia. 2020 May 07.
    SHMT inhibition is effective and synergizes with methotrexate in T-cell acute lymphoblastic leukemia.
    Juan C García-Cañaveras, Olga Lancho, Gregory S Ducker, Jonathan M Ghergurovich, Xincheng Xu, Victoria da Silva-Diz, Sonia Minuzzo, Stefano Indraccolo, Hahn Kim, Daniel Herranz, Joshua D Rabinowitz.
      Folate metabolism enables cell growth by providing one-carbon (1C) units for nucleotide biosynthesis. The 1C units are carried by tetrahydrofolate, whose production by the enzyme dihydrofolate reductase is targeted by the important anticancer drug methotrexate. 1C units come largely from serine catabolism by the enzyme serine hydroxymethyltransferase (SHMT), whose mitochondrial isoform is strongly upregulated in cancer. Here we report the SHMT inhibitor SHIN2 and demonstrate its in vivo target engagement with 13C-serine tracing. As methotrexate is standard treatment for T-cell acute lymphoblastic leukemia (T-ALL), we explored the utility of SHIN2 in this disease. SHIN2 increases survival in NOTCH1-driven mouse primary T-ALL in vivo. Low dose methotrexate sensitizes Molt4 human T-ALL cells to SHIN2, and cells rendered methotrexate resistant in vitro show enhanced sensitivity to SHIN2. Finally, SHIN2 and methotrexate synergize in mouse primary T-ALL and in a human patient-derived xenograft in vivo, increasing survival. Thus, SHMT inhibition offers a complementary strategy in the treatment of T-ALL.
    DOI:  https://doi.org/10.1038/s41375-020-0845-6
  13. Mitochondrion. 2020 Apr 30. pii: S1567-7249(19)30259-4. [Epub ahead of print]
    The Role of Mitochondrial-related Nuclear Genes in Age-related Common Disease.
    Huanzheng Li, Jesse Slone, Taosheng Huang.
      Mitochondria are critical organelles that provide energy as ATP to the cell. Besides 37 genes encoded by mitochondrial genome, it has been estimated that over 1500 nuclear genes are required for mitochondrial structure and function. Thus, mutations of many genes in the nuclear genome cause dysfunction of mitochondria that can lead to many severe conditions. Mitochondrial dysfunction often results in reduced ATP synthesis, higher levels of reactive oxygen species (ROS), imbalanced mitochondrial dynamics, and other detrimental effects. In addition to rare primary mitochondrial disorders, these mitochondrial-related genes are often associated with many common diseases. For example, in neurodegenerative diseases such as Parkinson's, Alzheimer's, and Huntington disease, mitochondrialand energy metabolism abnormalities can greatly affect brain function. Cancer cells are also known to exhibit repressed mitochondrial ATP production in favor of glycolysis, which fuels the aggressive proliferation and metastasis of tumor tissues, leading many to speculate on a possible relationship between compromised mitochondrial function and cancer. The association between mitochondrial dysfunction and diabetes is also unsurprising, given the organelle's crucial role in cellular energy utilization. Here, we will discuss the multiple lines of evidence connecting mitochondrial dysfunction associated with mitochondria-related nuclear genes to many of the well-known disease genes that also underlie common disease.
    Keywords:  Aging; Cancer; Diabetes; Mitochondria; Mitochondrial Genetics; Neurodegeneration
    DOI:  https://doi.org/10.1016/j.mito.2020.04.012
  14. Cancers (Basel). 2020 Apr 30. pii: E1119. [Epub ahead of print]12(5):
    Warburg and Beyond: The Power of Mitochondrial Metabolism to Collaborate or Replace Fermentative Glycolysis in Cancer.
    Shamir Cassim, Milica Vučetić, Maša Ždralević, Jacques Pouyssegur.
      A defining hallmark of tumor phenotypes is uncontrolled cell proliferation, while fermentative glycolysis has long been considered as one of the major metabolic pathways that allows energy production and provides intermediates for the anabolic growth of cancer cells. Although such a vision has been crucial for the development of clinical imaging modalities, it has become now evident that in contrast to prior beliefs, mitochondria play a key role in tumorigenesis. Recent findings demonstrated that a full genetic disruption of the Warburg effect of aggressive cancers does not suppress but instead reduces tumor growth. Tumor growth then relies exclusively on functional mitochondria. Besides having fundamental bioenergetic functions, mitochondrial metabolism indeed provides appropriate building blocks for tumor anabolism, controls redox balance, and coordinates cell death. Hence, mitochondria represent promising targets for the development of novel anti-cancer agents. Here, after revisiting the long-standing Warburg effect from a historic and dynamic perspective, we review the role of mitochondria in cancer with particular attention to the cancer cell-intrinsic/extrinsic mechanisms through which mitochondria influence all steps of tumorigenesis, and briefly discuss the therapeutic potential of targeting mitochondrial metabolism for cancer therapy.
    Keywords:  Krebs cycle; Warburg effect; metabolism; mitochondria; oxidative phosphorylation (OXPHOS); therapy; tumor
    DOI:  https://doi.org/10.3390/cancers12051119
  15. Nat Rev Mol Cell Biol. 2020 May 05.
    Mechanisms governing autophagosome biogenesis.
    Hitoshi Nakatogawa.
      Autophagosomes are double-membrane vesicles newly formed during autophagy to engulf a wide range of intracellular material and transport this autophagic cargo to lysosomes (or vacuoles in yeasts and plants) for subsequent degradation. Autophagosome biogenesis responds to a plethora of signals and involves unique and dynamic membrane processes. Autophagy is an important cellular mechanism allowing the cell to meet various demands, and its disruption compromises homeostasis and leads to various diseases, including metabolic disorders, neurodegeneration and cancer. Thus, not surprisingly, the elucidation of the molecular mechanisms governing autophagosome biogenesis has attracted considerable interest. Key molecules and organelles involved in autophagosome biogenesis, including autophagy-related (ATG) proteins and the endoplasmic reticulum, have been discovered, and their roles and relationships have been investigated intensely. However, several fundamental questions, such as what supplies membranes/lipids to build the autophagosome and how the membrane nucleates, expands, bends into a spherical shape and finally closes, have proven difficult to address. Nonetheless, owing to recent studies with new approaches and technologies, we have begun to unveil the mechanisms underlying these processes on a molecular level. We now know that autophagosome biogenesis is a highly complex process, in which multiple proteins and lipids from various membrane sources, supported by the formation of membrane contact sites, cooperate with biophysical phenomena, including membrane shaping and liquid-liquid phase separation, to ensure seamless segregation of the autophagic cargo. Together, these studies pave the way to obtaining a holistic view of autophagosome biogenesis.
    DOI:  https://doi.org/10.1038/s41580-020-0241-0
  16. Philos Trans R Soc Lond B Biol Sci. 2020 Jun 22. 375(1801): 20190410
    Linking mitochondrial and chloroplast retrograde signalling in plants.
    Yan Wang, Jennifer Selinski, Chunli Mao, Yanqiao Zhu, Oliver Berkowitz, James Whelan.
      Retrograde signalling refers to the regulation of nuclear gene expression in response to functional changes in organelles. In plants, the two energy-converting organelles, mitochondria and chloroplasts, are tightly coordinated to balance their activities. Although our understanding of components involved in retrograde signalling has greatly increased in the last decade, studies on the regulation of the two organelle signalling pathways have been largely independent. Thus, the mechanism of how mitochondrial and chloroplastic retrograde signals are integrated is largely unknown. Here, we summarize recent findings on the function of mitochondrial signalling components and their links to chloroplast retrograde responses. From this, a picture emerges showing that the major regulators are integrators of both organellar retrograde signalling pathways. This article is part of the theme issue 'Retrograde signalling from endosymbiotic organelles'.
    Keywords:  alternative oxidase; chloroplast; common regulators; mitochondria; retrograde signalling
    DOI:  https://doi.org/10.1098/rstb.2019.0410
  17. J Cell Mol Med. 2020 May 08.
    Cardiac metabolism as a driver and therapeutic target of myocardial infarction.
    Coert J Zuurbier, Luc Bertrand, Christoph R Beauloye, Ioanna Andreadou, Marisol Ruiz-Meana, Nichlas R Jespersen, Duvaraka Kula-Alwar, Hiran A Prag, Hans Eric Botker, Maija Dambrova, Christophe Montessuit, Tuuli Kaambre, Edgars Liepinsh, Paul S Brookes, Thomas Krieg.
      Reducing infarct size during a cardiac ischaemic-reperfusion episode is still of paramount importance, because the extension of myocardial necrosis is an important risk factor for developing heart failure. Cardiac ischaemia-reperfusion injury (IRI) is in principle a metabolic pathology as it is caused by abruptly halted metabolism during the ischaemic episode and exacerbated by sudden restart of specific metabolic pathways at reperfusion. It should therefore not come as a surprise that therapy directed at metabolic pathways can modulate IRI. Here, we summarize the current knowledge of important metabolic pathways as therapeutic targets to combat cardiac IRI. Activating metabolic pathways such as glycolysis (eg AMPK activators), glucose oxidation (activating pyruvate dehydrogenase complex), ketone oxidation (increasing ketone plasma levels), hexosamine biosynthesis pathway (O-GlcNAcylation; administration of glucosamine/glutamine) and deacetylation (activating sirtuins 1 or 3; administration of NAD+ -boosting compounds) all seem to hold promise to reduce acute IRI. In contrast, some metabolic pathways may offer protection through diminished activity. These pathways comprise the malate-aspartate shuttle (in need of novel specific reversible inhibitors), mitochondrial oxygen consumption, fatty acid oxidation (CD36 inhibitors, malonyl-CoA decarboxylase inhibitors) and mitochondrial succinate metabolism (malonate). Additionally, protecting the cristae structure of the mitochondria during IR, by maintaining the association of hexokinase II or creatine kinase with mitochondria, or inhibiting destabilization of FO F1 -ATPase dimers, prevents mitochondrial damage and thereby reduces cardiac IRI. Currently, the most promising and druggable metabolic therapy against cardiac IRI seems to be the singular or combined targeting of glycolysis, O-GlcNAcylation and metabolism of ketones, fatty acids and succinate.
    Keywords:  ischemia; metabolism; mitochondria
    DOI:  https://doi.org/10.1111/jcmm.15180
  18. Cell Discov. 2020 ;6 24
    Mendelian neurodegenerative disease genes involved in autophagy.
    Eleanna Stamatakou, Lidia Wróbel, Sandra Malmgren Hill, Claudia Puri, Sung Min Son, Motoki Fujimaki, Ye Zhu, Farah Siddiqi, Marian Fernandez-Estevez, Marco M Manni, So Jung Park, Julien Villeneuve, David Chaim Rubinsztein.
      The lysosomal degradation pathway of macroautophagy (herein referred to as autophagy) plays a crucial role in cellular physiology by regulating the removal of unwanted cargoes such as protein aggregates and damaged organelles. Over the last five decades, significant progress has been made in understanding the molecular mechanisms that regulate autophagy and its roles in human physiology and diseases. These advances, together with discoveries in human genetics linking autophagy-related gene mutations to specific diseases, provide a better understanding of the mechanisms by which autophagy-dependent pathways can be potentially targeted for treating human diseases. Here, we review mutations that have been identified in genes involved in autophagy and their associations with neurodegenerative diseases.
    Keywords:  Macroautophagy; Mechanisms of disease
    DOI:  https://doi.org/10.1038/s41421-020-0158-y
  19. Cell Metab. 2020 May 05. pii: S1550-4131(20)30196-0. [Epub ahead of print]31(5): 886-887
    OPA1 and Angiogenesis: Beyond the Fusion Function.
    Max-Hinderk Schuler, Adam L Hughes.
      In this issue of Cell Metabolism, Herkenne et al. (2020) show that the mitochondrial fusion protein OPA1 promotes angiogenesis independent of its function in mitochondrial dynamics, identifying a key new therapeutic target to prevent vascular growth during development and tumor formation.
    DOI:  https://doi.org/10.1016/j.cmet.2020.04.014
  20. Sci Rep. 2020 May 07. 10(1): 7714
    Vitamin K2 promotes PI3K/AKT/HIF-1α-mediated glycolysis that leads to AMPK-dependent autophagic cell death in bladder cancer cells.
    Fengsen Duan, Chunlei Mei, Luhao Yang, Junyan Zheng, Huiai Lu, Yanzhi Xia, Stacy Hsu, Huageng Liang, Ling Hong.
      Vitamin K2 has been shown to exert remarkable anticancer activity. However, the detailed mechanism remains unclear. Here, our study was the first to show that Vitamin K2 significantly promoted the glycolysis in bladder cancer cells by upregulating glucose consumption and lactate production, whereas inhibited TCA cycle by reducing the amounts of Acetyl-CoA. Moreover, suppression of PI3K/AKT and HIF-1α attenuated Vitamin K2-increased glucose consumption and lactate generation, indicating that Vitamin K2 promotes PI3K/AKT and HIF-1α-mediated glycolysis in bladder cancer cells. Importantly, upon glucose limitation, Vitamin K2-upregulated glycolysis markedly induced metabolic stress, along with AMPK activation and mTORC1 pathway suppression, which subsequently triggered AMPK-dependent autophagic cell death. Intriguingly, glucose supplementation profoundly abrogated AMPK activation and rescued bladder cancer cells from Vitamin K2-triggered autophagic cell death. Furthermore, both inhibition of PI3K/AKT/HIF-1α and attenuation of glycolysis significantly blocked Vitamin K2-induced AMPK activation and subsequently prevented autophagic cell death. Collectively, these findings reveal that Vitamin K2 could induce metabolic stress and trigger AMPK-dependent autophagic cell death in bladder cancer cells by PI3K/AKT/HIF-1α-mediated glycolysis promotion.
    DOI:  https://doi.org/10.1038/s41598-020-64880-x
  21. Cell Death Dis. 2020 May 05. 11(5): 321
    MCL-1Matrix maintains neuronal survival by enhancing mitochondrial integrity and bioenergetic capacity under stress conditions.
    Ujval Anilkumar, Mireille Khacho, Alexanne Cuillerier, Richard Harris, David A Patten, Maria Bilen, Mohamed Ariff Iqbal, Ding Yuan Guo, Louis-Eric Trudeau, David S Park, Mary-Ellen Harper, Yan Burelle, Ruth S Slack.
      Mitochondria play a crucial role in neuronal survival through efficient energy metabolism. In pathological conditions, mitochondrial stress leads to neuronal death, which is regulated by the anti-apoptotic BCL-2 family of proteins. MCL-1 is an anti-apoptotic BCL-2 protein localized to mitochondria either in the outer membrane (OM) or inner membrane (Matrix), which have distinct roles in inhibiting apoptosis and promoting bioenergetics, respectively. While the anti-apoptotic role for Mcl1 is well characterized, the protective function of MCL-1 Matrix remains poorly understood. Here, we show MCL-1OM and MCL-1Matrix prevent neuronal death through distinct mechanisms. We report that MCL-1Matrix functions to preserve mitochondrial energy transduction and improves respiratory chain capacity by modulating mitochondrial oxygen consumption in response to mitochondrial stress. We show that MCL-1Matrix protects neurons from stress by enhancing respiratory function, and by inhibiting mitochondrial permeability transition pore opening. Taken together, our results provide novel insight into how MCL-1Matrix may confer neuroprotection under stress conditions involving loss of mitochondrial function.
    DOI:  https://doi.org/10.1038/s41419-020-2498-9
  22. Cell. 2020 Apr 30. pii: S0092-8674(20)30336-6. [Epub ahead of print]181(3): 748-748.e1
    SnapShot: Lysosomal Functions.
    Lya K K Holland, Inger Ødum Nielsen, Kenji Maeda, Marja Jäättelä.
      In addition to their well-defined recycling function, lysosomes act as metabolic signaling hubs that adjust cellular metabolism according to the availability of nutrients and growth factors by regulating metabolic kinases and transcription factors on their surface. Moreover, lysosomal hydrolases and ions released to cytosol or extracellular space have recently emerged as important regulators of various cellular processes from cell death to cell division. To view this SnapShot, open or download the PDF.
    DOI:  https://doi.org/10.1016/j.cell.2020.03.043
  23. Philos Trans R Soc Lond B Biol Sci. 2020 Jun 22. 375(1801): 20190415
    Mitochondrial retrograde signalling in neurological disease.
    Lucy Granat, Rachel J Hunt, Joseph M Bateman.
      Neuronal mitochondrial dysfunction causes primary mitochondrial diseases and likely contributes to neurodegenerative diseases including Parkinson's and Alzheimer's disease. Mitochondrial dysfunction has also been documented in neurodevelopmental disorders such as tuberous sclerosis complex and autism spectrum disorder. Only symptomatic treatments exist for neurodevelopmental disorders, while neurodegenerative diseases are largely untreatable. Altered mitochondrial function activates mitochondrial retrograde signalling pathways, which enable signalling to the nucleus to reprogramme nuclear gene expression. In this review, we discuss the role of mitochondrial retrograde signalling in neurological diseases. We summarize how mitochondrial dysfunction contributes to neurodegenerative disease and neurodevelopmental disorders. Mitochondrial signalling mechanisms that have relevance to neurological disease are discussed. We then describe studies documenting retrograde signalling pathways in neurons and glia, and in animal models of neuronal mitochondrial dysfunction and neurological disease. Finally, we suggest how specific retrograde signalling pathways can be targeted to develop novel treatments for neurological diseases. This article is part of the theme issue 'Retrograde signalling from endosymbiotic organelles'.
    Keywords:  Alzheimer's; Parkinson's; disease; mitochondria; neuron; retrograde signalling
    DOI:  https://doi.org/10.1098/rstb.2019.0415
  24. Elife. 2020 May 05. pii: e55185. [Epub ahead of print]9
    The tumor microenvironment as a metabolic barrier to effector T cells and immunotherapy.
    Aaron R Lim, W Kimryn Rathmell, Jeffrey C Rathmell.
      Breakthroughs in anti-tumor immunity have led to unprecedented advances in immunotherapy, yet it is now clear that the tumor microenvironment (TME) restrains immunity. T cells must substantially increase nutrient uptake to mount a proper immune response and failure to obtain sufficient nutrients or engage the appropriate metabolic pathways can alter or prevent effector T cell differentiation and function. The TME, however, can be metabolically hostile due to insufficient vascular exchange and cancer cell metabolism that leads to hypoxia, depletion of nutrients, and accumulation of waste products. Further, inhibitory receptors present in the TME can inhibit T cell metabolism and alter T cell signaling both directly and through release of extracellular vesicles such as exosomes. This review will discuss the metabolic changes that drive T cells into different stages of their development and how the TME imposes barriers to the metabolism and activity of tumor infiltrating lymphocytes.
    Keywords:  cancer; cancer biology; immunology; immunometabolism; immunotherapy; inflammation; t cells; tumor microenvironment; tumor-infiltrating lymphocytes
    DOI:  https://doi.org/10.7554/eLife.55185
  25. Nat Metab. 2019 Jul;1(7): 717-730
    Entry of glucose- and glutamine-derived carbons into the citric acid cycle supports early steps of HIV-1 infection in CD4 T cells.
    Isabelle Clerc, Daouda Abba Moussa, Zoi Vahlas, Saverio Tardito, Leal Oburoglu, Thomas J Hope, Marc Sitbon, Valérie Dardalhon, Cédric Mongellaz, Naomi Taylor.
      The susceptibility of CD4 T cells to human immunodeficiency virus 1 (HIV-1) infection is regulated by glucose and glutamine metabolism, but the relative contributions of these nutrients to infection are not known. Here we show that glutaminolysis is the major pathway fuelling the tricarboxylic acid (TCA) cycle and oxidative phosphorylation (OXPHOS) in T-cell receptor-stimulated naïve, as well as memory CD4, subsets and is required for optimal HIV-1 infection. Under conditions of attenuated glutaminolysis, the α-ketoglutarate (α-KG) TCA rescues early steps in infection; exogenous α-KG promotes HIV-1 reverse transcription, rendering both naïve and memory cells more sensitive to infection. Blocking the glycolytic flux of pyruvate to lactate results in altered glucose carbon allocation to TCA and pentose phosphate pathway intermediates, an increase in OXPHOS and augmented HIV-1 reverse transcription. Moreover, HIV-1 infection is significantly higher in CD4 T cells selected on the basis of high mitochondrial biomass and OXPHOS activity. Therefore, the OXPHOS/aerobic glycolysis balance is a major regulator of HIV-1 infection in CD4 T lymphocytes.
    DOI:  https://doi.org/10.1038/s42255-019-0084-1
  26. Front Cell Dev Biol. 2020 ;8 239
    MitophAging: Mitophagy in Aging and Disease.
    Daniela Bakula, Morten Scheibye-Knudsen.
      Maintaining mitochondrial health is emerging as a keystone in aging and associated diseases. The selective degradation of mitochondria by mitophagy is of particular importance in keeping a pristine mitochondrial pool. Indeed, inherited monogenic diseases with defects in mitophagy display complex multisystem pathologies but particularly progressive neurodegeneration. Fortunately, therapies are being developed that target mitophagy allowing new hope for treatments for previously incurable diseases. Herein, we describe mitophagy and associated diseases, coin the term mitophaging and describe new small molecule interventions that target different steps in the mitophagic pathway. Consequently, several age-associated diseases may be treated by targeting mitophagy.
    Keywords:  aging; autophagy; interventions; mitophaging; mitophagy; monogenic disorders
    DOI:  https://doi.org/10.3389/fcell.2020.00239
  27. Mol Cancer Ther. 2020 May 05. pii: molcanther.0748.2019. [Epub ahead of print]
    EWS-FLI1-regulated serine synthesis and exogenous serine are necessary for Ewing sarcoma cellular proliferation and tumor growth.
    Sameer H Issaq, Arnulfo Mendoza, Ria Kidner, Tracy I Rosales, Damien Y Duveau, Christine M Heske, Jason M Rohde, Matthew B Boxer, Craig J Thomas, Ralph J DeBerardinis, Lee J Helman.
      Despite a growing body of knowledge about the genomic landscape of Ewing sarcoma (ES), translation of basic discoveries into targeted therapies and significant clinical gains has remained elusive. Recent insights have revealed that the oncogenic transcription factor EWS-FLI1 can impact ES cellular metabolism, regulating expression of 3-phosphoglycerate dehydrogenase (PHGDH), the first enzyme in de novo serine synthesis. Here, we have examined the importance of serine metabolism in ES tumorigenesis and evaluated the therapeutic potential of targeting serine metabolism in preclinical models of ES. We show that PHGDH knockdown resulted in decreased ES cell proliferation, especially under serine limitation, and significantly inhibited xenograft tumorigenesis in preclinical orthotopic models of ES. Additionally, the PHGDH inhibitor NCT-503 caused a dose-dependent decrease in cellular proliferation. Moreover, we report a novel drug combination in which nicotinamide phosphoribosyltransferase (NAMPT) inhibition, which blocks production of the PHGDH substrate NAD+, synergized with NCT-503 to abolish ES cell proliferation and tumor growth. Furthermore, we show that serine deprivation inhibited ES cell proliferation and tumorigenesis, indicating that ES cells depend on exogenous serine in addition to de novo serine synthesis. Our findings suggest that serine metabolism is critical for ES tumorigenesis, and that targeting metabolic dependencies should be further investigated as a potential therapeutic strategy for ES. In addition, the combination strategy presented herein may have broader clinical applications in other PHGDH-overexpressing cancers as well.
    DOI:  https://doi.org/10.1158/1535-7163.MCT-19-0748
  28. Nat Commun. 2020 May 08. 11(1): 2271
    Regulated repression governs the cell fate promoter controlling yeast meiosis.
    Janis Tam, Folkert J van Werven.
      Intrinsic signals and external cues from the environment drive cell fate decisions. In budding yeast, the decision to enter meiosis is controlled by nutrient and mating-type signals that regulate expression of the master transcription factor for meiotic entry, IME1. How nutrient signals control IME1 expression remains poorly understood. Here, we show that IME1 transcription is regulated by multiple sequence-specific transcription factors (TFs) that mediate association of Tup1-Cyc8 co-repressor to its promoter. We find that at least eight TFs bind the IME1 promoter when nutrients are ample. Remarkably, association of these TFs is highly regulated by different nutrient cues. Mutant cells lacking three TFs (Sok2/Phd1/Yap6) displayed reduced Tup1-Cyc8 association, increased IME1 expression, and earlier onset of meiosis. Our data demonstrate that the promoter of a master regulator is primed for rapid activation while repression by multiple TFs mediating Tup1-Cyc8 recruitment dictates the fate decision to enter meiosis.
    DOI:  https://doi.org/10.1038/s41467-020-16107-w
  29. Diabetes. 2020 May 04. pii: db191057. [Epub ahead of print]
    Maintaining Myocardial Glucose Utilization in Diabetic Cardiomyopathy Accelerates Mitochondrial Dysfunction.
    Adam R Wende, John C Schell, Chae-Myeong Ha, Mark E Pepin, Oleh Khalimonchuk, Hansjörg Schwertz, Renata O Pereira, Manoja K Brahma, Joseph Tuinei, Ariel Contreras-Ferrat, Li Wang, Chase A Andrizzi, Curtis D Olsen, Wayne E Bradley, Louis J Dell'Italia, Wolfgang H Dillmann, Sheldon E Litwin, E Dale Abel.
      Cardiac glucose uptake and oxidation are reduced in diabetes despite hyperglycemia. Mitochondrial dysfunction contributes to heart failure in diabetes. It is unclear if these changes are adaptive or maladaptive. To directly evaluate the relationship between glucose delivery and mitochondrial dysfunction in diabetic cardiomyopathy we generated transgenic mice with inducible cardiomyocyte-specific expression of the glucose transporter (GLUT4). We examined mice rendered hyperglycemic following low-dose streptozotocin prior to increasing cardiomyocyte glucose uptake by transgene induction. Enhanced myocardial glucose in non-diabetic mice decreased mitochondrial ATP generation and was associated with echocardiographic evidence of diastolic dysfunction. Increasing myocardial glucose delivery after short-term diabetes onset, exacerbated mitochondrial oxidative dysfunction. Transcriptomic analysis revealed that the largest changes, driven by glucose and diabetes, were in genes involved in mitochondrial function. This glucose-dependent transcriptional repression was in part mediated by O-GlcNAcylation of the transcription factor Sp1. Increased glucose uptake induced direct O-GlcNAcylation of many electron transport chain subunits and other mitochondrial proteins. These findings identify mitochondria as a major target of glucotoxicity. They also suggest reduced glucose utilization in diabetic cardiomyopathy might defend against glucotoxicity and caution that restoring glucose delivery to the heart in the context of diabetes could accelerate mitochondrial dysfunction by disrupting protective metabolic adaptations.
    DOI:  https://doi.org/10.2337/db19-1057
  30. Cell Rep. 2020 May 05. pii: S2211-1247(20)30562-3. [Epub ahead of print]31(5): 107613
    Extracellular Acidosis and mTOR Inhibition Drive the Differentiation of Human Monocyte-Derived Dendritic Cells.
    Fernando Erra Díaz, Valeria Ochoa, Antonela Merlotti, Ezequiel Dantas, Ignacio Mazzitelli, Virginia Gonzalez Polo, Juan Sabatté, Sebastián Amigorena, Elodie Segura, Jorge Geffner.
      During inflammation, recruited monocytes can differentiate either into macrophages or dendritic cells (DCs); however, little is known about the environmental factors that determine this cell fate decision. Low extracellular pH is a hallmark of a variety of inflammatory processes and solid tumors. Here, we report that low pH dramatically promotes the differentiation of monocytes into DCs (monocyte-derived DCs [mo-DCs]). This process is associated with a reduction in glucose consumption and lactate production, the upregulation of mitochondrial respiratory chain genes, and the inhibition of mTORC1 activity. Interestingly, we also find that both serum starvation and pharmacological inhibition of mTORC1 markedly promote the differentiation of mo-DCs. Our study contributes to better understanding the mechanisms that govern the differentiation of monocytes into DCs and reveals the role of both extracellular pH and mTORC1 as master regulators of monocyte cell fate.
    Keywords:  Monocytes; acidosis; dendritic cells; differentiation; inflammation; low pH; mTOR; metabolism; starvation
    DOI:  https://doi.org/10.1016/j.celrep.2020.107613
  31. Cell Rep. 2020 May 05. pii: S2211-1247(20)30556-8. [Epub ahead of print]31(5): 107607
    Distinct Roles of Mitochondrial HIGD1A and HIGD2A in Respiratory Complex and Supercomplex Biogenesis.
    Alba Timón-Gómez, Joshua Garlich, Rosemary A Stuart, Cristina Ugalde, Antoni Barrientos.
      The mitochondrial respiratory chain enzymes are organized as individual complexes and supercomplexes, whose biogenesis remains to be fully understood. To disclose the role of the human Hypoxia Inducible Gene Domain family proteins HIGD1A and HIGD2A in these processes, we generate and characterize HIGD-knockout (KO) cell lines. We show that HIGD2A controls and coordinates the modular assembly of isolated and supercomplexed complex IV (CIV) by acting on the COX3 assembly module. In contrast, HIGD1A regulates CIII and CIII-containing supercomplex biogenesis by supporting the incorporation of UQCRFS1. HIGD1A also clusters with COX4-1 and COX5A CIV subunits and, when overexpressed, suppresses the CIV biogenesis defect of HIGD2A-KO cells. We conclude that HIGD1A and HIGD2A have both independent and overlapping functions in the biogenesis of respiratory complexes and supercomplexes. Our data illuminate the existence of multiple pathways to assemble these structures by dynamic HIGD-mediated CIV biogenesis, potentially to adapt to changing environmental and nutritional conditions.
    Keywords:  COX7A2L; HIGD1A; HIGD2A; OXPHOS; mitochondrial respiratory chain; respirasomes; supercomplexes
    DOI:  https://doi.org/10.1016/j.celrep.2020.107607
  32. J Chromatogr A. 2020 Apr 27. pii: S0021-9673(20)30421-0. [Epub ahead of print] 461169
    Reductive amination of α-Ketoglutarate in metabolite extracts results in glutamate overestimation.
    Elizabeth K Wiese, Sadae Hitosugi, Sarah A Buhrow, Sharon T Loa, Annapoorna Sreedhar, Joel M Reid, Wilson I Gonsalves, Taro Hitosugi.
      Artifacts due to metabolite extraction, derivatization, and detection techniques can result in aberrant observations that are not accurate representations of actual cell metabolism. Here, we show that α-ketoglutarate (α-KG) is reductively aminated to glutamate in methanol:water metabolite extracts, which introduces an artifact into metabolomics studies. We also identify pyridoxamine and urea as amine donors for α-KG to produce glutamate in methanol:water buffer in vitro, and we demonstrate that the addition of ninhydrin to the methanol:water buffer suppresses the reductive amination of α-KG to glutamate in vitro and in metabolite extracts. Finally, we calculate that glutamate levels have been overestimated by 10-50%, depending on cell line, due to α-KG reductive amination. These findings suggest that precautions to account for α-KG reductive amination should be taken for the accurate quantification of glutamate in metabolomics studies.
    DOI:  https://doi.org/10.1016/j.chroma.2020.461169
  33. Development. 2020 May 06. pii: dev.188714. [Epub ahead of print]
    Nuclear encoded mitochondrial ribosomal proteins are required to initiate gastrulation.
    Agnes Cheong, Danielle Archambault, Rinat Degani, Elizabeth Iverson, Kimberly Tremblay, Jesse Mager.
      Mitochondria are essential for energy production and while they have their own genome, many nuclear-encoded mitochondrial ribosomal proteins (MRPs) are required for proper function of the organelle. Although mutations in MRPs have been associated with human diseases, little is known about their role during development. Presented here are the null phenotypes for 21 nuclear encoded mitochondrial proteins and in-depth characterization of five MRP mutants - Mrpl3, Mrpl22, Mrpl44, Mrps18c and Mrps22 Loss of each MRP results in successful implantation and egg-cylinder formation but then severe developmental delay and failure to initiate gastrulation by embryonic day (E) 7.5. The robust and similar single knockout phenotypes are somewhat surprising given there are over 70 MRPs and suggest little functional redundancy. Metabolic analysis reveals that Mrp knockout embryos produce significantly less ATP than controls, indicating compromised mitochondrial function. Histological and immunofluorescence analyses indicate abnormal organelle morphology and stalling at the G2/M checkpoint in Mrp null cells. The nearly identical pre-gastrulation phenotype observed for many different nuclear-encoded mitochondrial protein knockouts hints that distinct energy systems are critical at specific timepoints during mammalian development.
    Keywords:  Bcs1l; Clpx; Fastkd5; Gastrulation; Hlcs; Isca1; MRP; Mars2; Mitochondria; Mouse embryo; Mrpl22; Mrpl3; Mrpl44; Mrps18c; Mrps22; Mrps25; Mtpap; Nars2; Ndufa9; Ndufs8; Pmpcb; Sdhaf2; Timm22; Tomm20; Trit1
    DOI:  https://doi.org/10.1242/dev.188714
  34. Cell Metab. 2020 May 05. pii: S1550-4131(20)30191-1. [Epub ahead of print]31(5): 1032
    Fructose-1,6-Bisphosphatase 2 Inhibits Sarcoma Progression by Restraining Mitochondrial Biogenesis.
    Peiwei Huangyang, Fuming Li, Pearl Lee, Itzhak Nissim, Aalim M Weljie, Anthony Mancuso, Bo Li, Brian Keith, Sam S Yoon, M Celeste Simon.
      
    DOI:  https://doi.org/10.1016/j.cmet.2020.04.009
  35. Cancers (Basel). 2020 May 04. pii: E1153. [Epub ahead of print]12(5):
    Metabolism and Immune Modulation in Patients with Solid Tumors: Systematic Review of Preclinical and Clinical Evidence.
    Aurora Mirabile, Licia Rivoltini, Elena Daveri, Claudio Vernieri, Roberto Mele, Luca Porcu, Chiara Lazzari, Alessandra Bulotta, Maria Grazia Viganò, Stefano Cascinu, Vanesa Gregorc.
      Several immunotherapy agents are the standard of care of many solid malignancies. Nevertheless, the majority of patients do not benefit from the currently available immunotherapies. It is therefore of paramount importance to identify the prognostic and predictive factors of tumor response/resistance and to design effective therapeutic strategies to overcome primary resistance and improve the efficacy of immunotherapy. The aim of this review is to underline the influence of the tumor and host metabolism on the antitumor immune response and to discuss possible strategies to improve the efficacy of available treatments by targeting the specific metabolic pathways in tumors or immune cells and by modifying patients' nutritional statuses. A systematic search of the Medline and EMBASE databases was carried out to identify scientific papers published until February 2020, which reported original research articles on the influence of tumor or host metabolism on antitumor immune response. The literature data showed the key role of glycolysis and mitochondrial oxidative phosphorylation, arginine, tryptophan, glutamine, lipid metabolism and microbiome on immune cell function. Moreover, specific nutritional behaviors, such as a low dietary intake of vitamin C, low glycemic index and alpha-linolenic acid, eicosapentenoic acid, docosahexaenoic acid, ornithine ketoglutarate, tryptophan and probiotic supplementation were associated with the potential clinical benefits from the currently available immunotherapies.
    Keywords:  cancer metabolism; immune response; immune-nutrition; immunotherapy; nutrition
    DOI:  https://doi.org/10.3390/cancers12051153
  36. Metabolomics. 2020 May 04. 16(5): 65
    Tissue metabolic profiling shows that saccharopine accumulates during renal ischemic-reperfusion injury, while kynurenine and itaconate accumulate in renal allograft rejection.
    Ulf H Beier, Erum A Hartung, Seth Concors, Paul T Hernandez, Zhonglin Wang, Caroline Perry, Joseph A Baur, Michelle R Denburg, Wayne W Hancock, Terence P Gade, Matthew H Levine.
      To examine metabolic differences between renal allograft acute cellular rejection (ACR) and ischemic-reperfusion injury (IRI), we transplanted MHC-mismatched kidneys and induced 28 min warm-IRI, and collected the ACR and IRI kidneys as well as their respective native and collateral control kidneys. We extracted metabolites from the kidney tissues and found the lysine catabolite saccharopine 12.5-fold enriched in IRI kidneys, as well as the immunometabolites itaconate and kynurenine in ACR kidneys. Saccharopine accumulation is known to be toxic to mitochondria and may contribute to IRI pathophysiology, while itaconate and kynurenine may be reflective of counterregulatory responses to immune activation in ACR.
    Keywords:  Allograft rejection; Ischemia–reperfusion injury; Itaconate; Kynurenine; Renal transplant; Saccharopine
    DOI:  https://doi.org/10.1007/s11306-020-01682-2
  37. Philos Trans R Soc Lond B Biol Sci. 2020 Jun 22. 375(1801): 20190396
    Retrograde signals from endosymbiotic organelles: a common control principle in eukaryotic cells.
    Thomas Pfannschmidt, Matthew J Terry, Olivier Van Aken, Pedro M Quiros.
      Endosymbiotic organelles of eukaryotic cells, the plastids, including chloroplasts and mitochondria, are highly integrated into cellular signalling networks. In both heterotrophic and autotrophic organisms, plastids and/or mitochondria require extensive organelle-to-nucleus communication in order to establish a coordinated expression of their own genomes with the nuclear genome, which encodes the majority of the components of these organelles. This goal is achieved by the use of a variety of signals that inform the cell nucleus about the number and developmental status of the organelles and their reaction to changing external environments. Such signals have been identified in both photosynthetic and non-photosynthetic eukaryotes (known as retrograde signalling and retrograde response, respectively) and, therefore, appear to be universal mechanisms acting in eukaryotes of all kingdoms. In particular, chloroplasts and mitochondria both harbour crucial redox reactions that are the basis of eukaryotic life and are, therefore, especially susceptible to stress from the environment, which they signal to the rest of the cell. These signals are crucial for cell survival, lifespan and environmental adjustment, and regulate quality control and targeted degradation of dysfunctional organelles, metabolic adjustments, and developmental signalling, as well as induction of apoptosis. The functional similarities between retrograde signalling pathways in autotrophic and non-autotrophic organisms are striking, suggesting the existence of common principles in signalling mechanisms or similarities in their evolution. Here, we provide a survey for the newcomers to this field of research and discuss the importance of retrograde signalling in the context of eukaryotic evolution. Furthermore, we discuss commonalities and differences in retrograde signalling mechanisms and propose retrograde signalling as a general signalling mechanism in eukaryotic cells that will be also of interest for the specialist. This article is part of the theme issue 'Retrograde signalling from endosymbiotic organelles'.
    Keywords:  chloroplasts; intracellular communication; metabolites; mitochondria; plastids; signalling
    DOI:  https://doi.org/10.1098/rstb.2019.0396
  38. J Inherit Metab Dis. 2020 May 07.
    A biallelic pathogenic variant in the OGDH gene results in a neurological disorder with features of a mitochondrial disease.
    Zheng Yie Yap, Klaudia Strucinska, Satoshi Matsuzaki, Sukyeong Lee, Yue Si, Kenneth Humphries, Mark A Tarnopolsky, Wan Hee Yoon.
      BACKGROUND: 2-oxoglutarate dehydrogenase (OGDH) is a rate-liming enzyme in the mitochondrial TCA cycle, encoded by the OGDH gene. α-ketoglutarate dehydrogenase (OGDH) deficiency was previously reported in association with developmental delay, hypotonia, and movement disorders and metabolic decompensation, with no genetic data provided.METHODS: Using whole exome sequencing, we identified two individuals carrying a homozygous missense variant c.959A > G (p.N320S) in the OGDH gene. These individuals presented with global developmental delay, elevated lactate, ataxia and seizure. Fibroblast analysis and modeling of the mutation in Drosophila were used to evaluate pathogenicity of the variant.
    RESULTS: Skin fibroblasts from subject # 2 showed a decrease in both OGDH protein and enzyme activity. Transfection of human OGDH cDNA in HEK293 cells carrying p.N320S also produced significantly lower protein levels compared to those with wild-type cDNA. Loss of Drosophila Ogdh (dOgdh) caused early developmental lethality, rescued by expressing wild-type dOgdh (dOgdhWT ) or human OGDH (OGDHWT ) cDNA. In contrast, expression of the mutant OGDH (OGDHN320S ) or dOgdh carrying homologous mutations to human OGDH p.N320S variant (dOgdhN324S ) failed to rescue lethality of dOgdh null mutants. Knockdown of dOgdh in the nervous system resulted in locomotion defects which were rescued by dOgdhWT expression but not by dOgdhN324S expression.
    CONCLUSION: Collectively, the results indicate that c.959A > G variant in OGDH leads to an amino acid change (p.N320S) causing a severe loss of OGDH protein function. Our study establishes in the first time a genetic link between an OGDH gene mutation and OGDH deficiency. This article is protected by copyright. All rights reserved.
    Keywords:  OGDH; TCA cycle; alpha-ketoglutarate dehydrogenase deficiency; genetic disease
    DOI:  https://doi.org/10.1002/jimd.12248
  39. Trends Cell Biol. 2020 Apr 28. pii: S0962-8924(20)30075-1. [Epub ahead of print]
    Metabolic Regulation of Tissue Stem Cells.
    Suzanne N Shapira, Heather R Christofk.
      Adult tissue stem cells mediate organ homeostasis and regeneration and thus are continually making decisions about whether to remain quiescent, proliferate, or differentiate into mature cell types. These decisions often integrate external cues, such as energy balance and the nutritional status of the organism. Metabolic substrates and byproducts that regulate epigenetic and signaling pathways are now appreciated to have instructive rather than bystander roles in regulating cell fate decisions. In this review, we highlight recent literature focused on how metabolites and dietary manipulations can impact cell fate decisions, with a focus on the regulation of adult tissue stem cells.
    Keywords:  adult stem cells; diet; differentiation; metabolism; metabolomics
    DOI:  https://doi.org/10.1016/j.tcb.2020.04.004
  40. Cancer Discov. 2020 May 08. pii: CD-19-1352. [Epub ahead of print]
    Chromatin Regulator, CHD1, Remodels the Immunosuppressive Tumor Microenvironment in PTEN-Deficient Prostate Cancer.
    Di Zhao, Li Cai, Xin Lu, Xin Liang, Jiexi Li, Peiwen Chen, Michael Ittmann, Xiaoying Shang, Shan Jiang, Haoyan Li, Chenling Meng, Ivonne Flores, Jian H Song, James W Horner, Zhengdao Lan, Chang-Jiun Wu, Jun Li, Qing Chang, Ko-Chien Chen, Guocan Wang, Pingna Deng, Denise J Spring, Y Alan Wang, Ronald A DePinho.
      Genetic inactivation of PTEN is common in prostate cancer and correlates with poorer prognosis. We previously identified chromodomain-helicase-DNA-binding protein 1 (CHD1) as an essential gene in PTEN-deficient cancer cells. Here, we sought definitive in vivo genetic evidence for, and mechanistic understanding of, the essential role of CHD1 in PTEN-deficient prostate cancer. In Pten and Pten/Smad4 genetically engineered mouse models, prostate specific deletion of Chd1 resulted in markedly delayed tumor progression and prolonged survival. Chd1 deletion was associated with profound tumor microenvironment remodeling characterized by reduced MDSCs and increased CD8+ T cells. Further analysis identified IL-6 as a key transcriptional target of CHD1, which plays a major role in recruitment of immunosuppressive MDSCs. Given the prominent role of MDSCs in suppressing responsiveness to immune checkpoint inhibitors (ICI), our genetic and tumor biological findings support combined testing of anti-IL-6 and ICI therapies, specifically in PTEN-deficient prostate cancer.
    DOI:  https://doi.org/10.1158/2159-8290.CD-19-1352
  41. Mol Cell. 2020 Apr 24. pii: S1097-2765(20)30236-7. [Epub ahead of print]
    NAD+ Controls Circadian Reprogramming through PER2 Nuclear Translocation to Counter Aging.
    Daniel C Levine, Heekyung Hong, Benjamin J Weidemann, Kathryn M Ramsey, Alison H Affinati, Mark S Schmidt, Jonathan Cedernaes, Chiaki Omura, Rosemary Braun, Choogon Lee, Charles Brenner, Clara Bien Peek, Joseph Bass.
      Disrupted sleep-wake and molecular circadian rhythms are a feature of aging associated with metabolic disease and reduced levels of NAD+, yet whether changes in nucleotide metabolism control circadian behavioral and genomic rhythms remains unknown. Here, we reveal that supplementation with the NAD+ precursor nicotinamide riboside (NR) markedly reprograms metabolic and stress-response pathways that decline with aging through inhibition of the clock repressor PER2. NR enhances BMAL1 chromatin binding genome-wide through PER2K680 deacetylation, which in turn primes PER2 phosphorylation within a domain that controls nuclear transport and stability and that is mutated in human advanced sleep phase syndrome. In old mice, dampened BMAL1 chromatin binding, transcriptional oscillations, mitochondrial respiration rhythms, and late evening activity are restored by NAD+ repletion to youthful levels with NR. These results reveal effects of NAD+ on metabolism and the circadian system with aging through the spatiotemporal control of the molecular clock.
    Keywords:  NAD(+); SIRT1; aging; circadian; clock; heat shock factor 1; liver; nicotinamide mononucleotide; nicotinamide riboside; transcriptomics
    DOI:  https://doi.org/10.1016/j.molcel.2020.04.010
  42. Semin Cancer Biol. 2020 Jun;pii: S1044-579X(20)30091-2. [Epub ahead of print]63 iii-iv
    Emerging Role of Cell Competition in Cancer.
    Rajan Gogna, Eduardo Moreno.
      
    DOI:  https://doi.org/10.1016/j.semcancer.2020.04.005
  43. JCI Insight. 2020 May 07. pii: 128820. [Epub ahead of print]5(9):
    GCN2 regulates pancreatic β cell mass by sensing intracellular amino acid levels.
    Ayumi Kanno, Shun-Ichiro Asahara, Ayuko Furubayashi, Katsuhisa Masuda, Risa Yoshitomi, Emi Suzuki, Tomoko Takai, Maki Kimura-Koyanagi, Tomokazu Matsuda, Alberto Bartolome, Yushi Hirota, Norihide Yokoi, Yuka Inaba, Hiroshi Inoue, Michihiro Matsumoto, Kenichi Inoue, Takaya Abe, Fan-Yan Wei, Kazuhito Tomizawa, Wataru Ogawa, Susumu Seino, Masato Kasuga, Yoshiaki Kido.
      EIF2AK4, which encodes the amino acid deficiency-sensing protein GCN2, has been implicated as a susceptibility gene for type 2 diabetes in the Japanese population. However, the mechanism by which GCN2 affects glucose homeostasis is unclear. Here, we show that insulin secretion is reduced in individuals harboring the risk allele of EIF2AK4 and that maintenance of GCN2-deficient mice on a high-fat diet results in a loss of pancreatic β cell mass. Our data suggest that GCN2 senses amino acid deficiency in β cells and limits signaling by mechanistic target of rapamycin complex 1 to prevent β cell failure during the consumption of a high-fat diet.
    Keywords:  Endocrinology; Insulin signaling; Islet cells; Metabolism
    DOI:  https://doi.org/10.1172/jci.insight.128820
  44. EMBO Rep. 2020 May 06. 21(5): e50461
    Succinate induces skeletal muscle fiber remodeling via SUCNR1 signaling.
    Tao Wang, Ya-Qiong Xu, Ye-Xian Yuan, Ping-Wen Xu, Cha Zhang, Fan Li, Li-Na Wang, Cong Yin, Lin Zhang, Xing-Cai Cai, Can-Jun Zhu, Jing-Ren Xu, Bing-Qing Liang, Sarah Schaul, Pei-Pei Xie, Dong Yue, Zheng-Rui Liao, Lu-Lu Yu, Lv Luo, Gan Zhou, Jin-Ping Yang, Zhi-Hui He, Man Du, Yu-Ping Zhou, Bai-Chuan Deng, Song-Bo Wang, Ping Gao, Xiao-Tong Zhu, Qian-Yun Xi, Yong-Liang Zhang, Gang Shu, Qing-Yan Jiang.
      
    DOI:  https://doi.org/10.15252/embr.202050461
  45. FEBS J. 2020 May 08.
    CRY1-CBS binding regulates circadian clock function and metabolism.
    Sibel Cal-Kayitmazbatir, Eylem Kulkoyluoglu-Cotul, Jacqueline Growe, Christopher P Selby, Seth D Rhoades, Dania Malik, Hasimcan Oner, Hande Asimgil, Lauren J Francey, Aziz Sancar, Warren D Kruger, John B Hogenesch, Aalim Weljie, Ron C Anafi, Ibrahim Halil Kavakli.
      Circadian disruption influences metabolic health. Metabolism modulates circadian function. However, the mechanisms coupling circadian rhythms and metabolism remain poorly understood. Here we report that Cystathionine β-synthase (CBS), a central enzyme in one-carbon metabolism, functionally interacts with the core circadian protein Cryptochrome1 (CRY1). In cells, CBS augments CRY1 mediated repression of the CLOCK/BMAL1 complex and shortens circadian period. Notably, we find that mutant CBS-I278T protein, the most common cause of homocystinuria, does not bind CRY1 or regulate its repressor activity. Transgenic CbsZn/Zn  mice, while maintaining circadian locomotor activity period, exhibit reduced circadian power and increased expression of E-BOX outputs. CBS function is reciprocally influenced by CRY1 binding. CRY1 modulates enzymatic activity of the CBS. Liver extracts from Cry1-/-  mice show reduced CBS activity that normalizes after the addition of exogenous wild type (WT) CRY1. Metabolomic analysis of WT, CbsZn/Zn , Cry1-/- , and Cry2-/-  samples highlights the metabolic importance of endogenous CRY1. We observed temporal variation in one-carbon and transsulfuration pathways attributable to CRY1 induced CBS activation. CBS-CRY1 binding provides a post-translational switch to modulate cellular circadian physiology and metabolic control.
    Keywords:  Cryptochrome; Cystathionine β-synthase; circadian rhythm; hydrogen sulfate; metabolism; metabolomics; transcriptional regulation
    DOI:  https://doi.org/10.1111/febs.15360
  46. Nat Commun. 2020 May 04. 11(1): 2196
    TALPID3 and ANKRD26 selectively orchestrate FBF1 localization and cilia gating.
    Hao Yan, Chuan Chen, Huicheng Chen, Hui Hong, Yan Huang, Kun Ling, Jinghua Hu, Qing Wei.
      Transition fibers (TFs) regulate cilia gating and make the primary cilium a distinct functional entity. However, molecular insights into the biogenesis of a functional cilia gate remain elusive. In a forward genetic screen in Caenorhabditis elegans, we uncover that TALP-3, a homolog of the Joubert syndrome protein TALPID3, is a TF-associated component. Genetic analysis reveals that TALP-3 coordinates with ANKR-26, the homolog of ANKRD26, to orchestrate proper cilia gating. Mechanistically, TALP-3 and ANKR-26 form a complex with key gating component DYF-19, the homolog of FBF1. Co-depletion of TALP-3 and ANKR-26 specifically impairs the recruitment of DYF-19 to TFs. Interestingly, in mammalian cells, TALPID3 and ANKRD26 also play a conserved role in coordinating the recruitment of FBF1 to TFs. We thus report a conserved protein module that specifically regulates the functional component of the ciliary gate and suggest a correlation between defective gating and ciliopathy pathogenesis.
    DOI:  https://doi.org/10.1038/s41467-020-16042-w
  47. Trends Mol Med. 2020 May 01. pii: S1471-4914(20)30106-4. [Epub ahead of print]
    Metabolic Pathways That Control Skin Homeostasis and Inflammation.
    Danay Cibrian, Hortensia de la Fuente, Francisco Sánchez-Madrid.
      Keratinocytes and skin immune cells are actively metabolizing nutrients present in their microenvironment. This is particularly important in common chronic inflammatory skin diseases such as psoriasis and atopic dermatitis, characterized by hyperproliferation of keratinocytes and expansion of inflammatory cells, thus suggesting increased cell nutritional requirements. Proliferating inflammatory cells and keratinocytes express high levels of glucose transporter (GLUT)1, l-type amino acid transporter (LAT)1, and cationic amino acid transporters (CATs). Main metabolic regulators such as hypoxia-inducible factor (HIF)-1α, MYC, and mechanistic target of rapamycin (mTOR) control immune cell activation, proliferation, and cytokine release. Here, we provide an updated perspective regarding the potential role of nutrient transporters and metabolic pathways that could be common to immune cells and keratinocytes, to control psoriasis and atopic dermatitis.
    Keywords:  amino acid; atopic dermatitis; glucose; metabolism; psoriasis; transporters
    DOI:  https://doi.org/10.1016/j.molmed.2020.04.004
  48. Antioxid Redox Signal. 2020 May 05.
    Stable and temporary enzyme complexes and metabolons involved in energy and redox metabolism.
    Youjun Zhang, Alisdair R Fernie.
      SIGNIFICANCE: Alongside well-characterized permanent multimeric enzymes and multi-enzyme complexes relatively unstable transient enzyme-enzyme assemblies, including metabolons, provide an important mechanism for the regulation of energy and redox metabolism.CRITICAL ISSUES: Despite the fact that enzyme-enzyme assemblies have been proposed for many decades and experimentally analyzed for at least 40 years there are very few pathways for which unequivocal evidence for the presence of metabolite channeling, the most frequently evoked reason for their formation, has been provided. Furthermore, in contrast to the stronger, permanent interactions for which a deep understanding of the subunit interface exists the mechanism(s) underlying transient enzyme-enzyme interactions remain poorly studied. Recent advances: The widespread adoption of proteomic and cell biological approaches to characterize protein-protein interaction is defining an ever-increasing number of enzyme-enzyme assemblies as well as enzyme protein interactions that likely identify factors which stabilize such complexes. Moreover, the use of microfluidic technologies provided compelling support of a role for substrate-specific chemotaxis in complex assemblies.
    FUTURE DIRECTIONS: Embracing current and developing technologies should render the delineation of metabolons from other enzyme-enzyme complexes more facile. In parallel, attempts to confirm that the findings reported in microfluidic systems are indeed representative of the cellular situation will be critical to understanding the physiological circumstances requiring and evoking dynamic changes in the levels of the various transient enzyme-enzyme assemblies of the cell.
    DOI:  https://doi.org/10.1089/ars.2019.7981
  49. Mol Biol Cell. 2020 May 06. mbcE19100560
    Mitochondria regulate intestinal stem cell proliferation and epithelial homeostasis through FOXO.
    Fan Zhang, Mehdi Pirooznia, Hong Xu.
      A metabolic transition from glycolysis to oxidative phosphorylation often associates with differentiation of many types of stem cells. However, the link between mitochondrial respiration and stem cells' behavior is not fully understood. we genetically disrupted electron transport chain (ETC) complexes in the intestinal stem cells (ISCs) of Drosophila. We found that ISCs carrying impaired ETC proliferated much more slowly than normal, produced very few enteroblasts, which failed to further differentiate into enterocytes. One of the main impediments to ISC proliferation and lineage specification appeared to be abnormally elevated forkhead box O (FOXO) signaling in the ETC-deficient ISCs, as genetically suppressing the signaling pathway partially restored the number of enterocytes. Contrary to common belief, reactive oxygen species (ROS) accumulation did not appear to mediate the ETC mutant phenotype. Our results demonstrate that mitochondrial respiration is essential for Drosophila ISC proliferation and lineage specification in vivo and acts at least partially by repressing endogenous FOXO signaling.
    DOI:  https://doi.org/10.1091/mbc.E19-10-0560
  50. J Cell Biol. 2020 Jul 06. pii: e201907098. [Epub ahead of print]219(7):
    Structural insights into G domain dimerization and pathogenic mutation of OPA1.
    Caiting Yu, Jinghua Zhao, Liming Yan, Yuanbo Qi, Xiangyang Guo, Zhiyong Lou, Junjie Hu, Zihe Rao.
      The fusion of mammalian inner mitochondrial membranes (IMMs) is mediated by dynamin-like GTPase OPA1. Mutations in human OPA1 cause optic atrophy, but the molecular basis for membrane fusion and pathogenesis is not clear. Here, we determined the crystal structure of the minimal GTPase domain (MGD) of human OPA1. A three-helix bundle (HB) domain including two helices extending from the GTPase (G) domain and the last helix of OPA1 tightly associates with the G domain. In the presence of GDP and BeF3-, OPA1-MGD forms a dimer, the interface of which is critical for the maintenance of mitochondrial morphology. The catalytic core of OPA1 possesses unique features that are not present in other dynamin-like proteins. Biochemical experiments revealed that OPA1-MGD forms nucleotide-dependent dimers, which is important for membrane-stimulated GTP hydrolysis, and an N-terminal extension mediates nucleotide-independent dimerization that facilitates efficient membrane association. Our results suggest a multifaceted assembly of OPA1 and explain the effect of most OPA1 mutations on optic atrophy.
    DOI:  https://doi.org/10.1083/jcb.201907098
  51. Autophagy. 2020 May 05.
    Autophagy Suppresses TRP53/p53 and Oxidative Stress to Enable Mammalian Survival.
    Yang Yang, Eileen White.
      Macroautophagy (hereafter autophagy) plays an important role in maintaining cellular homeostasis under stress conditions. We previously demonstrated that conditional autophagy deficiency in adult mice causes selective tissue damage, is lethal upon fasting, and shortens lifespan to less than three months primarily due to neurodegeneration, but not all the mechanisms are known. We conditionally deleted Trp53/p53 and/or the essential autophagy gene Atg7 throughout adult mice to test whether TRP53 is responsible for any of these phenotypes. atg7Δ/Δ trp53Δ/Δ mice have extended lifespan due to delayed tissue damage and neurodegeneration, and are resistant to death upon fasting compared to atg7Δ/Δ mice. Atg7 also suppresses apoptosis induced by the TRP53 activator Nutlin-3 in liver and brain. We then deleted Atg7 in the presence or absence of the master regulator of antioxidant defense NFE2L2/NRF2 (nuclear factor, erythroid derived 2, like 2) to test if increased oxidative stress causes TRP53 activation in atg7Δ/Δ mice. nfe2l2-/-atg7Δ/Δ mice die rapidly due to intestinal damage, which is not rescued by trp53 co-deletion. Therefore, these data demonstrate the tissue specificities and functional dependencies between autophagy, TRP53 and NFE2L2 stress response mechanisms.
    Keywords:  ATG7; DNA damage; NRF2; apoptosis; autophagy; brain; intestine; liver; oxidative stress; p53
    DOI:  https://doi.org/10.1080/15548627.2020.1765522
  52. Proc Natl Acad Sci U S A. 2020 May 05. pii: 201913767. [Epub ahead of print]
    Metabolic cost of rapid adaptation of single yeast cells.
    Gabrielle Woronoff, Philippe Nghe, Jean Baudry, Laurent Boitard, Erez Braun, Andrew D Griffiths, Jérôme Bibette.
      Cells can rapidly adapt to changing environments through nongenetic processes; however, the metabolic cost of such adaptation has never been considered. Here we demonstrate metabolic coupling in a remarkable, rapid adaptation process (1 in 1,000 cells adapt per hour) by simultaneously measuring metabolism and division of thousands of individual Saccharomyces cerevisiae cells using a droplet microfluidic system: droplets containing single cells are immobilized in a two-dimensional (2D) array, with osmotically induced changes in droplet volume being used to measure cell metabolism, while simultaneously imaging the cells to measure division. Following a severe challenge, most cells, while not dividing, continue to metabolize, displaying a remarkably wide diversity of metabolic trajectories from which adaptation events can be anticipated. Adaptation requires a characteristic amount of energy, indicating that it is an active process. The demonstration that metabolic trajectories predict a priori adaptation events provides evidence of tight energetic coupling between metabolism and regulatory reorganization in adaptation. This process allows S. cerevisiae to adapt on a physiological timescale, but related phenomena may also be important in other processes, such as cellular differentiation, cellular reprogramming, and the emergence of drug resistance in cancer.
    Keywords:  adaptation; droplet-based microfluidics; genetic rewiring; single-cell metabolism
    DOI:  https://doi.org/10.1073/pnas.1913767117
  53. FASEB J. 2020 May 05.
    CHCHD10-regulated OPA1-mitofilin complex mediates TDP-43-induced mitochondrial phenotypes associated with frontotemporal dementia.
    Tian Liu, Jung-A A Woo, Mohammed Zaheen Bukhari, Patrick LePochat, Ann Chacko, Maj-Linda B Selenica, Yan Yan, Peter Kotsiviras, Sara Cazzaro Buosi, Xingyu Zhao, David E Kang.
      Mutations in CHCHD10, a gene coding for a mitochondrial protein, are implicated in ALS-FTD spectrum disorders, which are pathologically characterized by transactive response DNA binding protein 43 kDa (TDP-43) accumulation. While both TDP-43 and CHCHD10 mutations drive mitochondrial pathogenesis, mechanisms underlying such phenotypes are unclear. Moreover, despite the disruption of the mitochondrial mitofilin protein complex at cristae junctions in patient fibroblasts bearing the CHCHD10S59L mutation, the role of CHCHD10 variants in mitofilin-associated protein complexes in brain has not been examined. Here, we utilized novel CHCHD10 transgenic mouse variants (WT, R15L, & S59L), TDP-43 transgenic mice, FTLD-TDP patient brains, and transfected cells to assess the interplay between CHCHD10 and TDP-43 on mitochondrial phenotypes. We show that CHCHD10 mutations disrupt mitochondrial OPA1-mitofilin complexes in brain, associated with impaired mitochondrial fusion and respiration. Likewise, CHCHD10 levels and OPA1-mitofilin complexes are significantly reduced in brains of FTLD-TDP patients and TDP-43 transgenic mice. In cultured cells, CHCHD10 knockdown results in OPA1-mitofilin complex disassembly, while TDP-43 overexpression also reduces CHCHD10, promotes OPA1-mitofilin complex disassembly via CHCHD10, and impairs mitochondrial fusion and respiration, phenotypes that are rescued by wild type (WT) CHCHD10. These results indicate that disruption of CHCHD10-regulated OPA1-mitofilin complex contributes to mitochondrial abnormalities in FTLD-TDP and suggest that CHCHD10 restoration could ameliorate mitochondrial dysfunction in FTLD-TDP.
    Keywords:  CHCHD10; OPA1; TDP-43; frontotemporal dementia; mitofilin
    DOI:  https://doi.org/10.1096/fj.201903133RR
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