bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2019‒02‒17
88 papers selected by
Christian Frezza,

  1. Mitochondrial GPT2 plays a pivotal role in metabolic adaptation to the perturbation of mitochondrial glutamine metabolism.
  2. Tricarboxylic acid cycle metabolites in the control of macrophage activation and effector phenotypes.
  3. Mapping Metabolic Events in the Cancer Cell Cycle Reveals Arginine Catabolism in the Committed SG2M Phase.
  4. Post-Translational Modifications of Mitochondrial Fission and Fusion Proteins in Cardiac Physiology and Pathophysiology.
  5. CaMKII Does not Control Mitochondrial Ca2+ Uptake in Cardiac Myocytes.
  6. Altered mitochondrial quality control in Atg7-deficient VSMCs promotes enhanced apoptosis and is linked to unstable atherosclerotic plaque phenotype.
  7. Mitochondrial disorders.
  8. Coenzyme Q10 protects against burn-induced mitochondrial dysfunction and impaired insulin signaling in mouse skeletal muscle.
  9. WWOX somatic ablation in skeletal muscles alters glucose metabolism.
  10. Exploring the molecular interface between hypoxia-inducible factor signalling and mitochondria.
  11. BNIP3L/NIX and FUNDC1-Mediated Mitophagy is Required for Mitochondrial Network Remodeling during Cardiac Progenitor Cell Differentiation.
  12. SIRT5 deficiency suppresses mitochondrial ATP production and promotes AMPK activation in response to energy stress.
  13. Metabolic and oncogenic adaptations to pyruvate dehydrogenase inactivation in fibroblasts.
  14. Dimeric ferrochelatase bridges ABCB7 and ABCB10 homodimers in an architecturally defined molecular complex required for heme biosynthesis.
  15. Fhit-Fdxr interaction in the mitochondria: modulation of reactive oxygen species generation and apoptosis in cancer cells.
  16. A concert of RNA-binding proteins coordinates mitochondrial function.
  17. Dual Role of Mitochondrial Porin in Metabolite Transport across the Outer Membrane and Protein Transfer to the Inner Membrane.
  18. Brown and Brite: The Fat Soldiers in the Anti-obesity Fight.
  19. Hypoxia-Modified Cancer Cell Metabolism.
  20. Mitochondrial Dysfunctions in Barth Syndrome.
  21. Singlet molecular oxygen regulates vascular tone and blood pressure in inflammation.
  22. Adrenoceptor regulation of mTOR in muscle and adipose tissue.
  23. MPC1 deficiency accelerates lung adenocarcinoma progression through the STAT3 pathway.
  24. Suppression of Tafazzin promotes thyroid cancer apoptosis via activating the JNK signaling pathway and enhancing INF2-mediated mitochondrial fission.
  25. Niclosamide activates the NLRP3 inflammasome by intracellular acidification and mitochondrial inhibition.
  26. The exceptional longevity of the naked mole-rat may be explained by mitochondrial antioxidant defenses.
  27. Doxorubicin-induced cardiomyopathy associated with inhibition of autophagic degradation process and defects in mitochondrial respiration.
  28. Role of mitochondrial calcium uniporter-mediated Ca2+ and iron accumulation in traumatic brain injury.
  29. Excessive Cell Growth Causes Cytoplasm Dilution And Contributes to Senescence.
  30. Porin Associates with Tom22 to Regulate the Mitochondrial Protein Gate Assembly.
  31. Expression and Activation of BKCa Channels in Mice Protects Against Ischemia-Reperfusion Injury of Isolated Hearts by Modulating Mitochondrial Function.
  32. Sirt6 Suppresses High Glucose-Induced Mitochondrial Dysfunction and Apoptosis in Podocytes through AMPK Activation.
  33. Inborn errors of coenzyme A metabolism and neurodegeneration.
  34. Regulation of permeability transition pore opening in mitochondria by external NAD(H).
  35. The coordinated regulation of mitochondrial structure and function by Drp1 for mitochondrial quality surveillance.
  36. mTORC2-mediated PDHE1α nuclear translocation links EBV-LMP1 reprogrammed glucose metabolism to cancer metastasis in nasopharyngeal carcinoma.
  37. Mitochondrial integrity in neurodegeneration.
  38. LCAL1 enhances lung cancer survival via inhibiting AMPK-related antitumor functions.
  39. Peroxisomal dysfunction in neurodegenerative diseases.
  40. The different response of cardiomyocytes and cardiac fibroblasts to mitochondria inhibition and the underlying role of STAT3.
  41. Mitochondrial superoxide dismutase 2 mediates γ-irradiation-induced cancer cell invasion.
  42. Imaging tumor acidosis: a survey of the available techniques for mapping in vivo tumor pH.
  43. Mitochondrial protein E2F3d, a distinctive E2F3 product, mediates hypoxia-induced mitophagy in cancer cells.
  44. KDEL receptor regulates secretion by lysosome relocation- and autophagy-dependent modulation of lipid-droplet turnover.
  45. Preoperative Metabolic Signatures of Prostate Cancer Recurrence Following Radical Prostatectomy.
  46. Inhibition of upper small intestinal mTOR lowers plasma glucose levels by inhibiting glucose production.
  47. Squalene accumulation in cholesterol auxotrophic lymphomas prevents oxidative cell death.
  48. The physiological mTOR complex 1 inhibitor DDIT4 mediates therapy resistance in glioblastoma.
  49. The beneficial roles of exercise training via autophagy in neurological diseases and possible mechanisms.
  50. Macrophage achieves self-protection against oxidative stress-induced ageing through the Mst-Nrf2 axis.
  51. MT-ATP6 Mitochondrial Disease Variants: Phenotypic and biochemical features analysis in 218 published cases and cohort of 14 new cases.
  52. CFP suppresses breast cancer cell growth by TES-mediated upregulation of the transcription factor DDIT3.
  53. Mitochondrial Heterogeneity.
  54. Crystal structure of MICU2 and comparison with MICU1 reveal insights into the uniporter gating mechanism.
  55. TRPM7 is the central gatekeeper of intestinal mineral absorption essential for postnatal survival.
  56. Kynurenine 3-monooxygenase is a critical regulator of renal ischemia-reperfusion injury.
  57. The dynamic side of the Warburg effect: glycolytic intermediates as buffer for fluctuating glucose and O 2 supply in tumor cells.
  58. Copy-choice recombination during mitochondrial L-strand synthesis causes DNA deletions.
  59. Elevated expression of the V-ATPase D2 subunit triggers increased energy metabolite levels in KrasG12D -driven cancer cells.
  60. Reduced mitochondrial respiration and increased calcium deposits in the EDL muscle, but not in soleus, from 12-week-old dystrophic mdx mice.
  61. Amino acid and Fatty Acid Metabolomic Profile during Fasting and Hyperinsulinemia in girls with Polycystic Ovarian Syndrome.
  62. MtBrowse: An integrative genomics browser for human mitochondrial DNA.
  63. Double bonds of unsaturated fatty acids differentially regulate mitochondrial cardiolipin remodeling.
  64. C9orf72-dependent lysosomal functions regulate epigenetic control of autophagy and lipid metabolism.
  65. Dimers of mitochondrial ATP synthase induce membrane curvature and self-assemble into rows.
  66. Structure of the complex I-like molecule NDH of oxygenic photosynthesis.
  67. Mitochondria-centric bioenergetic characteristics in cancer stem-like cells.
  68. Glutamine Metabolism in Macrophages: A Novel Target for Obesity/Type 2 Diabetes.
  69. mTOR-dependent upregulation of xCT blocks melanin synthesis and promotes tumorigenesis.
  70. What's in a name? How organelles of endosymbiotic origin can be distinguished from endosymbionts.
  71. MDH1 and MPP7 regulate autophagy in pancreatic ductal adenocarcinoma.
  72. Glutathione Metabolism: An Achilles' Heel of ARID1A-Deficient Tumors.
  73. Mitochondrial reactive oxygen species enable proinflammatory signaling through disulfide linkage of NEMO.
  74. NADP+ is an endogenous PARP inhibitor in DNA damage response and tumor suppression.
  75. Mitophagy inhibits amyloid-β and tau pathology and reverses cognitive deficits in models of Alzheimer's disease.
  76. Neoadjuvant anti-PD-1 immunotherapy promotes a survival benefit with intratumoral and systemic immune responses in recurrent glioblastoma.
  77. Glycogen metabolism and glycogen storage disorders.
  78. Bcl9 and Pygo synergise downstream of Apc to effect intestinal neoplasia in FAP mouse models.
  79. Fatty acid oxidation disorders.
  80. TP53 Mutations Are Immunogenic in Epithelial Cancer.
  81. YAP1-LATS2 feedback loop dictates senescent or malignant cell fate to maintain tissue homeostasis.
  82. Dimethyl fumarate, a two-edged drug: Current status and future directions.
  83. Amino acid disorders.
  84. NETO2 promotes invasion and metastasis of gastric cancer cells via activation of PI3K/Akt/NF-κB/Snail axis and predicts outcome of the patients.
  85. Organic acid disorders.
  86. Deacylative transformations of ketones via aromatization-promoted C-C bond activation.
  87. Emerging Roles in the Biogenesis of Cytochrome c Oxidase for Members of the Mitochondrial Carrier Family.
  88. Mitochondrial metabolism is inhibited by the HIF1α-MYC-PGC-1β axis in BRAF V600E thyroid cancer.
  1. Oncogene. 2019 Feb 14.
    Mitochondrial GPT2 plays a pivotal role in metabolic adaptation to the perturbation of mitochondrial glutamine metabolism.
    Minjoong Kim, Jihye Gwak, Sunsook Hwang, Seungyeon Yang, Seung Min Jeong.
      Cancer cells exhibit metabolic dependence on mitochondrial glutamine metabolism that provides them with the substrates required for rapid proliferation. Despite the extensive efforts to target this glutamine addiction for therapeutic purposes, the adaptive metabolic responses and the mechanisms whereby cells maintain their unlimited growth remain areas of active investigation. Here we report that mitochondrial glutamate-pyruvate transaminase 2 (GPT2) contributes to cell survival and growth by sustaining the tricarboxylic acid (TCA) cycle anaplerosis after the inhibition of glutaminase (GLS), the first enzyme for mitochondrial glutamine metabolism. We found that elevated reactive oxygen species upon GLS inhibition induce GPT2 expression via activating transcription factor 4. Moreover, inhibition of GPT2 synergized with suppression of GLS activity to induce a pronounced reduction in proliferation and an increase in cell death of cancer cells. Our data uncover GPT2 as an important component of the adaptive metabolic response for glutamine deprivation and indicate that targeting this pathway in combination with GLS inhibition may be an effective therapeutic approach for cancer treatment.
    DOI:  https://doi.org/10.1038/s41388-019-0751-4
  2. J Leukoc Biol. 2019 Feb 15.
    Tricarboxylic acid cycle metabolites in the control of macrophage activation and effector phenotypes.
    Jordan T Noe, Robert A Mitchell.
      The tricarboxylic acid (TCA) cycle is a mitochondrial metabolic hub that coordinates the metabolism of carbohydrates, proteins, and fats into carbon dioxide and ATP. At specific points in the cycle, the diversion, import, or export of TCA metabolites allows for the dynamic regulation of a variety of tissue and/or cell-specific phenotypic processes. Recent studies have identified that a number of TCA metabolites are important in controlling monocyte/macrophage phenotypes and effector functions while specific macrophage activation or polarization states functionally determine the relative utilization of each. This review focuses on the metabolic reprogramming of the TCA cycle in macrophages and how individual metabolites play a variety of context-specific roles in determining physiologic and pathologic macrophage activation and homeostatic functions. We discuss the implications of these findings and address unanswered questions regarding the role of the TCA cycle in guiding macrophage-dependent immune responses.
    Keywords:  TCA cycle; effector functions; macrophage; metabolism; phenotypic plasticity; transcription factors
    DOI:  https://doi.org/10.1002/JLB.3RU1218-496R
  3. Cell Rep. 2019 Feb 12. pii: S2211-1247(19)30088-9. [Epub ahead of print]26(7): 1691-1700.e5
    Mapping Metabolic Events in the Cancer Cell Cycle Reveals Arginine Catabolism in the Committed SG2M Phase.
    Irena Roci, Jeramie D Watrous, Kim A Lagerborg, Lorenzo Lafranchi, Arne Lindqvist, Mohit Jain, Roland Nilsson.
      Alterations in cell-cycle regulation and cellular metabolism are associated with cancer transformation, and enzymes active in the committed cell-cycle phase may represent vulnerabilities of cancer cells. Here, we map metabolic events in the G1 and SG2M phases by combining cell sorting with mass spectrometry-based isotope tracing, revealing hundreds of cell-cycle-associated metabolites. In particular, arginine uptake and ornithine synthesis are active during SG2M in transformed but not in normal cells, with the mitochondrial arginase 2 (ARG2) enzyme as a potential mechanism. While cancer cells exclusively use ARG2, normal epithelial cells synthesize ornithine via ornithine aminotransferase (OAT). Knockdown of ARG2 markedly reduces cancer cell growth and causes G2M arrest, while not inducing compensation via OAT. In human tumors, ARG2 is highly expressed in specific tumor types, including basal-like breast tumors. This study sheds light on the interplay between metabolism and cell cycle and identifies ARG2 as a potential metabolic target.
    Keywords:  ARG2; OAT; arginase 2; basal-like breast cancer; cancer metabolism; isotope tracing; mass spectrometry; ornithine; polyamines
    DOI:  https://doi.org/10.1016/j.celrep.2019.01.059
  4. Am J Physiol Cell Physiol. 2019 Feb 13.
    Post-Translational Modifications of Mitochondrial Fission and Fusion Proteins in Cardiac Physiology and Pathophysiology.
    Stephane M Adaniya, Jin O-Uchi, Michael W Cypress, Yoichiro Kusakari, Bong Sook Jhun.
      Mitochondrial fragmentation frequently occurs in chronic pathological conditions as seen in various human diseases. In fact, abnormal mitochondrial morphology and mitochondrial dysfunction are hallmarks of heart failure (HF) in both human patients and HF animal models. A link between mitochondrial fragmentation and cardiac pathologies has widely been proposed, but the physiological relevance of mitochondrial fission/fusion in the heart is still unclear. Recent studies have increasingly shown that post-translational modifications (PTMs) of fission/fusion proteins are capable of directly modulating the stability, localization, and/or activity of these proteins. These PTMs include phosphorylation, acetylation, ubiquitination, SUMOylation, and O-linked-N-acetyl-glucosamine glycosylation, and proteolysis. Thus, understanding the PTMs of fission/fusion proteins may allow us to understand the complexities that determine the balance of mitochondrial fission and fusion as well as mitochondrial function in various cell-types/organs including cardiomyocytes/heart. In this review, we summarize the current knowledge regarding the function and regulation of mitochondrial fission and fusion in cardiomyocytes, specifically focusing on the PTMs of each mitochondrial fission/fusion protein. We also discuss the molecular mechanisms underlying abnormal mitochondrial morphology in HF and their contributions to the development of cardiac diseases, highlighting the crucial roles of PTMs of mitochondrial fission/fusion proteins. Lastly, we discuss the future potential of manipulating PTMs of fission/fusion proteins as a therapeutic strategy for preventing and/or treating HF.
    Keywords:  DLP1; Drp1; Mfn; Mitophagy; OPA1
    DOI:  https://doi.org/10.1152/ajpcell.00523.2018
  5. J Physiol. 2019 Feb 16.
    CaMKII Does not Control Mitochondrial Ca2+ Uptake in Cardiac Myocytes.
    Alexander G Nickel, Michael Kohlhaas, Edoardo Bertero, Daniel Wilhelm, Michael Wagner, Vasco Sequeira, Michael M Kreusser, Matthias Dewenter, Reinhard Kappl, Markus Hoth, Jan Dudek, Johannes Backs, Christoph Maack.
      KEY POINTS: Mitochondrial Ca2+ uptake stimulates the Krebs cycle to regenerate the reduced forms of pyridine nucleotides (NADH, NADPH and FADH2 ) required for ATP production and ROS elimination. It was previously proposed that Ca2+ /calmodulin-dependent protein kinase II (CaMKII) regulates mitochondrial Ca2+ uptake via MCU phosphorylation. We used two mouse models with either global deletion of CaMKIIδ (CaMKIIδ KO) or cardiomyocyte-specific deletion of CaMKIIδ and γ (CaMKIIδ/γ DKO) to interrogate whether CaMKII controls mitochondrial Ca2+ uptake in isolated mitochondria and during β-adrenergic stimulation in cardiac myocytes. CaMKIIδ/γ controlled neither Ca2+ uptake, respiration nor ROS emission in isolated cardiac mitochondria nor in isolated cardiac myocytes during β-adrenergic stimulation and pacing. Our results argue against a relevant role of CaMKII for mitochondrial Ca2+ uptake in cardiac myocytes under physiological conditions.ABSTRACT: Mitochondria are the main source of ATP and reactive oxygen species (ROS) in cardiac myocytes. Furthermore, activation of the mitochondrial permeability transition pore (mPTP) induces programmed cell death. These processes are essentially controlled by Ca2+ , which is taken up into mitochondria via the Ca2+ uniporter (MCU). It was recently proposed that Ca2+ /calmodulin-dependent protein kinase II (CaMKII) regulates Ca2+ uptake by interacting with the MCU, thereby affecting mPTP activation and programmed cell death. Here, we addressed the role of CaMKII under physiological conditions in which mitochondrial Ca2+ uptake matches energy supply to demand of cardiac myocytes. To this end, we measured mitochondrial Ca2+ uptake in isolated mitochondria and cardiac myocytes harvested from cardiomyocyte-specific CaMKII δ and γ double KO (CaMKIIδ/γ DKO) and global CaMKIIδ KO mice. To simulate a physiological workload increase, cardiac myocytes were subjected to β-adrenergic stimulation (by isoproterenol superfusion) and increase in stimulation frequency (from 0.5 to 5 Hz). No differences in mitochondrial Ca2+ accumulation were detected in isolated mitochondria or cardiac myocytes from both CaMKII KO models compared with wild-type (WT) littermates. Mitochondrial redox state and ROS production were unchanged in CaMKIIδ/γ DKO, whereas we observed a mild oxidation of mitochondrial redox state and an increase in H2 O2 emission from CaMKIIδ KO cardiac myocytes exposed to an increase in workload. In conclusion, our results argue against a relevant regulation of mitochondrial Ca2+ uptake via the MCU or mPTP activation by CaMKII in cardiac myocytes under physiological conditions. This article is protected by copyright. All rights reserved.
    DOI:  https://doi.org/10.1113/JP276766
  6. Cell Death Dis. 2019 Feb 11. 10(2): 119
    Altered mitochondrial quality control in Atg7-deficient VSMCs promotes enhanced apoptosis and is linked to unstable atherosclerotic plaque phenotype.
    Hripsimé Nahapetyan, Manon Moulis, Elisa Grousset, Julien Faccini, Marie-Hélène Grazide, Elodie Mucher, Meyer Elbaz, Wim Martinet, Cécile Vindis.
      Vascular smooth muscle cells (VSMCs) are one of the main cellular determinants in arterial pathology. A large body of evidence indicates that death of VSMCs is associated with features of high-risk/vulnerable atherosclerotic plaques. Mitochondrial turnover is an essential aspect of the mitochondrial quality control in which dysfunctional mitochondria are selectively eliminated through autophagy and replaced through expansion of preexisting mitochondria. Even though successful autophagy promotes VSMC survival, it is unclear whether reduced autophagic flux affects mitochondrial quality control of VSMCs in atherosclerotic plaques. By using apolipoprotein E-deficient (ApoE-/-) mice carrying a VSMC-specific deletion of the essential autophagy gene Atg7, we show in the present study that impaired VSMC autophagy promotes an unstable plaque phenotype, as well as the accumulation of fragmented mitochondria with reduced bioenergetic efficiency and more oxidative stress. Furthermore, we demonstrate that disrupted autophagic flux is linked to defective mitophagy and biogenesis of mitochondria, which exacerbate VSMC apoptosis and in turn plaque vulnerability. Overall, our data indicate that mitochondrial quality control is a promising therapeutic target to stabilize atherosclerotic plaques.
    DOI:  https://doi.org/10.1038/s41419-019-1400-0
  7. Ann Transl Med. 2018 Dec;6(24): 475
    Mitochondrial disorders.
    Shibani Kanungo, Jacob Morton, Mekala Neelakantan, Kevin Ching, Jasmine Saeedian, Amy Goldstein.
      Primary mitochondrial disorders are a group of clinically variable and heterogeneous inborn errors of metabolism (IEMs), resulting from defects in cellular energy, and can affect every organ system of the body. Clinical presentations vary and may include symptoms of fatigue, skeletal muscle weakness, exercise intolerance, short stature, failure to thrive, blindness, ptosis and ophthalmoplegia, nystagmus, hearing loss, hypoglycemia, diabetes mellitus, learning difficulties, intellectual disability, seizures, stroke-like episodes, spasticity, dystonia, hypotonia, pain, neuropsychiatric symptoms, gastrointestinal reflux, dysmotility, gastrointestinal pseudo-obstruction, cardiomyopathy, cardiac conduction defects, and other endocrine, renal, cardiac, and liver problems. Most phenotypic manifestations are multi-systemic, with presentations varying at different age of onset and may show great variability within members of the same family; making these truly complex IEMs. Most primary mitochondrial diseases are autosomal recessive (AR); but maternally-inherited [from mitochondrial (mt) DNA], autosomal dominant and X-linked inheritance are also known. Mitochondria are unique energy-generating cellular organelles, geared for survival and contain their own unique genetic coding material, a circular piece of mtDNA about 16,000 base pairs in size. Additional nuclear (n)DNA encoded genes maintain mitochondrial biogenesis by supervising mtDNA replication, repair and synthesis, which is modified during increased energy demands or physiological stress. Despite our growing knowledge of the hundreds of genetic etiologies for this group of disorders, diagnosis can also remain elusive due to unique aspects of mitochondrial genetics. Though cure and FDA-approved therapies currently elude these IEMs, and current suggested therapies which include nutritional supplements and vitamins are of questionable efficacy; multi-center, international clinical trials are in progress for primary mitochondrial disorders.
    Keywords:  Mitochondria; energy metabolism; heteroplasmy; mtDNA; nDNA
    DOI:  https://doi.org/10.21037/atm.2018.12.13
  8. FEBS Open Bio. 2019 Feb;9(2): 348-363
    Coenzyme Q10 protects against burn-induced mitochondrial dysfunction and impaired insulin signaling in mouse skeletal muscle.
    Harumasa Nakazawa, Kazuhiro Ikeda, Shohei Shinozaki, Shingo Yasuhara, Yong-Ming Yu, J A Jeevendra Martyn, Ronald G Tompkins, Tomoko Yorozu, Satoshi Inoue, Masao Kaneki.
      Mitochondrial dysfunction is associated with metabolic alterations in various disease states, including major trauma (e.g., burn injury). Metabolic derangements, including muscle insulin resistance and hyperlactatemia, are a clinically significant complication of major trauma. Coenzyme Q10 (CoQ10) is an essential cofactor for mitochondrial electron transport, and its reduced form acts as a lipophilic antioxidant. Here, we report that burn injury induces impaired muscle insulin signaling, hyperlactatemia, mitochondrial dysfunction (as indicated by suppressed mitochondrial oxygen consumption rates), morphological alterations of the mitochondria (e. g., enlargement, and loss of cristae structure), mitochondrial oxidative stress, and disruption of mitochondrial integrity (as reflected by increased mitochondrial DNA levels in the cytosol and circulation). All of these alterations were significantly alleviated by CoQ10 treatment compared with vehicle alone. These findings indicate that CoQ10 treatment is efficacious in protecting against mitochondrial dysfunction and insulin resistance in skeletal muscle of burned mice. Our data highlight CoQ10 as a potential new strategy to prevent mitochondrial damage and metabolic dysfunction in burn patients.
    Keywords:  burn injury; coenzyme Q10; insulin resistance; mitochondrial dysfunction; skeletal muscle
    DOI:  https://doi.org/10.1002/2211-5463.12580
  9. Mol Metab. 2019 Jan 31. pii: S2212-8778(18)31195-5. [Epub ahead of print]
    WWOX somatic ablation in skeletal muscles alters glucose metabolism.
    Muhannad Abu-Remaileh, Monther Abu-Remaileh, Rania Akkawi, Ibrahim Knani, Shiran Udi, Micheal E Pacold, Joseph Tam, Rami I Aqeilan.
      OBJECTIVE: WWOX, a well-established tumor suppressor, is frequently lost in cancer and plays important roles in DNA damage response and cellular metabolism.METHODS: We re-analyzed several genome-wide association studies (GWAS) using the Type 2 Diabetes Knowledge Portal website to uncover WWOX's association with metabolic syndrome (MetS). Using several engineered mouse models, we studied the effect of somatic WWOX loss on glucose homeostasis.
    RESULTS: Several WWOX variants were found to be strongly associated with MetS disorders. In mouse models, somatic ablation of Wwox in skeletal muscle (WwoxΔSKM) results in weight gain, glucose intolerance, and insulin resistance. Furthermore, WwoxΔSKM mice display reduced amounts of slow-twitch fibers, decreased mitochondrial quantity and activity, and lower glucose oxidation levels. Mechanistically, we found that WWOX physically interacts with the cellular energy sensor AMP-activated protein kinase (AMPK) and that its loss is associated with impaired activation of AMPK, and with significant accumulation of the hypoxia inducible factor 1 alpha (HIF1α) in SKM.
    CONCLUSIONS: Our studies uncover an unforeseen role of the tumor suppressor WWOX in whole-body glucose homeostasis and highlight the intimate relationship between cancer progression and metabolic disorders, particularly obesity and type-2 diabetes.
    SUBJECT AREAS: Genetics, Metabolic Syndrome, Diabetes.
    Keywords:  AMPK; Metabolic syndrome; T2D; Tumor suppressor; WWOX
    DOI:  https://doi.org/10.1016/j.molmet.2019.01.010
  10. Cell Mol Life Sci. 2019 Feb 14.
    Exploring the molecular interface between hypoxia-inducible factor signalling and mitochondria.
    Luke W Thomas, Margaret Ashcroft.
      Oxygen is required for the survival of the majority of eukaryotic organisms, as it is important for many cellular processes. Eukaryotic cells utilize oxygen for the production of biochemical energy in the form of adenosine triphosphate (ATP) generated from the catabolism of carbon-rich fuels such as glucose, lipids and glutamine. The intracellular sites of oxygen consumption-coupled ATP production are the mitochondria, double-membraned organelles that provide a dynamic and multifaceted role in cell signalling and metabolism. Highly evolutionarily conserved molecular mechanisms exist to sense and respond to changes in cellular oxygen levels. The primary transcriptional regulators of the response to decreased oxygen levels (hypoxia) are the hypoxia-inducible factors (HIFs), which play important roles in both physiological and pathophysiological contexts. In this review we explore the relationship between HIF-regulated signalling pathways and the mitochondria, including the regulation of mitochondrial metabolism, biogenesis and distribution.
    Keywords:  HIF; Hypoxia; Metabolism; Mitochondrial biogenesis; Oxphos; Oxygen; Respiratory chain
    DOI:  https://doi.org/10.1007/s00018-019-03039-y
  11. Autophagy. 2019 Feb 11.
    BNIP3L/NIX and FUNDC1-Mediated Mitophagy is Required for Mitochondrial Network Remodeling during Cardiac Progenitor Cell Differentiation.
    Mark A Lampert, Amabel M Orogo, Rita H Najor, Babette C Hammerling, Leonardo J Leon, Bingyan J Wang, Taeyong Kim, Mark A Sussman, Åsa B Gustafsson.
      Cell-based therapies represent a very promising strategy to repair and regenerate the injured heart to prevent progression to heart failure. To date, these therapies have had limited success due to a lack of survival and retention of the infused cells. Therefore, it is important to increase our understanding of the biology of these cells and utilize this information to enhance their survival and function in the injured heart. Mitochondria are critical for progenitor cell function and survival. Here, we demonstrate the importance of mitochondrial autophagy, or mitophagy, in the differentiation process in adult cardiac progenitor cells (CPCs). We found that mitophagy was rapidly induced upon initiation of differentiation in CPCs. We also found that mitophagy was mediated by mitophagy receptors, rather than the PINK1-PRKN/PARKIN pathway. Mitophagy mediated by BNIP3L/NIX and FUNDC1 was not involved in regulating progenitor cell fate determination, mitochondrial biogenesis, or reprogramming. Instead, mitophagy facilitated the CPCs to undergo proper mitochondrial network reorganization during differentiation. Abrogating BNIP3L- and FUNDC1-mediated mitophagy during differentiation led to sustained mitochondrial fission and formation of donut-shaped impaired mitochondria. It also resulted in increased susceptibility to cell death and failure to survive the infarcted heart. Finally, aging is associated with accumulation of mitochondrial DNA (mtDNA) damage in cells and we found that acquiring mtDNA mutations selectively disrupted the differentiation-activated mitophagy program in CPCs. These findings demonstrate the importance of BNIP3L- and FUNDC1-mediated mitophagy as a critical regulator of mitochondrial network formation during differentiation, as well as the consequences of accumulating mtDNA mutations.
    Keywords:  CPCs; autophagy; differentiation; heart; heart failure; mitochondria; mitophagy; stem cells
    DOI:  https://doi.org/10.1080/15548627.2019.1580095
  12. PLoS One. 2019 ;14(2): e0211796
    SIRT5 deficiency suppresses mitochondrial ATP production and promotes AMPK activation in response to energy stress.
    Mengli Zhang, Jian Wu, Renqiang Sun, Xiaoting Tao, Xiaoxia Wang, Qi Kang, Hui Wang, Lei Zhang, Peng Liu, Jinye Zhang, Yukun Xia, Yuzheng Zhao, Yi Yang, Yue Xiong, Kun-Liang Guan, Yunzeng Zou, Dan Ye.
      Sirtuin 5 (SIRT5) is a member of the NAD+-dependent sirtuin family of protein deacylase that catalyzes removal of post-translational modifications, such as succinylation, malonylation, and glutarylation on lysine residues. In light of the SIRT5's roles in regulating mitochondrion function, we show here that SIRT5 deficiency leads to suppression of mitochondrial NADH oxidation and inhibition of ATP synthase activity. As a result, SIRT5 deficiency decreases mitochondrial ATP production, increases AMP/ATP ratio, and subsequently activates AMP-activated protein kinase (AMPK) in cultured cells and mouse hearts under energy stress conditions. Moreover, Sirt5 knockout attenuates transverse aortic constriction (TAC)-induced cardiac hypertrophy and cardiac dysfunction in mice, which is associated with decreased ATP level, increased AMP/ATP ratio and enhanced AMPK activation. Our study thus uncovers an important role of SIRT5 in regulating cellular energy metabolism and AMPK activation in response to energy stress.
    DOI:  https://doi.org/10.1371/journal.pone.0211796
  13. J Biol Chem. 2019 Feb 12. pii: jbc.RA118.005200. [Epub ahead of print]
    Metabolic and oncogenic adaptations to pyruvate dehydrogenase inactivation in fibroblasts.
    Huabo Wang, Jie Lu, Sucheta Kulkarni, Weiqi Zhang, Joanna E Gorka, Jordan A Mandel, Eric S Goetzman, Edward V Prochownik.
      Eukaryotic cell metabolism consists of processes that generate available energy, such as glycolysis, the tricarboxylic acid (TCA) cycle and oxidative phosphorylation (OXPHOS) and those that consume it, including macromolecular synthesis, the maintenance of ionic gradients and cellular detoxification. By converting pyruvate to acetyl-CoA (AcCoA), the pyruvate dehydrogenase (PDH) complex (PDC) links glycolysis and the TCA cycle. Surprisingly, disrupting the connection between glycolysis and the TCA cycle by inactivation PDC has only minor effects on cell replication. However, the molecular basis for this metabolic re-equilibration is unclear. We report here that CRISPR/Cas9-generated PDH-knockout (PDH-KO) rat fibroblasts reprogramed their metabolism and their response to short-term c-Myc (Myc) oncoprotein overexpression. PDH-KO cells replicated normally, but produced surprisingly little lactate. They also exhibited higher rates of glycolysis and OXPHOS.  In addition, PDH-KO cells showed altered cytoplasmic and mitochondrial pH, redox states, and mitochondrial membrane potential (ΔΨμ). Conditionally activated Myc expression affected some of these parameters in a PDH-dependent manner. PDH-KO cells had increased oxygen consumption rates in response to glutamate, but not to malate, and were depleted in all TCA cycle substrates between α-ketoglutarate and malate despite high rates of glutaminolysis, as determined by flux studies with isotopically labeled glutamine. Malate and pyruvate were diverted to produce aspartate, thereby potentially explaining the failure to accumulate lactate. We conclude that PDH-KO cells maintain proliferative capacity by utilizing glutamine to supply high rates of AcCoA-independent flux through the bottom portion of the TCA cycle while accumulating pyruvate and aspartate that rescue their redox defects.
    Keywords:  Myc (c-Myc); Warburg effect; fatty acid oxidation; glutaminolysis; pyruvate carboxylase (PC); reverse carboxylation; tricarboxylic acid cycle (TCA cycle) (Krebs cycle)
    DOI:  https://doi.org/10.1074/jbc.RA118.005200
  14. Haematologica. 2019 Feb 14. pii: haematol.2018.214320. [Epub ahead of print]
    Dimeric ferrochelatase bridges ABCB7 and ABCB10 homodimers in an architecturally defined molecular complex required for heme biosynthesis.
    Nunziata Maio, Ki Soon Kim, Gregory Holmes-Hampton, Anamika Singh, Tracey A Rouault.
      Loss-of-function mutations in the ABC transporter of the inner mitochondrial membrane, ABCB7, cause X-linked sideroblastic anemia with ataxia, a phenotype that remains largely unexplained by the proposed role of ABCB7 in exporting a special sulfur species for use in cytosolic iron-sulfur (Fe-S) cluster biogenesis. Here, we generated inducible ABCB7-knockdown cell lines to examine the time-dependent consequences of loss of ABCB7. We found that knockdown of ABCB7 led to significant loss of mitochondrial Fe-S proteins, which preceded the development of milder defects in cytosolic Fe-S enzymes. In erythroid cells, loss of ABCB7 altered cellular iron distribution and caused mitochondrial iron overload due to activation of the Iron Regulatory Proteins 1 and 2 in the cytosol and to upregulation of the mitochondrial iron importer, mitoferrin-1. Despite the exceptionally large amount of iron imported into mitochondria, erythroid cells lacking ABCB7 showed a profound hemoglobinization defect and underwent apoptosis triggered by oxidative stress. In ABCB7-depleted cells, defective heme biosynthesis resulted from translational repression of ALAS2 by IRPs and from decreased stability of the terminal enzyme ferrochelatase (FECH). By combining chemical crosslinking, tandem mass spectrometry and mutational analyses, we characterized a complex formed of FECH, ABCB7 and ABCB10, and mapped the interfaces of interactions of its components. A dimeric ferrochelatase physically bridged ABCB7 and ABCB10 homodimers by binding near the NBDs of each ABC transporter. Our studies not only underscore the importance of ABCB7 for mitochondrial Fe-S biogenesis and iron homeostasis, but also provide the biochemical characterization of a multiprotein complex required for heme biosynthesis.
    Keywords:  Iron Metabolism; Red Cell Enzyme Abnormalities; Red Cells; heme; iron sulfur clusters
    DOI:  https://doi.org/10.3324/haematol.2018.214320
  15. Cell Death Dis. 2019 Feb 15. 10(3): 147
    Fhit-Fdxr interaction in the mitochondria: modulation of reactive oxygen species generation and apoptosis in cancer cells.
    Teresa Druck, Douglas G Cheung, Dongju Park, Francesco Trapasso, Flavia Pichiorri, Marco Gaspari, Tiziana Palumbo, Rami I Aqeilan, Eugenio Gaudio, Hiroshi Okumura, Rodolfo Iuliano, Cinzia Raso, Kari Green, Kay Huebner, Carlo M Croce.
      Fhit protein is lost in cancers of most, perhaps all, cancer types; when restored, it can induce apoptosis and suppress tumorigenicity, as shown in vitro and in mouse tumor models in vivo. Following protein cross-linking and proteomics analyses, we characterized a Fhit protein complex involved in triggering Fhit-mediated apoptosis. The complex includes the heat-shock chaperonin pair, HSP60/10, which is likely involved in importing Fhit into the mitochondria, where it interacts with ferredoxin reductase, responsible for transferring electrons from NADPH to cytochrome P450 via ferredoxin, in electron transport chain complex III. Overexpression of Fhit protein in Fhit-deficient cancer cells modulates the production of intracellular reactive oxygen species, causing increased ROS, following peroxide treatment, with subsequent increased apoptosis of lung cancer cells under oxidative stress conditions; conversely, Fhit-negative cells escape ROS overproduction and ROS-induced apoptosis, likely carrying oxidative damage. Thus, characterization of Fhit-interacting proteins has identified direct effectors of a Fhit-mediated apoptotic signal pathway that is lost in many cancers. This is of translational interest considering the very recent emphasis in a number of high-profile publications, concerning the role of oxidative phosphorylation in the treatment of human cancers, and especially cancer stem cells that rely upon oxidative phosphorylation for survival. Additionally, we have shown that cells from a Fhit-deficient lung cancer cell line, are sensitive to killing by exposure to atovaquone, thought to act as a selective oxidative phosphorylation inhibitor by targeting the CoQ10 dependence of the mitochondrial complex III, while the Fhit-expressing sister clone is resistant to this treatment.
    DOI:  https://doi.org/10.1038/s41419-019-1414-7
  16. Crit Rev Biochem Mol Biol. 2018 Dec;53(6): 652-666
    A concert of RNA-binding proteins coordinates mitochondrial function.
    Désirée Schatton, Elena I Rugarli.
      Mitochondria are dynamic and plastic organelles, which flexibly adapt morphology, ATP production, and metabolic function to meet extrinsic challenges and demands. Regulation of mitochondrial biogenesis is essential during development and in adult life to survive stress and pathological insults, and is achieved not only by increasing mitochondrial mass, but also by remodeling the organellar proteome, metabolome, and lipidome. In the last decade, the post-transcriptional regulation of the expression of nuclear-encoded mitochondrial proteins has emerged as a fast, flexible, and powerful mechanism to shape mitochondrial function and coordinate it with other cellular processes. At the heart of post-transcriptional responses are a number of RNA-binding proteins that specifically bind mRNAs encoding mitochondrial proteins and define their fate, by influencing transcript maturation, stability, translation, and localization. Thus, RNA-binding proteins provide a uniquely complex regulatory code that orchestrates mitochondrial function during physiological and pathological conditions.
    Keywords:  CLUH; Post-transcriptional regulation; Puf3; RNA regulon; localized translation
    DOI:  https://doi.org/10.1080/10409238.2018.1553927
  17. Mol Cell. 2019 Jan 10. pii: S1097-2765(18)31068-2. [Epub ahead of print]
    Dual Role of Mitochondrial Porin in Metabolite Transport across the Outer Membrane and Protein Transfer to the Inner Membrane.
    Lars Ellenrieder, Martin P Dieterle, Kim Nguyen Doan, Christoph U Mårtensson, Alessia Floerchinger, María Luisa Campo, Nikolaus Pfanner, Thomas Becker.
      The mitochondrial inner membrane harbors a large number of metabolite carriers. The precursors of carrier proteins are synthesized in the cytosol and imported into mitochondria by the translocase of the outer membrane (TOM) and the carrier translocase of the inner membrane (TIM22). Molecular chaperones in the cytosol and intermembrane space bind to the hydrophobic precursors to prevent their aggregation. We report that the major metabolite channel of the outer membrane, termed porin or voltage-dependent anion channel (VDAC), promotes efficient import of carrier precursors. Porin interacts with carrier precursors arriving in the intermembrane space and recruits TIM22 complexes, thus ensuring an efficient transfer of the precursors to the inner membrane translocase. Porin channel mutants impaired in metabolite transport are not disturbed in carrier import into mitochondria. We conclude that porin serves distinct functions as outer membrane channel for metabolites and as coupling factor for protein translocation into the inner membrane.
    Keywords:  membrane contact sites; metabolite carrier; mitochondria; protein sorting; protein translocation
    DOI:  https://doi.org/10.1016/j.molcel.2018.12.014
  18. Front Physiol. 2019 ;10 38
    Brown and Brite: The Fat Soldiers in the Anti-obesity Fight.
    Shireesh Srivastava, Richard L Veech.
      Brown adipose tissue (BAT) is proposed to maintain thermal homeostasis through dissipation of chemical energy as heat by the uncoupling proteins (UCPs) present in their mitochondria. The recent demonstration of the presence of BAT in humans has invigorated research in this area. The research has provided many new insights into the biology and functioning of this tissue and the biological implications of its altered activities. Another finding of interest is browning of white adipose tissue (WAT) resulting in what is known as beige/brite cells, which have increased mitochondrial proteins and UCPs. In general, it has been observed that the activation of BAT is associated with various physiological improvements such as a reduction in blood glucose levels increased resting energy expenditure and reduced weight. Given the similar physiological functions of BAT and beige/ brite cells and the higher mass of WAT compared to BAT, it is likely that increasing the brite/beige cells in WATs may also lead to greater metabolic benefits. However, development of treatments targeting brown fat or WAT browning would require not only a substantial understanding of the biology of these tissues but also the effect of altering their activity levels on whole body metabolism and physiology. In this review, we present evidence from recent literature on the substrates utilized by BAT, regulation of BAT activity and browning by circulating molecules. We also present dietary and pharmacological activators of brown and beige/brite adipose tissue and the effect of physical exercise on BAT activity and browning.
    Keywords:  brown fat; dietary additive; exercise; hormones; metabolism
    DOI:  https://doi.org/10.3389/fphys.2019.00038
  19. Front Cell Dev Biol. 2019 ;7 4
    Hypoxia-Modified Cancer Cell Metabolism.
    Wafaa Al Tameemi, Tina P Dale, Rakad M Kh Al-Jumaily, Nicholas R Forsyth.
      While oxygen is critical to the continued existence of complex organisms, extreme levels of oxygen within a system, known as hypoxia (low levels of oxygen) and hyperoxia (excessive levels of oxygen), potentially promote stress within a defined biological environment. The consequences of tissue hypoxia, a result of a defective oxygen supply, vary in response to the gravity, extent and environment of the malfunction. Persistent pathological hypoxia is incompatible with normal biological functions, and as a result, multicellular organisms have been compelled to develop both organism-wide and cellular-level hypoxia solutions. Both direct, including oxidative phosphorylation down-regulation and inhibition of fatty-acid desaturation, and indirect processes, including altered hypoxia-sensitive transcription factor expression, facilitate the metabolic modifications that occur in response to hypoxia. Due to the dysfunctional vasculature associated with large areas of some cancers, sections of these tumors continue to develop in hypoxic environments. Crucial to drug development, a robust understanding of the significance of these metabolism changes will facilitate our understanding of cancer cell survival. This review defines our current knowledge base of several of the hypoxia-instigated modifications in cancer cell metabolism and exemplifies the correlation between metabolic change and its support of the hypoxic-adapted malignancy.
    Keywords:  Glut-1; HIF; Warburg effect; glycolysis; hypoxia; metabolism; mitochondria
    DOI:  https://doi.org/10.3389/fcell.2019.00004
  20. IUBMB Life. 2019 Feb 11.
    Mitochondrial Dysfunctions in Barth Syndrome.
    Sagnika Ghosh, Donna M Iadarola, Writoban Basu Ball, Vishal M Gohil.
      Barth syndrome (BTHS) is a rare multisystemic genetic disorder caused by mutations in the TAZ gene. TAZ encodes a mitochondrial enzyme that remodels the acyl chain composition of newly synthesized cardiolipin, a phospholipid unique to mitochondrial membranes. The clinical abnormalities observed in BTHS patients are caused by perturbations in various mitochondrial functions that rely on remodeled cardiolipin. However, the contribution of different cardiolipin-dependent mitochondrial functions to the pathology of BTHS is not fully understood. In this review, we will discuss recent findings from different genetic models of BTHS, including the yeast model of cardiolipin deficiency that has uncovered the specific in vivo roles of cardiolipin in mitochondrial respiratory chain biogenesis, bioenergetics, intermediary metabolism, mitochondrial dynamics, and quality control. We will also describe findings from higher eukaryotic models of BTHS that highlight a link between cardiolipin-dependent mitochondrial function and its impact on tissue and organ function. © 2019 IUBMB Life, 9999(9999):1-11, 2019.
    Keywords:  Barth syndrome; cardiolipin; mitochondria
    DOI:  https://doi.org/10.1002/iub.2018
  21. Nature. 2019 Feb 13.
    Singlet molecular oxygen regulates vascular tone and blood pressure in inflammation.
    Christopher P Stanley, Ghassan J Maghzal, Anita Ayer, Jihan Talib, Andrew M Giltrap, Sudhir Shengule, Kathryn Wolhuter, Yutang Wang, Preet Chadha, Cacang Suarna, Oleksandra Prysyazhna, Jenna Scotcher, Louise L Dunn, Fernanda M Prado, Nghi Nguyen, Jephthah O Odiba, Jonathan B Baell, Johannes-Peter Stasch, Yorihiro Yamamoto, Paolo Di Mascio, Philip Eaton, Richard J Payne, Roland Stocker.
      Singlet molecular oxygen (1O2) has well-established roles in photosynthetic plants, bacteria and fungi1-3, but not in mammals. Chemically generated 1O2 oxidizes the amino acid tryptophan to precursors of a key metabolite called N-formylkynurenine4, whereas enzymatic oxidation of tryptophan to N-formylkynurenine is catalysed by a family of dioxygenases, including indoleamine 2,3-dioxygenase 15. Under inflammatory conditions, this haem-containing enzyme is expressed in arterial endothelial cells, where it contributes to the regulation of blood pressure6. However, whether indoleamine 2,3-dioxygenase 1 forms 1O2 and whether this contributes to blood pressure control have remained unknown. Here we show that arterial indoleamine 2,3-dioxygenase 1 regulates blood pressure via formation of 1O2. We observed that in the presence of hydrogen peroxide, the enzyme generates 1O2 and that this is associated with the stereoselective oxidation of L-tryptophan to a tricyclic hydroperoxide via a previously unrecognized oxidative activation of the dioxygenase activity. The tryptophan-derived hydroperoxide acts in vivo as a signalling molecule, inducing arterial relaxation and decreasing blood pressure; this activity is dependent on Cys42 of protein kinase G1α. Our findings demonstrate a pathophysiological role for 1O2 in mammals through formation of an amino acid-derived hydroperoxide that regulates vascular tone and blood pressure under inflammatory conditions.
    DOI:  https://doi.org/10.1038/s41586-019-0947-3
  22. Br J Pharmacol. 2019 Feb 10.
    Adrenoceptor regulation of mTOR in muscle and adipose tissue.
    Ling Yeong Chia, Bronwyn A Evans, Saori Mukaida, Tore Bengtsson, Dana S Hutchinson, Masaaki Sato.
      A vital role of adrenoceptors in metabolism and energy balance has been well-documented in heart, skeletal muscle, and adipose tissue. It has been only recently demonstrated, however, that activation of mechanistic/mammalian target of rapamycin (mTOR) makes a significant contribution to various metabolic and physiological responses to adrenoceptor agonists. mTOR exists as two distinct complexes named mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2), and has been shown to play a critical role in protein synthesis, cell proliferation, hypertrophy, mitochondrial function, and glucose uptake. This review will describe the physiological significance of mTORC1/2 as a novel paradigm of adrenoceptor signalling in heart, skeletal muscle and adipose tissue. Understanding the detailed signalling cascades of adrenoceptors and how they regulate physiological responses is important for identifying new therapeutic targets and identifying novel therapeutic interventions.
    Keywords:  Adrenoceptor; GLUT4; cardiomyocyte; glucose uptake; mTOR; skeletal muscle
    DOI:  https://doi.org/10.1111/bph.14616
  23. Cell Death Dis. 2019 Feb 15. 10(3): 148
    MPC1 deficiency accelerates lung adenocarcinoma progression through the STAT3 pathway.
    Hongbo Zou, Qian Chen, Anmei Zhang, Songtao Wang, Hong Wu, Ye Yuan, Shuang Wang, Jing Yu, Mao Luo, Xianmei Wen, Wei Cui, Wenjuan Fu, Ruilian Yu, Lin Chen, Ming Zhang, Haitao Lan, Xia Zhang, Qichao Xie, Guoxiang Jin, Chuan Xu.
      Mitochondrial pyruvate carrier 1 (MPC1), a key factor that controls pyruvate transportation in the mitochondria, is known to be frequently dysregulated in tumor initiation and progression. However, the clinical relevance and potential molecular mechanisms of MPC1 in lung adenocarcinoma (LAC) progression remain to be illustrated. Herein, MPC1 was lowly expressed in LAC tissues and significantly associated with favorable survival of patients with LAC. Functionally, MPC1 markedly suppressed stemness, invasion, and migration in vitro and spreading growth of LAC cells in vivo. Further study revealed that MPC1 could interact with mitochondrial signal transducer and activator of transcription 3 (mito-STAT3), disrupting the distribution of STAT3 and reducing cytoplasmic signal transducer and activator of transcription 3 (cyto-STAT3) as well as its phosphorylation, while the activation of cyto-STAT3 by IL-6 reversed the attenuated malignant progression in MPC1-overexpression LAC cells. Collectively, we reveal that MPC1/STAT3 axis plays an important role in the progression of LAC, and our work may promote the development of new therapeutic strategies for LAC.
    DOI:  https://doi.org/10.1038/s41419-019-1324-8
  24. J Cell Physiol. 2019 Feb 11.
    Suppression of Tafazzin promotes thyroid cancer apoptosis via activating the JNK signaling pathway and enhancing INF2-mediated mitochondrial fission.
    Xiaobin Li, Mengwei Wu, Dawei An, Hongwei Yuan, Zengze Li, Yimin Song, Ziwen Liu.
      Tafazzin has been found to be associated with tumor progression. Mitochondrial homeostasis regulates cancer cell viability and metastasis. However, the roles of Tafazzin and mitochondrial homeostasis in thyroid cancer have not been explored. The aim of our study is to investigate the influences of Tafazzin on thyroid cancer apoptosis with a focus on mitochondrial fission. Our results indicated that Tafazzin deletion induced death in thyroid cancer via apoptosis. Biological analysis demonstrated that mitochondrial stress, including mitochondrial bioenergetics disorder, mitochondrial oxidative stress, and mitochondrial apoptosis, was activated by Tafazzin deletion. Furthermore, we found that Tafazzin affected mitochondrial stress by triggering inverted formin 2 (INF2)-related mitochondrial fission. The loss of INF2 sustained mitochondrial function and promoted cancer cell survival. Molecular investigation illustrated that Tafazzin regulated INF2 expression via the JNK signaling pathway; moreover, the blockade of JNK prevented Tafazzin-mediated INF2 expression and improved cancer cell survival. Taken together, our results highlight the key role of Tafazzin as a master regulator of thyroid cancer viability via the modulation of INF2-related mitochondrial fission and the JNK signaling pathway. These findings defined Tafazzin deletion and INF2-related mitochondrial fission as tumor suppressors that act by promoting cancer apoptosis via the JNK signaling pathway, with potential implications for new approaches to thyroid cancer therapy.
    Keywords:  INF2; JNK signaling pathway; Tafazzin; mitochondrial fission; thyroid cancer
    DOI:  https://doi.org/10.1002/jcp.28287
  25. Commun Biol. 2019 ;2 2
    Niclosamide activates the NLRP3 inflammasome by intracellular acidification and mitochondrial inhibition.
    Uyen Thi Tran, Toshimori Kitami.
      The NLRP3 inflammasome is unique among pattern recognition receptors in using changes in cellular physiology as a mechanism for sensing host danger. To dissect the physiological network controlling inflammasome activation, we screened for small-molecule activators and suppressors of IL-1β release in macrophages. Here we identified niclosamide, a mitochondrial uncoupler, as an activator of NLRP3 inflammasome. We find that niclosamide inhibits mitochondria and induces intracellular acidification, both of which are necessary for inflammasome activation. Intracellular acidification, by inhibiting glycolysis, works together with mitochondrial inhibition to induce intracellular ATP loss, which compromises intracellular potassium maintenance, a key event to NLRP3 inflammasome activation. A modest decline in intracellular ATP or pH within an optimal range induces maximum IL-1β release while their excessive decline suppresses IL-1β release. Our work illustrates how energy metabolism converges upon intracellular potassium to activate NLRP3 inflammasome and highlights a biphasic relationship between cellular physiology and IL-1β release.
    DOI:  https://doi.org/10.1038/s42003-018-0244-y
  26. Aging Cell. 2019 Feb 15. e12916
    The exceptional longevity of the naked mole-rat may be explained by mitochondrial antioxidant defenses.
    Daniel Munro, Cécile Baldy, Matthew E Pamenter, Jason R Treberg.
      Naked mole-rats (NMRs) are mouse-sized mammals that exhibit an exceptionally long lifespan (>30 vs. <4 years for mice), and resist aging-related pathologies such as cardiovascular and pulmonary diseases, cancer, and neurodegeneration. However, the mechanisms underlying this exceptional longevity and disease resistance remain poorly understood. The oxidative stress theory of aging posits that (a) senescence results from the accumulation of oxidative damage inflicted by reactive oxygen species (ROS) of mitochondrial origin, and (b) mitochondria of long-lived species produce less ROS than do mitochondria of short-lived species. However, comparative studies over the past 28 years have produced equivocal results supporting this latter prediction. We hypothesized that, rather than differences in ROS generation, the capacity of mitochondria to consume ROS might distinguish long-lived species from short-lived species. To test this hypothesis, we compared mitochondrial production and consumption of hydrogen peroxide (H2 O2 ; as a proxy of overall ROS metabolism) between NMR and mouse skeletal muscle and heart. We found that the two species had comparable rates of mitochondrial H2 O2 generation in both tissues; however, the capacity of mitochondria to consume ROS was markedly greater in NMRs. Specifically, maximal observed consumption rates were approximately two and fivefold greater in NMRs than in mice, for skeletal muscle and heart, respectively. Our results indicate that differences in matrix ROS detoxification capacity between species may contribute to their divergence in lifespan.
    Keywords:   Heterocephalus glaber ; antioxidants; mitochondria; reactive oxygen species; skeletal muscle heart
    DOI:  https://doi.org/10.1111/acel.12916
  27. Sci Rep. 2019 Feb 14. 9(1): 2002
    Doxorubicin-induced cardiomyopathy associated with inhibition of autophagic degradation process and defects in mitochondrial respiration.
    Chowdhury S Abdullah, Shafiul Alam, Richa Aishwarya, Sumitra Miriyala, Mohammad Alfrad Nobel Bhuiyan, Manikandan Panchatcharam, Christopher B Pattillo, A Wayne Orr, Junichi Sadoshima, Joseph A Hill, Md Shenuarin Bhuiyan.
      Doxorubicin (Dox) is a highly effective anticancer drug but cause acute ventricular dysfunction, and also induce late-onset cardiomyopathy and heart failure. Despite extensive studies, the pathogenic sequelae leading to the progression of Dox-associated cardiomyopathy remains unknown. We assessed temporal changes in autophagy, mitochondrial dynamics, and bioenergetics in mouse models of acute and chronic Dox-cardiomyopathy. Time course study of acute Dox-treatment showed accumulation of LC3B II in heart lysates. Autophagy flux assays confirmed that the Dox-induced accumulation of autophagosomes occurs due to blockage of the lysosomal degradation process. Dox-induced autophagosomes and autolysosome accumulation were confirmed in vivo by using GFP-LC3 and mRFP-GFP-LC3 transgenic (Tg) mice. Mitochondria isolated from acute Dox-treated hearts showed significant suppression of oxygen consumption rate (OCR). Chronic Dox-cardiotoxicity also exhibited time-dependent accumulation of LC3B II levels and increased accumulation of green puncta in GFP-LC3 Tg hearts. Mitochondria isolated from chronic Dox-treated hearts also showed significant suppression of mitochondrial OCR. The in vivo impairment of autophagic degradation process and mitochondrial dysfunction data were confirmed in vitro using cultured neonatal cardiomyocytes. Both acute and chronic Dox-associated cardiomyopathy involves a multifocal disease process resulting from autophagosomes and autolysosomes accumulation, altered expression of mitochondrial dynamics and oxidative phosphorylation regulatory proteins, and mitochondrial respiratory dysfunction.
    DOI:  https://doi.org/10.1038/s41598-018-37862-3
  28. J Cell Mol Med. 2019 Feb 12.
    Role of mitochondrial calcium uniporter-mediated Ca2+ and iron accumulation in traumatic brain injury.
    Li Zhang, Handong Wang, Xiaoming Zhou, Lei Mao, Ke Ding, Zhigang Hu.
      Previous studies have suggested that the cellular Ca2+ and iron homeostasis, which can be regulated by mitochondrial calcium uniporter (MCU), is associated with oxidative stress, apoptosis and many neurological diseases. However, little is known about the role of MCU-mediated Ca2+ and iron accumulation in traumatic brain injury (TBI). Under physiological conditions, MCU can be inhibited by ruthenium red (RR) and activated by spermine (Sper). In the present study, we used RR and Sper to reveal the role of MCU in mouse and neuron TBI models. Our results suggested that the Ca2+ and iron concentrations were obviously increased after TBI. In addition, TBI models showed a significant generation of reactive oxygen species (ROS), decrease in adenosine triphosphate (ATP), deformation of mitochondria, up-regulation of deoxyribonucleic acid (DNA) damage and increase in apoptosis. Blockage of MCU by RR prevented Ca2+ and iron accumulation, abated the level of oxidative stress, improved the energy supply, stabilized mitochondria, reduced DNA damage and decreased apoptosis both in vivo and in vitro. Interestingly, Sper did not increase cellular Ca2+ and iron concentrations, but suppressed the Ca2+ and iron accumulation to benefit the mice in vivo. However, Sper had no significant impact on TBI in vitro. Taken together, our data demonstrated for the first time that blockage of MCU-mediated Ca2+ and iron accumulation was essential for TBI. These findings indicated that MCU could be a novel therapeutic target for treating TBI.
    Keywords:  Ca2+; iron; mitochondrial calcium uniporter; neuroprotection; traumatic brain injury
    DOI:  https://doi.org/10.1111/jcmm.14206
  29. Cell. 2019 Jan 29. pii: S0092-8674(19)30051-0. [Epub ahead of print]
    Excessive Cell Growth Causes Cytoplasm Dilution And Contributes to Senescence.
    Gabriel E Neurohr, Rachel L Terry, Jette Lengefeld, Megan Bonney, Gregory P Brittingham, Fabien Moretto, Teemu P Miettinen, Laura Pontano Vaites, Luis M Soares, Joao A Paulo, J Wade Harper, Stephen Buratowski, Scott Manalis, Folkert J van Werven, Liam J Holt, Angelika Amon.
      Cell size varies greatly between cell types, yet within a specific cell type and growth condition, cell size is narrowly distributed. Why maintenance of a cell-type specific cell size is important remains poorly understood. Here we show that growing budding yeast and primary mammalian cells beyond a certain size impairs gene induction, cell-cycle progression, and cell signaling. These defects are due to the inability of large cells to scale nucleic acid and protein biosynthesis in accordance with cell volume increase, which effectively leads to cytoplasm dilution. We further show that loss of scaling beyond a certain critical size is due to DNA becoming limiting. Based on the observation that senescent cells are large and exhibit many of the phenotypes of large cells, we propose that the range of DNA:cytoplasm ratio that supports optimal cell function is limited and that ratios outside these bounds contribute to aging.
    DOI:  https://doi.org/10.1016/j.cell.2019.01.018
  30. Mol Cell. 2019 Jan 31. pii: S1097-2765(19)30003-6. [Epub ahead of print]
    Porin Associates with Tom22 to Regulate the Mitochondrial Protein Gate Assembly.
    Haruka Sakaue, Takuya Shiota, Naoya Ishizaka, Shin Kawano, Yasushi Tamura, Kher Shing Tan, Kenichiro Imai, Chie Motono, Takatsugu Hirokawa, Kentaro Taki, Non Miyata, Osamu Kuge, Trevor Lithgow, Toshiya Endo.
      Mitochondria import nearly all of their resident proteins from the cytosol, and the TOM complex functions as their entry gate. The TOM complex undergoes a dynamic conversion between the majority population of a three-channel gateway ("trimer") and the minor population that lacks Tom22 and has only two Tom40 channels ("dimer"). Here, we found that the porin Por1 acts as a sink to bind newly imported Tom22. This Por1 association thereby modulates Tom22 integration into the TOM complex, guaranteeing formation of the functional trimeric TOM complex. Por1 sequestration of Tom22 dissociated from the trimeric TOM complex also enhances the dimeric TOM complex, which is preferable for the import of TIM40/MIA-dependent proteins into mitochondria. Furthermore, Por1 appears to contribute to cell-cycle-dependent variation of the functional trimeric TOM complex by chaperoning monomeric Tom22, which arises from the cell-cycle-controlled variation of phosphorylated Tom6.
    Keywords:  TOM complex; Tom22; Tom40; Tom6; VDAC; mitochondria; porin; protein import
    DOI:  https://doi.org/10.1016/j.molcel.2019.01.003
  31. Front Cardiovasc Med. 2018 ;5 194
    Expression and Activation of BKCa Channels in Mice Protects Against Ischemia-Reperfusion Injury of Isolated Hearts by Modulating Mitochondrial Function.
    Sumanta Kumar Goswami, Devasena Ponnalagu, Ahmed T Hussain, Kajol Shah, Priyanka Karekar, Shubha Gururaja Rao, Andrea L Meredith, Mahmood Khan, Harpreet Singh.
      Aims: Activation and expression of large conductance calcium and voltage-activated potassium channel (BKCa) by pharmacological agents have been implicated in cardioprotection from ischemia-reperfusion (IR) injury possibly by regulating mitochondrial function. Given the non-specific effects of pharmacological agents, it is not clear whether activation of BKCa is critical to cardioprotection. In this study, we aimed to decipher the mechanistic role of BKCa in cardioprotection from IR injury by genetically activating BKCa channels. Methods and Results: Hearts from adult (3 months old) wild-type mice (C57/BL6) and mice expressing genetically activated BKCa (Tg-BKCa R207Q, referred as Tg-BKCa) along with wild-type BKCa were subjected to 20 min of ischemia and 30 min of reperfusion with or without ischemic preconditioning (IPC, 2 times for 2.5 min interval each). Left ventricular developed pressure (LVDP) was recorded using Millar's Mikrotip® catheter connected to ADInstrument data acquisition system. Myocardial infarction was quantified by 2,3,5-triphenyl tetrazolium chloride (TTC) staining. Our results demonstrated that Tg-BKCa mice are protected from IR injury, and BKCa also contributes to IPC-mediated cardioprotection. Cardiac function parameters were also measured by echocardiography and no differences were observed in left ventricular ejection fraction, fractional shortening and aortic velocities. Amplex Red® was used to assess reactive oxygen species (ROS) production in isolated mitochondria by spectrofluorometry. We found that genetic activation of BKCa reduces ROS after IR stress. Adult cardiomyocytes and mitochondria from Tg-BKCa mice were isolated and labeled with Anti-BKCa antibodies. Images acquired via confocal microscopy revealed localization of cardiac BKCa in the mitochondria. Conclusions: Activation of BKCa is essential for recovery of cardiac function after IR injury and is likely a factor in IPC mediated cardioprotection. Genetic activation of BKCa reduces ROS produced by complex I and complex II/III in Tg-BKCa mice after IR, and IPC further decreases it. These results implicate BKCa-mediated cardioprotection, in part, by reducing mitochondrial ROS production. Localization of Tg-BKCa in adult cardiomyocytes of transgenic mice was similar to BKCa in wild-type mice.
    Keywords:  BKCa channels; cardiac mitochondria; ischemia-reperfusion injury; ischemic preconditioning; myocardial infarction; reactive oxygen species
    DOI:  https://doi.org/10.3389/fcvm.2018.00194
  32. Int J Biol Sci. 2019 ;15(3): 701-713
    Sirt6 Suppresses High Glucose-Induced Mitochondrial Dysfunction and Apoptosis in Podocytes through AMPK Activation.
    Yanqin Fan, Qian Yang, Yingjie Yang, Zhao Gao, Yiqiong Ma, Lu Zhang, Wei Liang, Guohua Ding.
      Previous studies have shown that mitochondrial dysfunction plays an important role in high- glucose(HG)-induced podocyte injury and thus contributes to the progression of diabetic nephropathy(DN). The histone deacetylase Sirtuin6 (Sirt6) has been revealed to have an essential role in the regulation of mitochondrial function in skeletal muscle and cardiomyocytes. However, its specific role in mitochondrial homeostasis in podocytes is undetermined. Here, we aimeds to explore the physiological function of Sirt6 in podocyte mitochondria and apoptosis under HG conditions and explore the possible mechanism. Herein, we observed that Sirt6-WT-1 colocalization was suppressed in the glomeruli of patients with DN. In addition, diabetic mice exhibited reduced Sirt6 expression and AMP kinase (AMPK) dephosphorylation accompanied by mitochondrial morphological abnormalities. In vitro, podocytes exposed to HG presented with mitochondrial morphological alterations and podocyte apoptosis accompanied by Sirt6 and p-AMPK downregulation. In addition, HG promoted a decrease in mitochondrial number and an increase in mitochondrial superoxide production as well as a decreased mitochondrial membrane potential. ROS production was also increased in HG-treated podocytes. Conversely, all these mitochondrial defects induced by HG were significantly alleviated by Sirt6 plasmid transfection. Sirt6 overexpression simultaneously alleviated HG-induced podocyte apoptosis and oxidative stress, as well as increased AMPK phosphorylation. Increased levels of H3K9ac and H3K56ac induced by HG were attenuated in podocytes transfected with Sirt6 plasmids. Therefore, these results elucidated that Sirt6 protects mitochondria of podocytes and exerts anti-apoptotic effects via activating AMPK pathway. The present findings provide key insights into the pivotal role of mitochondria regulation by SIRT6 in its protective effects on podocytes.
    Keywords:  Sirt6; apoptosis; diabetic nephropathy; mitochondrial dysfunction; podocytes
    DOI:  https://doi.org/10.7150/ijbs.29323
  33. J Inherit Metab Dis. 2019 Jan;42(1): 49-56
    Inborn errors of coenzyme A metabolism and neurodegeneration.
    Ivano Di Meo, Miryam Carecchio, Valeria Tiranti.
      Two inborn errors of coenzyme A (CoA) metabolism are responsible for distinct forms of neurodegeneration with brain iron accumulation (NBIA), a heterogeneous group of neurodegenerative diseases having as a common denominator iron accumulation mainly in the inner portion of globus pallidus. Pantothenate kinase-associated neurodegeneration (PKAN), an autosomal recessive disorder with progressive impairment of movement, vision and cognition, is the most common form of NBIA and is caused by mutations in the pantothenate kinase 2 gene (PANK2), coding for a mitochondrial enzyme, which phosphorylates vitamin B5 in the first reaction of the CoA biosynthetic pathway. Another very rare but similar disorder, denominated CoPAN, is caused by mutations in coenzyme A synthase gene (COASY) coding for a bi-functional mitochondrial enzyme, which catalyzes the final steps of CoA biosynthesis. It still remains a mystery why dysfunctions in CoA synthesis lead to neurodegeneration and iron accumulation in specific brain regions, but it is now evident that CoA metabolism plays a crucial role in the normal functioning and metabolism of the nervous system.
    DOI:  https://doi.org/10.1002/jimd.12026
  34. Biochim Biophys Acta Gen Subj. 2019 Feb 11. pii: S0304-4165(19)30003-0. [Epub ahead of print]
    Regulation of permeability transition pore opening in mitochondria by external NAD(H).
    Ekaterina S Kharechkina, Anna B Nikiforova, Vera V Teplova, Irina V Odinokova, Olga V Krestinina, Yulia L Baburina, Svetlana A Kruglova, Alexey G Kruglov.
      BACKGROUND: The opening of the permeability transition pore (PTP) in mitochondria plays a critical role in the pathogenesis of numerous diseases. Mitochondrial matrix pyridine nucleotides are potent regulators of the PTP, but the role of extramitochondrial nucleotides is unclear.METHODS: The PTP opening was explored in isolated mitochondria and mitochondria in permeabilized differentiated and undifferentiated cells in the presence of added NAD(P)(H) in combination with Mg2+, adenine nucleotides (AN), and the inhibitors of AN translocase (ANT), voltage-dependent anion channel (VDAC), and cyclophilin D.
    RESULTS: Added NAD(H) and AN, but not NADP(H), inhibited the PTP opening with comparable potency. PTP suppression required neither NAD(H) oxidation nor reduction. The protective effects of NAD(H) and cyclosporin A were synergistic, and the effects of NAD(H) and millimolar AN were additive. The conformation-specific ANT inhibitors were unable to cancel the protective effect of NADH even under total ANT inhibition. Besides, NAD(H) activated the efflux of mitochondrial AN via ANT. VDAC ligand (Mg2+) and blockers (G3139 and 4,4'-diisothiocyano-2,2'-stilbenedisulfonic acid) potentiated and attenuated the protective effect of NAD(H), respectively. However, in embryonic and cancer (undifferentiated) cells, in contrast to isolated differentiated hepatocytes and cardiocytes, the suppression of PTP opening by NADH was negligible though all cells tested possessed a full set of VDAC isoforms.
    CONCLUSIONS: The study revealed a novel mechanism of PTP regulation by external (cytosolic) NAD(H) through the allosteric site in the OM or the intermembrane space.
    GENERAL SIGNIFICANCE: The mechanism might contribute to the resistance of differentiated cells under different pathological conditions including ischemia/reperfusion.
    Keywords:  ATP; Differentiated cells; External site; NADH; Permeability transition pore; Poly(ADP-ribose) polymerase
    DOI:  https://doi.org/10.1016/j.bbagen.2019.01.003
  35. BMB Rep. 2019 Feb 14. pii: 4520. [Epub ahead of print]
    The coordinated regulation of mitochondrial structure and function by Drp1 for mitochondrial quality surveillance.
    Hyo Min Cho, Woong Sun.
      Mitochondrial morphology is known to be continuously changing via fusion and fission, but it is unclear what the biological importance of this energy-consuming process is and how it develops. Several data have suggested that mitochondrial fission executed by Drp1 is necessary to select out a damaged spot from the interconnected mitochondrial network, but the precise mechanism for the recognition and isolation of a damaged sub-mitochondrial region during mitochondrial fission is yet unclear. Recently, Cho et al. found that the characteristic mitochondrial membrane potential (MMP) is transiently reduced by the physical interaction of Drp1 and mitochondrial Zinc transporter, Zip1, at the fission site prior to the typical mitochondrial division, and we found that this event is essential for a mitochondrial quality surveillance. In this review, Cho et al. discuss the role of a mitochondrial fission in the mitochondrial quality surveillance system.
  36. Oncogene. 2019 Feb 11.
    mTORC2-mediated PDHE1α nuclear translocation links EBV-LMP1 reprogrammed glucose metabolism to cancer metastasis in nasopharyngeal carcinoma.
    Jun Zhang, Lin Jia, Tengfei Liu, Yim Ling Yip, Wing Chung Tang, Weitao Lin, Wen Deng, Kwok Wai Lo, Chanping You, Maria Li Lung, Hong Lok Lung, Annie Lai-Man Cheung, Sai Wah Tsao, Chi Man Tsang.
      EBV infection of preinvasive nasopharyngeal epithelium is believed to be an initiation step during pathogenesis of nasopharyngeal carcinoma (NPC), but the mechanisms remain poorly understood. Here we report a novel mechanism driving NPC metastasis through the EBV-encoded LMP1-mediated metabolic reprogramming, via activation of IGF1-mTORC2 signaling and nuclear acetylation of the Snail promoter by the PDHE1α, an enzyme involved in glucose metabolism. Mechanistically, EBV-LMP1 increases the cellular secretion of IGF1 which promotes phosphorylation of IGF1R to activate mTORC2/AKT signaling linking glucose metabolism to cell motility. LMP1 expression facilitates translocation of mitochondrial PDHE1α into the nucleus in a phosphorylation-dependent manner at Ser293 residue. Functionally, nuclear PDHE1α promotes H3K9 acetylation on the Snail promoter to enhance cell motility, thereby driving cancer metastasis. Importantly, the IGF1/mTORC2/PDHE1α/Snail axis correlates significantly with disease progression and poor prognosis in NPC patients. This study highlights the functional importance of IGF1-mTORC2-PDHE1α signaling mediated by EBV-LMP1 in NPC pathogenesis.
    DOI:  https://doi.org/10.1038/s41388-019-0749-y
  37. CNS Neurosci Ther. 2019 Feb 11.
    Mitochondrial integrity in neurodegeneration.
    Katrina Cowan, Oleg Anichtchik, Shouqing Luo.
      The mitochondrion is a unique organelle with a diverse range of functions. Mitochondrial dysfunction is a key pathological process in several neurodegenerative diseases. Mitochondria are mostly important for energy production; however, they also have roles in Ca2+ homeostasis, ROS production, and apoptosis. There are two major systems in place, which regulate mitochondrial integrity, mitochondrial dynamics, and mitophagy. These two processes remove damaged mitochondria from cells and protect the functional mitochondrial population. These quality control systems often become dysfunctional during neurodegenerative diseases, such as Parkinson's and Alzheimer's disease, causing mitochondrial dysfunction and severe neurological symptoms.
    Keywords:  cytotoxicity; mitochondrion; mitophagy; neurodegeneration
    DOI:  https://doi.org/10.1111/cns.13105
  38. Mol Cell Biochem. 2019 Feb 11.
    LCAL1 enhances lung cancer survival via inhibiting AMPK-related antitumor functions.
    Jun-Yu Li, Zhi-Qiang Luo.
      Lung cancer is one of the most common cancers and has been the most common cause of cancer deaths for several decades. Recently, lung cancer-associated lncRNA 1 (LCAL1) has been identified to be overexpressed in lung cancer tissues, while inhibiting LCAL1 expression has shown potential to inhibiting lung cancer growth. However, the molecular mechanism between LCAL1 and lung cancer cell survival remains poorly understood. In the present study, we provided the first evidence that LCAL1 may support lung cancer survival via inhibiting the activity of AMP-activated protein kinase (AMPK). According to our results, LCAL1 may physically interact with the catalytic subunit of tumor suppressor AMPK, prevent AMPK activation by upstream kinase (liver kinase B1), and thus inhibit the downstream AMPK signaling network. Our study revealed that overexpressed LCAL1 may induce aerobic glycolysis in lung cancer cells through AMPK/HIF1α axis, enhance protein synthesis through AMPK/mTOR/S6K axis, and suppress autophagic cell death through AMPK/ULK1 pathway. All these alterations supported rapid proliferation of lung cancer cells, while knockdown of LCAL1 expression demonstrated the potential of inhibiting lung cancer growth by reversing the tumorigenic phenotypes triggered by the loss of AMPK activity, and could become a promising therapeutic strategy for lung cancer treatment.
    Keywords:  AMPK; LCAL1; LncRNA; Lung cancer
    DOI:  https://doi.org/10.1007/s11010-019-03507-w
  39. Arch Pharm Res. 2019 Feb 09.
    Peroxisomal dysfunction in neurodegenerative diseases.
    Doo Sin Jo, Dong-Hyung Cho.
      Peroxisomes and their (patho-)physiological importance in heath and disease have attracted increasing interest during last few decades. Together with mitochondria, peroxisomes comprise key metabolic platforms for oxidation of various fatty acids and redox regulation. In addition, peroxisomes contribute to bile acid, cholesterol, and plasmalogen biosynthesis. The importance of functional peroxisomes for cellular metabolism is demonstrated by the marked brain and systemic organ abnormalities occuring in peroxisome biogenesis disorders and peroxisomal enzyme deficiencies. Current evidences indicate that peroxisomal function is declined with aging, with peroxisomal dysfunction being linked to early onset of multiple age-related diseases including neurodegenerative diseases. Herein, we review recent progress toward understanding the physiological roles and pathological implications of peroxisomal dysfunctions, focusing on neurodegenerative disease.
    Keywords:  Alzheimer’s disease; Neurodegenerative disease; Parkinson’s disease; Peroxisome
    DOI:  https://doi.org/10.1007/s12272-019-01131-2
  40. Basic Res Cardiol. 2019 Feb 14. 114(2): 12
    The different response of cardiomyocytes and cardiac fibroblasts to mitochondria inhibition and the underlying role of STAT3.
    Jing Zhao, Jin-Lai Gao, Jun-Xue Zhu, Hai-Bin Zhu, Xuan Peng, Man Jiang, Yao Fu, Juan Xu, Xi-Hai Mao, Nan Hu, Ming-Hui Ma, De-Li Dong.
      Cardiomyocyte loss and cardiac fibrosis are the main characteristics of cardiac ischemia and heart failure, and mitochondrial function of cardiomyocytes is impaired in cardiac ischemia and heart failure, so the aim of this study is to identify fate variability of cardiomyocytes and cardiac fibroblasts with mitochondria inhibition and explore the underlying mechanism. The mitochondrial respiratory function was measured by using Oxygraph-2k high-resolution respirometry. The STAT3 expression and activity were evaluated by western blot. Cardiomyocytes and cardiac fibroblasts displayed different morphology. The mitochondrial respiratory function and the expressions of mitochondrial complex I, II, III, IV, and V of cardiac fibroblasts were lower than that of cardiomyocytes. Mitochondrial respiratory complex I inhibitor rotenone and H2O2 (100 µM, 4 h) treatment induced cell death of cardiomyocyte but not cardiac fibroblasts. The function of complex I/II was impaired in cardiomycytes but not cardiac fibroblasts stimulated with H2O2 (100 µM, 4 h) and in ischemic heart of mice. Rotenone and H2O2 (100 µM, 4 h) treatment reduced STAT3 expression and activity in cardiomyocytes but not cardiac fibroblasts. Inhibition of STAT3 impaired mitochondrial respiratory capacity and exacerbated H2O2-induced cell injury in cardiomycytes but not significantly in cardiac fibroblasts. In conclusion, the different susceptibility of cardiomyocytes and cardiac fibroblasts to mitochondria inhibition determines the cell fate under the same pathological stimuli and in which STAT3 plays a critical role.
    Keywords:  Cardiac fibroblasts; Cardiomyocytes; H2O2; Mitochondria; STAT3
    DOI:  https://doi.org/10.1007/s00395-019-0721-6
  41. Exp Mol Med. 2019 Feb 12. 51(2): 14
    Mitochondrial superoxide dismutase 2 mediates γ-irradiation-induced cancer cell invasion.
    Chan-Hun Jung, Eun Mi Kim, Jie-Young Song, Jong Kuk Park, Hong-Duck Um.
      Sublethal doses of γ-rays promote cancer cell invasion by stimulating a signaling pathway that sequentially involves p53, sulfatase 2 (SULF2), β-catenin, interleukin-6 (IL-6), signal transducer and activator of transcription 3 (STAT3), and Bcl-XL. Given that Bcl-XL can increase O2•- production by stimulating respiratory complex I, the possible role of mitochondrial reactive oxygen species (ROS) in γ-irradiation-induced cell invasion was investigated. Indeed, γ-irradiation promoted cell invasion by increasing mitochondrial ROS levels, which was prevented by metformin, an inhibitor of complex I. γ-Irradiation-stimulated STAT3 increased the expression of superoxide dismutase 2 (SOD2), a mitochondrial enzyme that catalyzes the conversion of O2•- to hydrogen peroxide (H2O2). In contrast to O2•-, H2O2 functions as a signaling molecule. γ-Irradiation consistently stimulated the Src-dependent invasion pathway in a manner dependent on both complex I and SOD2. SOD2 was also essential for the invasion of un-irradiated cancer cells induced by upregulation of Bcl-XL, an intracellular oncogene, or extracellular factors, such as SULF2 and IL-6. Overall, these data suggested that SOD2 is critical for the malignant effects of radiotherapy and tumor progression through diverse endogenous factors.
    DOI:  https://doi.org/10.1038/s12276-019-0207-5
  42. Cancer Metastasis Rev. 2019 Feb 14.
    Imaging tumor acidosis: a survey of the available techniques for mapping in vivo tumor pH.
    Annasofia Anemone, Lorena Consolino, Francesca Arena, Martina Capozza, Dario Livio Longo.
      Cancer cells are characterized by a metabolic shift in cellular energy production, orchestrated by the transcription factor HIF-1α, from mitochondrial oxidative phosphorylation to increased glycolysis, regardless of oxygen availability (Warburg effect). The constitutive upregulation of glycolysis leads to an overproduction of acidic metabolic products, resulting in enhanced acidification of the extracellular pH (pHe ~ 6.5), which is a salient feature of the tumor microenvironment. Despite the importance of pH and tumor acidosis, there is currently no established clinical tool available to image the spatial distribution of tumor pHe. The purpose of this review is to describe various imaging modalities for measuring intracellular and extracellular tumor pH. For each technique, we will discuss main advantages and limitations, pH accuracy and sensitivity of the applied pH-responsive probes and potential translatability to the clinic. Particular attention is devoted to methods that can provide pH measurements at high spatial resolution useful to address the task of tumor heterogeneity and to studies that explored tumor pH imaging for assessing treatment response to anticancer therapies.
    Keywords:  Chemical Exchange Saturation Transfer (CEST) imaging; Iopamidol; Magnetic resonance imaging; Tumor acidosis; pH imaging; pH-responsive probes
    DOI:  https://doi.org/10.1007/s10555-019-09782-9
  43. Commun Biol. 2019 ;2 3
    Mitochondrial protein E2F3d, a distinctive E2F3 product, mediates hypoxia-induced mitophagy in cancer cells.
    Keigo Araki, Keiko Kawauchi, Wataru Sugimoto, Daisuke Tsuda, Hiroya Oda, Ryosuke Yoshida, Kiyoshi Ohtani.
      Mitochondrial damage is caused by changes in the micro-environmental conditions during tumor progression. Cancer cells require mechanisms for mitochondrial quality control during this process; however, how mitochondrial integrity is maintained is unclear. Here we show that E2F3d, a previously unidentified E2F3 isoform, mediates hypoxia-induced mitophagy in cancer cells. Aberrant activity and expression of the E2F3 transcription factor is frequently observed in many cancer cells. Loss of retinoblastoma (Rb) protein family function increases the expression of E2F3d and E2F3a. E2F3d localizes to the outer mitochondrial membrane and its cytosolic domain contains an LC3-interacting region motif. Overexpression of E2F3d induces mitochondrial fragmentation and mitophagy, suggesting that E2F3d plays an important role in mitophagy. Furthermore, depletion of E2F3s attenuates hypoxia-induced mitophagy and increases intracellular levels of reactive oxygen species, which is reversed by the reintroduction of E2F3d. This study presents another key player that regulates mitochondrial quality control in cancer cells.
    DOI:  https://doi.org/10.1038/s42003-018-0246-9
  44. Nat Commun. 2019 Feb 13. 10(1): 735
    KDEL receptor regulates secretion by lysosome relocation- and autophagy-dependent modulation of lipid-droplet turnover.
    Diego Tapia, Tomás Jiménez, Constanza Zamora, Javier Espinoza, Riccardo Rizzo, Alexis González-Cárdenas, Danitza Fuentes, Sergio Hernández, Viviana A Cavieres, Andrea Soza, Fanny Guzmán, Gloria Arriagada, María Isabel Yuseff, Gonzalo A Mardones, Patricia V Burgos, Alberto Luini, Alfonso González, Jorge Cancino.
      Inter-organelle signalling has essential roles in cell physiology encompassing cell metabolism, aging and temporal adaptation to external and internal perturbations. How such signalling coordinates different organelle functions within adaptive responses remains unknown. Membrane traffic is a fundamental process in which membrane fluxes need to be sensed for the adjustment of cellular requirements and homeostasis. Studying endoplasmic reticulum-to-Golgi trafficking, we found that Golgi-based, KDEL receptor-dependent signalling promotes lysosome repositioning to the perinuclear area, involving a complex process intertwined to autophagy, lipid-droplet turnover and Golgi-mediated secretion that engages the microtubule motor protein dynein-LRB1 and the autophagy cargo receptor p62/SQSTM1. This process, here named 'traffic-induced degradation response for secretion' (TIDeRS) discloses a cellular mechanism by which nutrient and membrane sensing machineries cooperate to sustain Golgi-dependent protein secretion.
    DOI:  https://doi.org/10.1038/s41467-019-08501-w
  45. J Proteome Res. 2019 Feb 13.
    Preoperative Metabolic Signatures of Prostate Cancer Recurrence Following Radical Prostatectomy.
    Chaevien S Clendinen, David A Gaul, Maria Eugenia Monge, Rebecca S Arnold, Arthur S Edison, John A Petros, Facundo M Fernandez.
      Technological advances in mass spectrometry (MS), liquid chromatography (LC) separations, nuclear magnetic resonance (NMR) spectroscopy, and big data analytics have made possible studying metabolism at an "omics" or systems level. Here, we applied a multi-platform (NMR+LC-MS) metabolomics approach to the study of preoperative metabolic alterations associated with prostate cancer recurrence. Thus far, predicting which patients will recur even after radical prostatectomy has not been possible. Correlation analysis on metabolite abundances detected on serum samples collected prior to surgery from prostate cancer patients (n=40 remission vs. n=40 recurrence) showed significant alterations in a number of pathways, including amino acid metabolism, purine and pyrimidine synthesis, tricarboxylic acid cycle, tryptophan catabolism, glucose, and lactate. Lipidomics experiments indicated higher lipid abundances on recurrent patients for a number of classes that included triglycerides, lysophosphatidylcholines, phosphatidylethanolamines, phosphatidylinositols, diglycerides, acyl carnitines, and ceramides. Machine learning approaches led to the selection of a 20-metabolite panel from a single preoperative blood sample that enabled prediction of recurrence with 92.6% accuracy, 94.4% sensitivity, and 91.9% specificity under cross-validation conditions.
    DOI:  https://doi.org/10.1021/acs.jproteome.8b00926
  46. Nat Commun. 2019 Feb 12. 10(1): 714
    Inhibition of upper small intestinal mTOR lowers plasma glucose levels by inhibiting glucose production.
    T M Zaved Waise, Mozhgan Rasti, Frank A Duca, Song-Yang Zhang, Paige V Bauer, Christopher J Rhodes, Tony K T Lam.
      Glucose homeostasis is partly controlled by the energy sensor mechanistic target of rapamycin (mTOR) in the muscle and liver. However, whether mTOR in the small intestine affects glucose homeostasis in vivo remains unknown. Here, we first report that delivery of rapamycin or an adenovirus encoding the dominant negative acting mTOR-mutated protein into the upper small intestine is sufficient to inhibit small intestinal mTOR signaling and lower glucose production in rodents with high fat diet-induced insulin resistance. Second, we found that molecular activation of small intestinal mTOR blunts the glucose-lowering effect of the oral anti-diabetic agent metformin, while inhibiting small intestinal mTOR alone lowers plasma glucose levels by inhibiting glucose production in rodents with diabetes as well. Thus, these findings illustrate that inhibiting upper small intestinal mTOR is sufficient and necessary to lower glucose production and enhance glucose homeostasis, and thereby unveil a previously unappreciated glucose-lowering effect of small intestinal mTOR.
    DOI:  https://doi.org/10.1038/s41467-019-08582-7
  47. Nature. 2019 Feb 13.
    Squalene accumulation in cholesterol auxotrophic lymphomas prevents oxidative cell death.
    Javier Garcia-Bermudez, Lou Baudrier, Erol Can Bayraktar, Yihui Shen, Konnor La, Rohiverth Guarecuco, Burcu Yucel, Danilo Fiore, Bernardo Tavora, Elizaveta Freinkman, Sze Ham Chan, Caroline Lewis, Wei Min, Giorgio Inghirami, David M Sabatini, Kıvanç Birsoy.
      Cholesterol is essential for cells to grow and proliferate. Normal mammalian cells meet their need for cholesterol through its uptake or de novo synthesis1, but the extent to which cancer cells rely on each of these pathways remains poorly understood. Here, using a competitive proliferation assay on a pooled collection of DNA-barcoded cell lines, we identify a subset of cancer cells that is auxotrophic for cholesterol and thus highly dependent on its uptake. Through metabolic gene expression analysis, we pinpoint the loss of squalene monooxygenase expression as a cause of cholesterol auxotrophy, particularly in ALK+ anaplastic large cell lymphoma (ALCL) cell lines and primary tumours. Squalene monooxygenase catalyses the oxidation of squalene to 2,3-oxidosqualene in the cholesterol synthesis pathway and its loss results in accumulation of the upstream metabolite squalene, which is normally undetectable. In ALK+ ALCLs, squalene alters the cellular lipid profile and protects cancer cells from ferroptotic cell death, providing a growth advantage under conditions of oxidative stress and in tumour xenografts. Finally, a CRISPR-based genetic screen identified cholesterol uptake by the low-density lipoprotein receptor as essential for the growth of ALCL cells in culture and as patient-derived xenografts. This work reveals that the cholesterol auxotrophy of ALCLs is a targetable liability and, more broadly, that systematic approaches can be used to identify nutrient dependencies unique to individual cancer types.
    DOI:  https://doi.org/10.1038/s41586-019-0945-5
  48. Br J Cancer. 2019 Feb 12.
    The physiological mTOR complex 1 inhibitor DDIT4 mediates therapy resistance in glioblastoma.
    Martha Foltyn, Anna-Luisa Luger, Nadja I Lorenz, Benedikt Sauer, Michel Mittelbronn, Patrick N Harter, Joachim P Steinbach, Michael W Ronellenfitsch.
      BACKGROUND: Despite significant advances in the understanding of glioblastoma genetics and biology, survival is still poor. Hypoxia and nutrient depletion in the tumour microenvironment induce adaptive signalling and metabolic responses, which can influence sensitivity to therapeutic regimens. DNA damage-inducible transcript 4 (DDIT4) is a protein induced by hypoxia and in response to DNA stress. Mechanistically, DDIT4 inhibits mammalian target of rapamycin complex 1 (mTORC1) signalling by activation of the tuberous sclerosis 1/2 (TSC1/2) complex.METHODS: Using short hairpin RNA-mediated gene suppression as well as doxycycline-regulated gene induction, we developed a glioblastoma cell model to study effects of DDIT4 under conditions of the glioblastoma microenvironment and therapy.
    RESULTS: We found an intact DDIT4-mTORC1 signalling axis in human glioblastoma cells that was inducible by hypoxia. Temozolomide and radiotherapy also induced DDIT4 and repressed mTORC1 activity in some glioblastoma cell lines. DDIT4 gene suppression sensitised glioma cells towards hypoxia-induced cell death, while DDIT4 overexpression protected them. Additionally, in clonogenic survival analyses, DDIT4 induction conferred protection from radiotherapy and temozolomide, while DDIT4 gene suppression sensitised cells.
    CONCLUSIONS: We identified DDIT4 as a cell-intrinsic regulator for adaptive responses and therapy resistance in glioblastoma cells which may interfere with cell death induction by temozolomide, radiotherapy or hypoxia by inhibiting mTORC1 activity.
    DOI:  https://doi.org/10.1038/s41416-018-0368-3
  49. Life Sci. 2019 Feb 12. pii: S0024-3205(19)30116-X. [Epub ahead of print]
    The beneficial roles of exercise training via autophagy in neurological diseases and possible mechanisms.
    Ying Xing, Si-Dong Yang, Man-Man Wang, Ya-Shuo Feng, Fang Dong, Feng Zhang.
      Autophagy is a conservative catabolism process, participating in delivering the cytosol and cytosolic components to the lysosome. Abnormal autophagy is related to human pathologies, for instance diabetes, neurodegeneration, cardiovascular, macular degeneration, pulmonary, and cancer. Enormous evidences indicate that autophagy may mediate the cellular pathological condition in the process of neurological diseases. Exercise as a form of physiological stress may cause an adaptation, and autophagy is a necessary process for adaptational response to exercise. Autophagy during exercise may improve neurological function, control tissue maintain tissue integrity, and activate different signals pathway for adaptation. In this review, we summarize the possible mechanisms of exercise training via autophagy in neurological diseases.
    Keywords:  Autophagy; Exercise; Neurological diseases
    DOI:  https://doi.org/10.1016/j.lfs.2019.02.026
  50. Nat Commun. 2019 Feb 14. 10(1): 755
    Macrophage achieves self-protection against oxidative stress-induced ageing through the Mst-Nrf2 axis.
    Ping Wang, Jing Geng, Jiahui Gao, Hao Zhao, Junhong Li, Yiran Shi, Bingying Yang, Chen Xiao, Yueyue Linghu, Xiufeng Sun, Xin Chen, Lixin Hong, Funiu Qin, Xun Li, Jau-Song Yu, Han You, Zengqiang Yuan, Dawang Zhou, Randy L Johnson, Lanfen Chen.
      Reactive oxygen species (ROS) production in phagocytes is a major defense mechanism against pathogens. However, the cellular self-protective mechanism against such potential damage from oxidative stress remains unclear. Here we show that the kinases Mst1 and Mst2 (Mst1/2) sense ROS and maintain cellular redox balance by modulating the stability of antioxidant transcription factor Nrf2. Site-specific ROS release recruits Mst1/2 from the cytosol to the phagosomal or mitochondrial membrane, with ROS subsequently activating Mst1/2 to phosphorylate kelch like ECH associated protein 1 (Keap1) and prevent Keap1 polymerization, thereby blocking Nrf2 ubiquitination and degradation to protect cells against oxidative damage. Treatment with the antioxidant N-acetylcysteine disrupts ROS-induced interaction of Mst1/2 with phagosomes or mitochondria, and thereby diminishes the Mst-Nrf2 signal. Consistently, loss of Mst1/2 results in increased oxidative injury, phagocyte ageing and death. Thus, our results identify the Mst-Nrf2 axis as an important ROS-sensing and antioxidant mechanism during an antimicrobial response.
    DOI:  https://doi.org/10.1038/s41467-019-08680-6
  51. Hum Mutat. 2019 Feb 14.
    MT-ATP6 Mitochondrial Disease Variants: Phenotypic and biochemical features analysis in 218 published cases and cohort of 14 new cases.
    Rebecca D Ganetzky, Claudia Stendel, Elizabeth M McCormick, Zarazuela Zolkipli-Cunningham, Amy C Goldstein, Thomas Klopstock, Marni J Falk.
      Mitochondrial complex V (CV) generates cellular energy as adenosine triphosphate (ATP). Mitochondrial disease caused by the m.8993T>G pathogenic variant in CV subunit gene, MT-ATP6, was among the first described human mitochondrial DNA (mtDNA) diseases. Due to a lack of clinically-available functional assays, validating the definitive pathogenicity of additional MT-ATP6 variants remains challenging. We reviewed all reported MT-ATP6 disease cases (n=218) to date, to assess for MT-ATP6 variants, heteroplasmy levels, and inheritance correlation with clinical presentation and biochemical findings. We further describe the clinical and biochemical features of a new cohort of 14 kindreds with MT-ATP6 variants. Despite extensive overlap in the heteroplasmy levels of MT-ATP6 variant carriers with and without a wide range of clinical symptoms, previously reported symptomatic subjects had significantly higher heteroplasmy load (p=1.6x10-39 ). Pathogenic MT-ATP6 variants resulted in diverse biochemical features. The most common findings were reduced ATP synthesis rate, preserved ATP hydrolysis capacity, and abnormally increased mitochondrial membrane potential. However, no single biochemical feature was universally observed. Extensive heterogeneity exists among both clinical and biochemical features of distinct MT-ATP6 variants. Improved mechanistic understanding and development of consistent biochemical diagnostic analyses are needed to permit accurate pathogenicity assessment of variants of uncertain significance in MT-ATP6. This article is protected by copyright. All rights reserved.
    Keywords:  Leigh Syndrome; Mitochondria; NARP, neurogenic ataxia and retinitis pigmentosa; genotype-phenotype correlation; heteroplasmy
    DOI:  https://doi.org/10.1002/humu.23723
  52. Oncogene. 2019 Feb 12.
    CFP suppresses breast cancer cell growth by TES-mediated upregulation of the transcription factor DDIT3.
    Ines Block, Carolin Müller, Daniel Sdogati, Henriette Pedersen, Markus List, Aleksandra M Jaskot, Silje Damkjær Syse, Pernille Lund Hansen, Steffen Schmidt, Helle Christiansen, Cinzia Casella, Sidsel Bering Olsen, Monica M Blomstrøm, Angela Riedel, Mads Thomassen, Torben A Kruse, Søren W Karlskov Hansen, Petra Kioschis, Jan Mollenhauer.
      Breast cancer is a heterogeneous genetic disease driven by the accumulation of individual mutations per tumor. Whole-genome sequencing approaches have identified numerous genes with recurrent mutations in primary tumors. Although mutations in well characterized tumor suppressors and oncogenes are overrepresented in these sets, the majority of the genetically altered genes have so far unknown roles in breast cancer progression. To improve the basic understanding of the complex disease breast cancer and to potentially identify novel drug targets or regulators of known cancer-driving pathways, we analyzed 86 wild-type genes and 94 mutated variants for their effect on cell growth using a serially constructed panel of MCF7 cell lines. We demonstrate in subsequent experiments that the metal cation transporter CNNM4 regulates growth by induction of apoptosis and identified a tumor suppressive role of complement factor properdin (CFP) in vitro and in vivo. CFP appears to induce the intracellular upregulation of the pro-apoptotic transcription factor DDIT3 which is associated with endoplasmic reticulum-stress response.
    DOI:  https://doi.org/10.1038/s41388-019-0739-0
  53. Front Genet. 2018 ;9 718
    Mitochondrial Heterogeneity.
    Juvid Aryaman, Iain G Johnston, Nick S Jones.
      Cell-to-cell heterogeneity drives a range of (patho)physiologically important phenomena, such as cell fate and chemotherapeutic resistance. The role of metabolism, and particularly of mitochondria, is increasingly being recognized as an important explanatory factor in cell-to-cell heterogeneity. Most eukaryotic cells possess a population of mitochondria, in the sense that mitochondrial DNA (mtDNA) is held in multiple copies per cell, where the sequence of each molecule can vary. Hence, intra-cellular mitochondrial heterogeneity is possible, which can induce inter-cellular mitochondrial heterogeneity, and may drive aspects of cellular noise. In this review, we discuss sources of mitochondrial heterogeneity (variations between mitochondria in the same cell, and mitochondrial variations between supposedly identical cells) from both genetic and non-genetic perspectives, and mitochondrial genotype-phenotype links. We discuss the apparent homeostasis of mtDNA copy number, the observation of pervasive intra-cellular mtDNA mutation (which is termed "microheteroplasmy"), and developments in the understanding of inter-cellular mtDNA mutation ("macroheteroplasmy"). We point to the relationship between mitochondrial supercomplexes, cristal structure, pH, and cardiolipin as a potential amplifier of the mitochondrial genotype-phenotype link. We also discuss mitochondrial membrane potential and networks as sources of mitochondrial heterogeneity, and their influence upon the mitochondrial genome. Finally, we revisit the idea of mitochondrial complementation as a means of dampening mitochondrial genotype-phenotype links in light of recent experimental developments. The diverse sources of mitochondrial heterogeneity, as well as their increasingly recognized role in contributing to cellular heterogeneity, highlights the need for future single-cell mitochondrial measurements in the context of cellular noise studies.
    Keywords:  cellular noise; complementation; heteroplasmy variance; macroheteroplasmy; microheteroplasmy; mitochondria
    DOI:  https://doi.org/10.3389/fgene.2018.00718
  54. Proc Natl Acad Sci U S A. 2019 Feb 12. pii: 201817759. [Epub ahead of print]
    Crystal structure of MICU2 and comparison with MICU1 reveal insights into the uniporter gating mechanism.
    Kimberli J Kamer, Wei Jiang, Virendar K Kaushik, Vamsi K Mootha, Zenon Grabarek.
      The mitochondrial uniporter is a Ca2+-channel complex resident within the organelle's inner membrane. In mammalian cells the uniporter's activity is regulated by Ca2+ due to concerted action of MICU1 and MICU2, two paralogous, but functionally distinct, EF-hand Ca2+-binding proteins. Here we present the X-ray structure of the apo form of Mus musculus MICU2 at 2.5-Å resolution. The core structure of MICU2 is very similar to that of MICU1. It consists of two lobes, each containing one canonical Ca2+-binding EF-hand (EF1, EF4) and one structural EF-hand (EF2, EF3). Two molecules of MICU2 form a symmetrical dimer stabilized by highly conserved hydrophobic contacts between exposed residues of EF1 of one monomer and EF3 of another. Similar interactions stabilize MICU1 dimers, allowing exchange between homo- and heterodimers. The tight EF1-EF3 interface likely accounts for the structural and functional coupling between the Ca2+-binding sites in MICU1, MICU2, and their complex that leads to the previously reported Ca2+-binding cooperativity and dominant negative effect of mutation of the Ca2+-binding sites in either protein. The N- and C-terminal segments of the two proteins are distinctly different. In MICU2 the C-terminal helix is significantly longer than in MICU1, and it adopts a more rigid structure. MICU2's C-terminal helix is dispensable in vitro for its interaction with MICU1 but required for MICU2's function in cells. We propose that in the MICU1-MICU2 oligomeric complex the C-terminal helices of both proteins form a central semiautonomous assembly which contributes to the gating mechanism of the uniporter.
    Keywords:  EF-hand; MICU2; MR-SAD; calcium; mitochondria
    DOI:  https://doi.org/10.1073/pnas.1817759116
  55. Proc Natl Acad Sci U S A. 2019 Feb 15. pii: 201810633. [Epub ahead of print]
    TRPM7 is the central gatekeeper of intestinal mineral absorption essential for postnatal survival.
    Lorenz Mittermeier, Lusine Demirkhanyan, Benjamin Stadlbauer, Andreas Breit, Camilla Recordati, Anne Hilgendorff, Masayuki Matsushita, Attila Braun, David G Simmons, Eleonora Zakharian, Thomas Gudermann, Vladimir Chubanov.
      Zn2+, Mg2+, and Ca2+ are essential minerals required for a plethora of metabolic processes and signaling pathways. Different categories of cation-selective channels and transporters are therefore required to tightly control the cellular levels of individual metals in a cell-specific manner. However, the mechanisms responsible for the organismal balance of these essential minerals are poorly understood. Herein, we identify a central and indispensable role of the channel-kinase TRPM7 for organismal mineral homeostasis. The function of TRPM7 was assessed by single-channel analysis of TRPM7, phenotyping of TRPM7-deficient cells in conjunction with metabolic profiling of mice carrying kidney- and intestine-restricted null mutations in Trpm7 and animals with a global "kinase-dead" point mutation in the gene. The TRPM7 channel reconstituted in lipid bilayers displayed a similar permeability to Zn2+ and Mg2+ Consistently, we found that endogenous TRPM7 regulates the total content of Zn2+ and Mg2+ in cultured cells. Unexpectedly, genetic inactivation of intestinal rather than kidney TRPM7 caused profound deficiencies specifically of Zn2+, Mg2+, and Ca2+ at the organismal level, a scenario incompatible with early postnatal growth and survival. In contrast, global ablation of TRPM7 kinase activity did not affect mineral homeostasis, reinforcing the importance of the channel activity of TRPM7. Finally, dietary Zn2+ and Mg2+ fortifications significantly extended the survival of offspring lacking intestinal TRPM7. Hence, the organismal balance of divalent cations critically relies on one common gatekeeper, the intestinal TRPM7 channel.
    Keywords:  TRP channels; TRPM7; calcium; magnesium; zinc
    DOI:  https://doi.org/10.1073/pnas.1810633116
  56. Exp Mol Med. 2019 Feb 13. 51(2): 15
    Kynurenine 3-monooxygenase is a critical regulator of renal ischemia-reperfusion injury.
    Xiaozhong Zheng, Ailiang Zhang, Margaret Binnie, Kris McGuire, Scott P Webster, Jeremy Hughes, Sarah E M Howie, Damian J Mole.
      Acute kidney injury (AKI) following ischemia-reperfusion injury (IRI) has a high mortality and lacks specific therapies. Here, we report that mice lacking kynurenine 3-monooxygenase (KMO) activity (Kmonull mice) are protected against AKI after renal IRI. We show that KMO is highly expressed in the kidney and exerts major metabolic control over the biologically active kynurenine metabolites 3-hydroxykynurenine, kynurenic acid, and downstream metabolites. In experimental AKI induced by kidney IRI, Kmonull mice had preserved renal function, reduced renal tubular cell injury, and fewer infiltrating neutrophils compared with wild-type (Kmowt) control mice. Together, these data confirm that flux through KMO contributes to AKI after IRI, and supports the rationale for KMO inhibition as a therapeutic strategy to protect against AKI during critical illness.
    DOI:  https://doi.org/10.1038/s12276-019-0210-x
  57. F1000Res. 2018 ;7 1177
    The dynamic side of the Warburg effect: glycolytic intermediates as buffer for fluctuating glucose and O 2 supply in tumor cells.
    Johannes H G M van Beek.
      Background: Tumor cells show the Warburg effect: high glucose uptake and lactate production despite sufficient oxygen supply. Otto Warburg found this effect in tissue slices and in suspensions of Ehrlich ascites tumor cells. Remarkably, these ascites tumor cells can transiently take up glucose an order of magnitude faster than the steady high rate measured by Warburg for hours. Methods: The purpose of the transiently very high glucose uptake is investigated here with a computational model of glycolysis, oxidative phosphorylation and ATP consumption which reproduces short kinetic experiments on the ascites tumor cells as well as the long-lasting Warburg, Crabtree and Pasteur effects. The model, extended with equations for glucose and O 2 transport in tissue, is subsequently used to predict metabolism in tumor cells during fluctuations of tissue blood flow resulting in cycling hypoxia. Results: The model analysis suggests that the head section of the glycolytic chain in the tumor cells is partially inhibited in about a minute when substantial amounts of glucose have been taken up intracellularly; this head section of the glycolytic chain is subsequently disinhibited slowly when concentrations of glycolytic intermediates are low. Based on these dynamic characteristics, simulations of tissue with fluctuating O 2 and glucose supply predict that tumor cells greedily take up glucose when this periodically becomes available, leaving very little for other cells. The glucose is stored as fructose 1,6-bisphosphate and other glycolytic intermediates, which are used for ATP production during   O 2 and glucose shortages. Conclusions: The head section of glycolysis which phosphorylates glucose may be dynamically regulated and takes up glucose at rates exceeding the Warburg effect if glucose levels have been low for some time. The hypothesis is put forward here that dynamic regulation of the powerful glycolytic enzyme system in tumors is used to buffer oxygen and nutrient fluctuations in tissue.
    Keywords:  cancer; cancer metabolism; computational model; cycling hypoxia; glycolysis; hypoxia; nutrient fluctuation; nutrient shortage; oxidative phosphorylation
    DOI:  https://doi.org/10.12688/f1000research.15635.1
  58. Nat Commun. 2019 Feb 15. 10(1): 759
    Copy-choice recombination during mitochondrial L-strand synthesis causes DNA deletions.
    Örjan Persson, Yazh Muthukumar, Swaraj Basu, Louise Jenninger, Jay P Uhler, Anna-Karin Berglund, Robert McFarland, Robert W Taylor, Claes M Gustafsson, Erik Larsson, Maria Falkenberg.
      Mitochondrial DNA (mtDNA) deletions are associated with mitochondrial disease, and also accumulate during normal human ageing. The mechanisms underlying mtDNA deletions remain unknown although several models have been proposed. Here we use deep sequencing to characterize abundant mtDNA deletions in patients with mutations in mitochondrial DNA replication factors, and show that these have distinct directionality and repeat characteristics. Furthermore, we recreate the deletion formation process in vitro using only purified mitochondrial proteins and defined DNA templates. Based on our in vivo and in vitro findings, we conclude that mtDNA deletion formation involves copy-choice recombination during replication of the mtDNA light strand.
    DOI:  https://doi.org/10.1038/s41467-019-08673-5
  59. J Cell Biochem. 2019 Feb 11.
    Elevated expression of the V-ATPase D2 subunit triggers increased energy metabolite levels in KrasG12D -driven cancer cells.
    Jigang Yang, Feihu Guo, Leilei Yuan, Guangxin Lv, Jianhua Gong, Jing Chen.
      Mutations of the Ras oncogene are frequently detected in human cancers. Among Ras-mediated tumorigenesis, Kras-driven cancers are the most dominant mutation types. Here, we investigated molecular markers related to the Kras mutation, which is involved in energy metabolism in Kras mutant-driven cancer. We first generated a knock-in KrasG12D cell line as a model. The genotype and phenotype of the Kras G12D -driven cells were first confirmed. Dramatically elevated metabolite characterization was observed in Kras G12D -driven cells compared with wild-type cells. Analysis of mitochondrial metabolite-related genes showed that two of the 84 genes in Kras G12D -driven cells differed from control cells by at least twofold. The messenger RNA and protein levels of ATP6V0D2 were significantly upregulated in Kras G12D -driven cells. Knockdown of ATP6V0D2 expression inhibited motility and invasion but did not affect the proliferation of Kras G12D -driven cells. We further investigated ATP6V0D2 expression in tumor tissue microarrays. ATP6V0D2 overexpression was observed in most carcinoma tissues, such as melanoma, pancreas, and kidney. Thus, we suggest that ATP6V0D2, as one of the V-ATPase (vacuolar-type H + -ATPase) subunit isoforms, may be a potential therapeutic target for Kras mutation cancer.
    Keywords:  ATP6V0D2; Kras mutation; V-ATPases; energy metabolite; motility and invasion
    DOI:  https://doi.org/10.1002/jcb.28448
  60. Sci Rep. 2019 Feb 13. 9(1): 1986
    Reduced mitochondrial respiration and increased calcium deposits in the EDL muscle, but not in soleus, from 12-week-old dystrophic mdx mice.
    Rhayanna B Gaglianone, Anderson Teixeira Santos, Flavia Fonseca Bloise, Tania Maria Ortiga-Carvalho, Manoel Luis Costa, Thereza Quirico-Santos, Wagner Seixas da Silva, Claudia Mermelstein.
      Mitochondria play an important role in providing ATP for muscle contraction. Muscle physiology is compromised in Duchenne muscular dystrophy (DMD) and several studies have shown the involvement of bioenergetics. In this work we investigated the mitochondrial physiology in fibers from fast-twitch muscle (EDL) and slow-twitch muscle (soleus) in the mdx mouse model for DMD and in control C57BL/10J mice. In our study, multiple mitochondrial respiratory parameters were investigated in permeabilized muscle fibers from 12-week-old animals, a critical age where muscle regeneration is observed in the mdx mouse. Using substrates of complex I and complex II from the electron transport chain, ADP and mitochondrial inhibitors, we found in the mdx EDL, but not in the mdx soleus, a reduction in coupled respiration suggesting that ATP synthesis is affected. In addition, the oxygen consumption after addition of complex II substrate is reduced in mdx EDL; the maximal consumption rate (measured in the presence of uncoupler) also seems to be reduced. Mitochondria are involved in calcium regulation and we observed, using alizarin stain, calcium deposits in mdx muscles but not in control muscles. Interestingly, more calcium deposits were found in mdx EDL than in mdx soleus. These data provide evidence that in 12-week-old mdx mice, calcium is accumulated and mitochondrial function is disturbed in the fast-twitch muscle EDL, but not in the slow-twitch muscle soleus.
    DOI:  https://doi.org/10.1038/s41598-019-38609-4
  61. Am J Physiol Endocrinol Metab. 2019 Feb 12.
    Amino acid and Fatty Acid Metabolomic Profile during Fasting and Hyperinsulinemia in girls with Polycystic Ovarian Syndrome.
    Melanie Cree-Green, Anne-Marie Carreau, Haseeb Rahat, Yesenia Garcia-Reyes, Bryan C Bergman, Laura Pyle, Kristen J Nadeau.
      Polycystic Ovarian Syndrome (PCOS) is associated with insulin resistance (IR) and altered muscle mitochondrial oxidative phosphorylation. IR in adults with obesity and diabetes is associated with changes in amino acid, free fatty acid (FFA) and mitochondrial acylcarnitine (AC) metabolism. We sought to determine if these metabolites are associated with IR and/or androgens in youth-onset PCOS. We enrolled obese girls with PCOS [n = 15, 14.5 ± 1.6 years, BMI %ile 98.5 ± 1.0] and without PCOS [n = 6, 13.2 ± 1.2 years, BMI %ile 98.0 ± 1.1]. Insulin sensitivity was assessed by hyperinsulinemic-euglycemic clamp. Untargeted metabolomics of plasma was performed fasting and during hyperinsulinemia. Fasting arginine, glutamine, histidine, lysine, phenylalanine and tyrosine were higher (p< 0.04 for all but valine p< 0.001) as were glutamine and histidine during hyperinsulinemia (p< 0.03) were higher. Higher valine during hyperinsulinemia was associated with IR (r =0.59, p=0.006). Surprisingly, end-clamp AC C4 was lower in PCOS and lower C4 was associated with IR (r =-0.44, p= 0.04). End-clamp, FFAs C14:0, C:16:1 and C18:1 were higher in PCOS girls and C16:1 and C18:1 strongly associated with IR (r =0.73 and 0.53, p< 0.01). Free androgen index related negatively to short, medium and long-chain AC (r =-0.41 to -0.71, p< 0.01), but not FFA or amino acids. Obese girls with PCOS have a distinct metabolic signature during fasting and hyperinsulinemia. As in diabetes, IR related to valine and FFAs, with an unexpected relationship with AC C4, suggesting unique metabolism in obese girls with PCOS.
    Keywords:  amino acids; free fatty acids; insulin resistance; metabolomics; polycystic ovarian syndrome
    DOI:  https://doi.org/10.1152/ajpendo.00532.2018
  62. Mitochondrion. 2019 Feb 06. pii: S1567-7249(18)30126-0. [Epub ahead of print]
    MtBrowse: An integrative genomics browser for human mitochondrial DNA.
    Vipin Singh, Bani Jolly, Neeraj K Rajput, Sayan Pramanik, Anshu Bhardwaj.
      The human mitochondrion is a unique semi-autonomous organelle with a genome of its own and also requires nuclear encoded components to carry out its functions. In addition to being the powerhouse of the cell, mitochondria plays a central role in several metabolic pathways. It is therefore challenging to delineate the cause-effect relationship in context of mitochondrial dysfunction. Several studies implicate mutations in mitochondrial DNA (mtDNA) in various complex diseases. The human mitochondrial DNA (mtDNA) encodes a set of 37 genes, 13 protein coding, 22 tRNAs and two ribosomal RNAs, which are essential structural and functional components of the electron transport chain. As mentioned above, variations in these genes have been implicated in a broad spectrum of diseases and are extensively reported in literature and various databases. A large number of databases and prediction methods have been published to elucidate the role of human mitochondrial DNA in various disease phenotypes. However, there is no centralized resource to visualize this genotype-phenotype data. Towards this, we have developed MtBrowse: an integrative genomics browser for human mtDNA. As of now, MtBrowse has four categories - Gene, Disease, Reported variation and Variation prediction. These categories have 105 tracks and house data on mitochondrial reference genes, around 600 variants reported in literature with respect to various disease phenotypes and predictions for potential pathogenic variations in protein-coding genes. MtBrowse also hosts genomic variation data from over 5000 individuals on 22 disease phenotypes. MtBrowse may be accessed at http://ab-openlab.csir.res.in/cgi-bin/gb2/gbrowse.
    DOI:  https://doi.org/10.1016/j.mito.2019.02.003
  63. Lipids Health Dis. 2019 Feb 14. 18(1): 53
    Double bonds of unsaturated fatty acids differentially regulate mitochondrial cardiolipin remodeling.
    Hsiu-Chi Ting, Li-Tzu Chen, Jo-Yu Chen, Yi-Li Huang, Rui-Cheng Xin, Jui-Fen Chan, Yuan-Hao Howard Hsu.
      BACKGROUND: Supplemented fatty acids can incorporate into cardiolipin (CL) and affect its remodeling. The change in CL species may alter the mitochondrial membrane composition, potentially disturbing the mitochondrial structure and function during inflammation.METHOD: To investigate the effect of the unsaturation of fatty acids on CL, we supplemented macrophage-like RAW264.7 cells with 18-carbon unsaturated fatty acids including oleic acid (OA, 18:1), linoleic acid (LA, 18:2), α-linolenic acid (ALA, 18:3), γ-linolenic acid (GLA, 18:3), and stearidonic acid (SDA, 18:4). Mitochondrial changes in CL were measured through mass spectrometry.
    RESULT: Our data indicated that OA(18:1) was the most efficient fatty acid that incorporated into CL, forming symmetrical CL without fatty acid elongation and desaturation. In addition, LA(18:2) and ALA(18:3) were further elongated before incorporation, significantly increasing the number of double bonds and the chain length of CL. GLA and SDA were not optimal substrates for remodeling enzymes. The findings of RT-qPCR experiments revealed that none of these changes in CL occurred through the regulation of CL remodeling- or synthesis-related genes. The fatty acid desaturase and transportation genes-Fads2 and Cpt1a, respectively-were differentially regulated by the supplementation of five unsaturated 18-carbon fatty acids.
    CONCLUSIONS: The process of fatty acid incorporation to CL was regulated by the fatty acid desaturation and transportation into mitochondria in macrophage. The double bonds of fatty acids significantly affect the incorporation process and preference. Intact OA(18:1) was incorporated to CL; LA(18:2) and ALA(18:3) were desaturated and elongated to long chain fatty acid before the incorporation; GLA(18:3) and SDA(18:4) were unfavorable for the CL incorporation.
    Keywords:  18-carbon unsaturated fatty acids; Cardiolipin; Mass spectrometry; Mitochondrial membrane composition
    DOI:  https://doi.org/10.1186/s12944-019-0990-y
  64. Autophagy. 2019 Feb 15.
    C9orf72-dependent lysosomal functions regulate epigenetic control of autophagy and lipid metabolism.
    Yang Liu, Jiou Wang.
      Cellular adaption to nutrient stress is exquisitely regulated, and its dysregulation could underlie human diseases including neurodegeneration. C9orf72 is linked to the most common forms of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) as well as rare cases of other neurological disorders. Recent studies have implicated C9orf72 functions in the autophagy-lysosome pathway, but the exact roles of C9orf72 remain unclear. We found that C9orf72 is required for the lysosomal targeting and degradation of CARM1, which is an important epigenetic regulator of macroautophagy/autophagy and lipid metabolism. In cells with C9orf72 deficiency including those derived from ALS-FTD patients, CARM1 is abnormally accumulated especially under glucose starvation stress, leading to dysregulated autophagy and lipid metabolism. These findings suggest that C9orf72 is a key regulator in the negative feedback control of the autophagy-lysosome pathway during nutrient stress responses.
    Keywords:  ALS; C9orf72; CARM1; FTD; NOX2; autophagy; fatty acid; lipid droplet; lipid metabolism; lysosome
    DOI:  https://doi.org/10.1080/15548627.2019.1580106
  65. Proc Natl Acad Sci U S A. 2019 Feb 13. pii: 201816556. [Epub ahead of print]
    Dimers of mitochondrial ATP synthase induce membrane curvature and self-assemble into rows.
    Thorsten B Blum, Alexander Hahn, Thomas Meier, Karen M Davies, Werner Kühlbrandt.
      Mitochondrial ATP synthases form dimers, which assemble into long ribbons at the rims of the inner membrane cristae. We reconstituted detergent-purified mitochondrial ATP synthase dimers from the green algae Polytomella sp. and the yeast Yarrowia lipolytica into liposomes and examined them by electron cryotomography. Tomographic volumes revealed that ATP synthase dimers from both species self-assemble into rows and bend the lipid bilayer locally. The dimer rows and the induced degree of membrane curvature closely resemble those in the inner membrane cristae. Monomers of mitochondrial ATP synthase reconstituted into liposomes do not bend membrane visibly and do not form rows. No specific lipids or proteins other than ATP synthase dimers are required for row formation and membrane remodelling. Long rows of ATP synthase dimers are a conserved feature of mitochondrial inner membranes. They are required for cristae formation and a main factor in mitochondrial morphogenesis.
    Keywords:  ATP synthase; electron cryotomography; membrane curvature; mitochondria; subtomogram averaging
    DOI:  https://doi.org/10.1073/pnas.1816556116
  66. Nature. 2019 Feb 11.
    Structure of the complex I-like molecule NDH of oxygenic photosynthesis.
    Thomas G Laughlin, Andrew N Bayne, Jean-François Trempe, David F Savage, Karen M Davies.
      Cyclic electron flow around photosystem I (PSI) is a mechanism by which photosynthetic organisms balance the levels of ATP and NADPH necessary for efficient photosynthesis1,2. NAD(P)H dehydrogenase-like complex (NDH) is a key component of this pathway in most oxygenic photosynthetic organisms3,4 and is the last large photosynthetic membrane-protein complex for which the structure remains unknown. Related to the respiratory NADH dehydrogenase complex (complex I), NDH transfers electrons originating from PSI to the plastoquinone pool while pumping protons across the thylakoid membrane, thereby increasing the amount of ATP produced per NADP+ molecule reduced4,5. NDH possesses 11 of the 14 core complex I subunits, as well as several oxygenic-photosynthesis-specific (OPS) subunits that are conserved from cyanobacteria to plants3,6. However, the three core complex I subunits that are involved in accepting electrons from NAD(P)H are notably absent in NDH3,5,6, and it is therefore not clear how NDH acquires and transfers electrons to plastoquinone. It is proposed that the OPS subunits-specifically NdhS-enable NDH to accept electrons from its electron donor, ferredoxin3-5,7. Here we report a 3.1 Å structure of the 0.42-MDa NDH complex from the thermophilic cyanobacterium Thermosynechococcus elongatus BP-1, obtained by single-particle cryo-electron microscopy. Our maps reveal the structure and arrangement of the principal OPS subunits in the NDH complex, as well as an unexpected cofactor close to the plastoquinone-binding site in the peripheral arm. The location of the OPS subunits supports a role in electron transfer and defines two potential ferredoxin-binding sites at the apex of the peripheral arm. These results suggest that NDH could possess several electron transfer routes, which would serve to maximize plastoquinone reduction and avoid deleterious off-target chemistry of the semi-plastoquinone radical.
    DOI:  https://doi.org/10.1038/s41586-019-0921-0
  67. Arch Pharm Res. 2019 Feb 15.
    Mitochondria-centric bioenergetic characteristics in cancer stem-like cells.
    Min-Kyue Shin, Jae-Ho Cheong.
      Metabolic and genotoxic stresses that arise during tumor progression and anti-cancer treatment, respectively, can impose a selective pressure to promote cancer evolution in the tumor microenvironment. This process ultimately selects for the most "fit" clones, which generally have a cancer stem cell like phenotype with features of drug resistance, epithelial-mesenchymal transition, invasiveness, and high metastatic potential. From a bioenergetics perspective, these cancer stem-like cells (CSCs) exhibit mitochondria-centric energy metabolism and are capable of opportunistically utilizing available nutrients such as fatty acids to generate ATP and other metabolic substances, providing a selective advantage for their survival in an impermissible environment and metabolic context. Thus, diverse therapeutic strategies are needed to efficiently tackle these CSCs and eliminate their advantage. Here, we review the metabolic and bioenergetic characteristics and vulnerabilities specific to CSCs, which can provide an unprecedented opportunity to curb CSC-driven cancer mortality rates. We particularly focus on the potential of a CSC bioenergetics-targeted strategy as a versatile therapeutic component of treatment modalities applicable to most cancer types. A cancer bioenergetics-targeted strategy can expand the inventory of combinatorial regimens in the current anti-cancer armamentarium.
    Keywords:  Bioenergetics; Cancer evolution; Cancer metabolism; Cancer stem cell; Fatty acid oxidation; Mitochondria; β-Oxidation
    DOI:  https://doi.org/10.1007/s12272-019-01127-y
  68. Adv Nutr. 2019 Feb 06.
    Glutamine Metabolism in Macrophages: A Novel Target for Obesity/Type 2 Diabetes.
    Wenkai Ren, Yaoyao Xia, Siyuan Chen, Guoyao Wu, Fuller W Bazer, Beiyan Zhou, Bie Tan, Guoqiang Zhu, Jinping Deng, Yulong Yin.
      Obesity is a nutritional disorder resulting from a chronic imbalance between energy intake and expenditure. This disease is characterized by inflammation in multiple cell types, including macrophages. M1 macrophage responses are correlated with the progression of obesity or diabetes; therefore, strategies that induce repolarization of macrophages from an M1 to an M2 phenotype may be promising for the prevention of obesity- or diabetes-associated pathology. Glutamine (the most abundant amino acid in the plasma of humans and many other mammals including rats) is effective in inducing polarization of M2 macrophages through the glutamine-UDP-N-acetylglucosamine pathway and α-ketoglutarate produced via glutaminolysis, whereas succinate synthesized via glutamine-dependent anerplerosis or the γ-aminobutyric acid shunt promotes polarization of M1 macrophages. Interestingly, patients with obesity or diabetes show altered glutamine metabolism, including decreases in glutamine and α-ketoglutarate concentrations in serum but increases in succinate concentrations. Thus, manipulation of macrophage polarization through glutamine metabolism may provide a potential target for prevention of obesity- or diabetes-associated pathology.
    DOI:  https://doi.org/10.1093/advances/nmy084
  69. Cell Death Differ. 2019 Feb 13.
    mTOR-dependent upregulation of xCT blocks melanin synthesis and promotes tumorigenesis.
    Chunjia Li, Hongyu Chen, Zhou Lan, Shaozong He, Rongrong Chen, Fang Wang, Zhibo Liu, Kai Li, Lili Cheng, Ye Liu, Kun Sun, Xiaofeng Wan, Xinxin Chen, Haiyong Peng, Li Li, Yanjun Zhang, Yanling Jing, Min Huang, Yanan Wang, Yan Wang, Jiandong Jiang, Xiaojun Zha, Ligong Chen, Hongbing Zhang.
      Loss of either TSC1 or TSC2 causes tuberous sclerosis complex (TSC) via activation of mTOR signaling pathway. The two prominent features of TSC are skin lesions including hypomelanic macules and benign tumors in multiple organs, whose molecular alterations are largely unknown. We report here that Xc- cystine/glutamate antiporter (xCT) was elevated in Tsc2-/- or Pten-/- cells, Tsc1 knockout mouse tissues and TSC2-deficient human kidney tumor. xCT was transcriptionally boosted by mTOR-mediated Oct1 signaling cascade. Augmented xCT led to reduction of eumelanin and elevation of pheomelanin in Tsc1 skin knockout mice through mTOR signaling pathway. Disruption of xCT suppressed the proliferation and tumorigenesis of Pten-null cells and Tsc2-null cells. mTOR hyperactive cells were more sensitive to inhibitors of mTOR or xCT. Combined inhibition of mTOR and xCT synergistically blocked the propagation and oncogenesis of mTOR hyperactive cells. Therefore, oncogenic mTOR activation of xCT is a key connection between aberrant melanin synthesis and tumorigenesis. We suggest that xCT is a novel therapeutic target for TSC and other aberrant mTOR-related diseases.
    DOI:  https://doi.org/10.1038/s41418-019-0274-0
  70. Microb Cell. 2019 Jan 21. 6(2): 123-133
    What's in a name? How organelles of endosymbiotic origin can be distinguished from endosymbionts.
    Ansgar Gruber.
      Mitochondria and plastids evolved from free-living bacteria, but are now considered integral parts of the eukaryotic species in which they live. Therefore, they are implicitly called by the same eukaryotic species name. Historically, mitochondria and plastids were known as "organelles", even before their bacterial origin became fully established. However, since organelle evolution by endosymbiosis has become an established theory in biology, more and more endosymbiotic systems have been discovered that show various levels of host/symbiont integration. In this context, the distinction between "host/symbiont" and "eukaryote/organelle" systems is currently unclear. The criteria that are commonly considered are genetic integration (via gene transfer from the endosymbiont to the nucleus), cellular integration (synchronization of the cell cycles), and metabolic integration (the mutual dependency of the metabolisms). Here, I suggest that these criteria should be evaluated according to the resulting coupling of genetic recombination between individuals and congruence of effective population sizes, which determines if independent speciation is possible for either of the partners. I would like to call this aspect of integration "sexual symbiont integration". If the partners lose their independence in speciation, I think that they should be considered one species. The partner who maintains its genetic recombination mechanisms and life cycle should then be the name giving "host"; the other one would be the organelle. Distinguishing between organelles and symbionts according to their sexual symbiont integration is independent of any particular mechanism or structural property of the endosymbiont/host system under investigation.
    Keywords:  chloroplast; endocytobiosis; eukaryogenesis; evolution; organelle; speciation; symbiogenesis
    DOI:  https://doi.org/10.15698/mic2019.02.668
  71. Cancer Res. 2019 Feb 14. pii: canres.2553.2018. [Epub ahead of print]
    MDH1 and MPP7 regulate autophagy in pancreatic ductal adenocarcinoma.
    Sharon A Tooze, Maria New, Tim Van Acker, Jun-Ichi Sakamaki, Ming Jiang, Rebecca E Saunders, Jaclyn Long, Victoria M-Y Wang, Axel Behrens, Padhmanand Sudhakar, Tamas Korcsmaros, Kevin M Ryan, Michael Howell, Joana Cerveira, Harold B J Jefferies.
      Pancreatic ductal adenocarcinoma (PDAC) is driven by metabolic changes in pancreatic cells caused by oncogenic mutations and dysregulation of p53. PDAC cell lines and PDAC-derived xenografts grow as a result of altered metabolic pathways, changes in stroma, and autophagy. Selective targeting and inhibition of one of these may open avenues for the development of new therapeutic strategies. In this study, we performed a genome-wide siRNA screen in a PDAC cell line using endogenous autophagy as a readout and identified several regulators of autophagy that were required for autophagy-dependent PDAC cell survival. Validation of two promising candidates, MPP7 (MAGUK p55 subfamily member 7, a scaffolding protein involved in cell-cell contacts) and MDH1 (cytosolic Malate dehydrogenase 1), revealed their role in early stages of autophagy during autophagosome formation. MPP7 was involved in activation of YAP1 (a transcriptional coactivator in the Hippo pathway), which in turn promoted autophagy, whereas MDH1 was required for maintenance of the levels of the essential autophagy initiator serine-threonine kinase ULK1, and increased in activity upon induction of autophagy. Our results provide a possible explanation for how autophagy is regulated by MPP7 and MDH1, which adds to our understanding of autophagy regulation in PDAC.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-18-2553
  72. Cancer Cell. 2019 Feb 11. pii: S1535-6108(19)30051-0. [Epub ahead of print]35(2): 161-163
    Glutathione Metabolism: An Achilles' Heel of ARID1A-Deficient Tumors.
    Chiara Gorrini, Tak W Mak.
      In this issue of Cancer Cell, Ogiwara et al. describe a novel link between the epigenetic regulator ARID1A and glutathione metabolism in cancer that is mediated by regulation of the cystine/glutamate transporter XCT. This work reveals that synthesis of reduced glutathione is a metabolic dependency of cancers with ARID1A-inactivating mutations.
    DOI:  https://doi.org/10.1016/j.ccell.2019.01.017
  73. Sci Signal. 2019 Feb 12. pii: eaar5926. [Epub ahead of print]12(568):
    Mitochondrial reactive oxygen species enable proinflammatory signaling through disulfide linkage of NEMO.
    Marc Herb, Alexander Gluschko, Katja Wiegmann, Alina Farid, Anne Wolf, Olaf Utermöhlen, Oleg Krut, Martin Krönke, Michael Schramm.
      A major function of macrophages during infection is initiation of the proinflammatory response, leading to the secretion of cytokines that help to orchestrate the immune response. Here, we identify reactive oxygen species (ROS) as crucial mediators of proinflammatory signaling leading to cytokine secretion in Listeria monocytogenes-infected macrophages. ROS produced by NADPH oxidases (Noxes), such as Nox2, are key components of the macrophage response to invading pathogens; however, our data show that the ROS that mediated proinflammatory signaling were produced by mitochondria (mtROS). We identified the inhibitor of κB (IκB) kinase (IKK) complex regulatory subunit NEMO [nuclear factor κB (NF-κB) essential modulator] as a target for mtROS. Specifically, mtROS induced intermolecular covalent linkage of NEMO through disulfide bonds formed by Cys54 and Cys347, which was essential for activation of the IKK complex and subsequent signaling through the extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) and NF-κB pathways that eventually led to the secretion of proinflammatory cytokines. We thus identify mtROS-dependent disulfide linkage of NEMO as an essential regulatory step of the proinflammatory response of macrophages to bacterial infection.
    DOI:  https://doi.org/10.1126/scisignal.aar5926
  74. Nat Commun. 2019 Feb 11. 10(1): 693
    NADP+ is an endogenous PARP inhibitor in DNA damage response and tumor suppression.
    Chunjing Bian, Chao Zhang, Tao Luo, Aditi Vyas, Shih-Hsun Chen, Chao Liu, Muzaffer Ahmad Kassab, Ying Yang, Mei Kong, Xiaochun Yu.
      ADP-ribosylation is a unique posttranslational modification catalyzed by poly(ADP-ribose) polymerases (PARPs) using NAD+ as ADP-ribose donor. PARPs play an indispensable role in DNA damage repair and small molecule PARP inhibitors have emerged as potent anticancer drugs. However, to date, PARP inhibitor treatment has been restricted to patients with BRCA1/2 mutation-associated breast and ovarian cancer. One of the major challenges to extend the therapeutic potential of PARP inhibitors to other cancer types is the absence of predictive biomarkers. Here, we show that ovarian cancer cells with higher level of NADP+, an NAD+ derivative, are more sensitive to PARP inhibitors. We demonstrate that NADP+ acts as a negative regulator and suppresses ADP-ribosylation both in vitro and in vivo. NADP+ impairs ADP-ribosylation-dependent DNA damage repair and sensitizes tumor cell to chemically synthesized PARP inhibitors. Taken together, our study identifies NADP+ as an endogenous PARP inhibitor that may have implications in cancer treatment.
    DOI:  https://doi.org/10.1038/s41467-019-08530-5
  75. Nat Neurosci. 2019 Feb 11.
    Mitophagy inhibits amyloid-β and tau pathology and reverses cognitive deficits in models of Alzheimer's disease.
    Evandro F Fang, Yujun Hou, Konstantinos Palikaras, Bryan A Adriaanse, Jesse S Kerr, Beimeng Yang, Sofie Lautrup, Md Mahdi Hasan-Olive, Domenica Caponio, Xiuli Dan, Paula Rocktäschel, Deborah L Croteau, Mansour Akbari, Nigel H Greig, Tormod Fladby, Hilde Nilsen, M Zameel Cader, Mark P Mattson, Nektarios Tavernarakis, Vilhelm A Bohr.
      Accumulation of damaged mitochondria is a hallmark of aging and age-related neurodegeneration, including Alzheimer's disease (AD). The molecular mechanisms of impaired mitochondrial homeostasis in AD are being investigated. Here we provide evidence that mitophagy is impaired in the hippocampus of AD patients, in induced pluripotent stem cell-derived human AD neurons, and in animal AD models. In both amyloid-β (Aβ) and tau Caenorhabditis elegans models of AD, mitophagy stimulation (through NAD+ supplementation, urolithin A, and actinonin) reverses memory impairment through PINK-1 (PTEN-induced kinase-1)-, PDR-1 (Parkinson's disease-related-1; parkin)-, or DCT-1 (DAF-16/FOXO-controlled germline-tumor affecting-1)-dependent pathways. Mitophagy diminishes insoluble Aβ1-42 and Aβ1-40 and prevents cognitive impairment in an APP/PS1 mouse model through microglial phagocytosis of extracellular Aβ plaques and suppression of neuroinflammation. Mitophagy enhancement abolishes AD-related tau hyperphosphorylation in human neuronal cells and reverses memory impairment in transgenic tau nematodes and mice. Our findings suggest that impaired removal of defective mitochondria is a pivotal event in AD pathogenesis and that mitophagy represents a potential therapeutic intervention.
    DOI:  https://doi.org/10.1038/s41593-018-0332-9
  76. Nat Med. 2019 Feb 11.
    Neoadjuvant anti-PD-1 immunotherapy promotes a survival benefit with intratumoral and systemic immune responses in recurrent glioblastoma.
    Timothy F Cloughesy, Aaron Y Mochizuki, Joey R Orpilla, Willy Hugo, Alexander H Lee, Tom B Davidson, Anthony C Wang, Benjamin M Ellingson, Julie A Rytlewski, Catherine M Sanders, Eric S Kawaguchi, Lin Du, Gang Li, William H Yong, Sarah C Gaffey, Adam L Cohen, Ingo K Mellinghoff, Eudocia Q Lee, David A Reardon, Barbara J O'Brien, Nicholas A Butowski, Phioanh L Nghiemphu, Jennifer L Clarke, Isabel C Arrillaga-Romany, Howard Colman, Thomas J Kaley, John F de Groot, Linda M Liau, Patrick Y Wen, Robert M Prins.
      Glioblastoma is the most common primary malignant brain tumor in adults and is associated with poor survival. The Ivy Foundation Early Phase Clinical Trials Consortium conducted a randomized, multi-institution clinical trial to evaluate immune responses and survival following neoadjuvant and/or adjuvant therapy with pembrolizumab in 35 patients with recurrent, surgically resectable glioblastoma. Patients who were randomized to receive neoadjuvant pembrolizumab, with continued adjuvant therapy following surgery, had significantly extended overall survival compared to patients that were randomized to receive adjuvant, post-surgical programmed cell death protein 1 (PD-1) blockade alone. Neoadjuvant PD-1 blockade was associated with upregulation of T cell- and interferon-γ-related gene expression, but downregulation of cell-cycle-related gene expression within the tumor, which was not seen in patients that received adjuvant therapy alone. Focal induction of programmed death-ligand 1 in the tumor microenvironment, enhanced clonal expansion of T cells, decreased PD-1 expression on peripheral blood T cells and a decreasing monocytic population was observed more frequently in the neoadjuvant group than in patients treated only in the adjuvant setting. These findings suggest that the neoadjuvant administration of PD-1 blockade enhances both the local and systemic antitumor immune response and may represent a more efficacious approach to the treatment of this uniformly lethal brain tumor.
    DOI:  https://doi.org/10.1038/s41591-018-0337-7
  77. Ann Transl Med. 2018 Dec;6(24): 474
    Glycogen metabolism and glycogen storage disorders.
    Shibani Kanungo, Kimberly Wells, Taylor Tribett, Areeg El-Gharbawy.
      Glucose is the main energy fuel for the human brain. Maintenance of glucose homeostasis is therefore, crucial to meet cellular energy demands in both - normal physiological states and during stress or increased demands. Glucose is stored as glycogen primarily in the liver and skeletal muscle with a small amount stored in the brain. Liver glycogen primarily maintains blood glucose levels, while skeletal muscle glycogen is utilized during high-intensity exertion, and brain glycogen is an emergency cerebral energy source. Glycogen and glucose transform into one another through glycogen synthesis and degradation pathways. Thus, enzymatic defects along these pathways are associated with altered glucose metabolism and breakdown leading to hypoglycemia ± hepatomegaly and or liver disease in hepatic forms of glycogen storage disorder (GSD) and skeletal ± cardiac myopathy, depending on the site of the enzyme defects. Overall, defects in glycogen metabolism mainly present as GSDs and are a heterogenous group of inborn errors of carbohydrate metabolism. In this article we review the genetics, epidemiology, clinical and metabolic findings of various types of GSD, and glycolysis defects emphasizing current treatment and implications for future directions.
    Keywords:  Glycogen; glycogen storage disorder (GSD); hepatomegaly; hypoglycemia; rhabdomyolysis
    DOI:  https://doi.org/10.21037/atm.2018.10.59
  78. Nat Commun. 2019 Feb 13. 10(1): 724
    Bcl9 and Pygo synergise downstream of Apc to effect intestinal neoplasia in FAP mouse models.
    Juliusz Mieszczanek, Laurens M van Tienen, Ashraf E K Ibrahim, Douglas J Winton, Mariann Bienz.
      Bcl9 and Pygo are Wnt enhanceosome components that effect β-catenin-dependent transcription. Whether they mediate β-catenin-dependent neoplasia is unclear. Here we assess their roles in intestinal tumourigenesis initiated by Apc loss-of-function (ApcMin), or by Apc1322T encoding a partially-functional Apc truncation commonly found in colorectal carcinomas. Intestinal deletion of Bcl9 extends disease-free survival in both models, and essentially cures Apc1322T mice of their neoplasia. Loss-of-Bcl9 synergises with loss-of-Pygo to shift gene expression within Apc-mutant adenomas from stem cell-like to differentiation along Notch-regulated secretory lineages. Bcl9 loss also promotes tumour retention in ApcMin mice, apparently via relocating nuclear β-catenin to the cell surface, but this undesirable effect is not seen in Apc1322T mice whose Apc truncation retains partial function in regulating β-catenin. Our results demonstrate a key role of the Wnt enhanceosome in β-catenin-dependent intestinal tumourigenesis and reveal the potential of BCL9 as a therapeutic target during early stages of colorectal cancer.
    DOI:  https://doi.org/10.1038/s41467-018-08164-z
  79. Ann Transl Med. 2018 Dec;6(24): 473
    Fatty acid oxidation disorders.
    J Lawrence Merritt, Marie Norris, Shibani Kanungo.
      Fatty acid oxidation disorders (FAODs) are inborn errors of metabolism due to disruption of either mitochondrial β-oxidation or the fatty acid transport using the carnitine transport pathway. The presentation of a FAOD will depend upon the specific disorder, but common elements may be seen, and ultimately require a similar treatment. Initial presentations of the FAODs in the neonatal period with severe symptoms include cardiomyopathy, while during infancy and childhood liver dysfunction and hypoketotic hypoglycemia are common. Episodic rhabdomyolysis is frequently the initial presentation during or after adolescence; although, these symptoms may develop at any age for most of the FAODs The treatment of all FAOD's include avoidance of fasting, aggressive treatment during illness, and supplementation of carnitine, if necessary. The long-chain FAODs differ by requiring a fat-restricted diet and supplementation of medium chain triglyceride oil and often docosahexaenoic acid (DHA)-an essential fatty acid, crucial for brain, visual, and immune functions and prevention of fat soluble vitamin deficiencies. The FAOD are a group of autosomal recessive disorders associated with significant morbidity and mortality, but early diagnosis on newborn screening (NBS) and early initiation of treatment are improving outcomes. There is a need for clinical studies including randomized, controlled, therapeutic trials to continue to evaluate current understanding and to implement future therapies.
    Keywords:  Fatty acid oxidation disorders (FAODs); carnitine; hypoketotic hypoglycemia; mitochondrial β-oxidation; trifunctional protein
    DOI:  https://doi.org/10.21037/atm.2018.10.57
  80. Cancer Discov. 2019 Feb 15.
    TP53 Mutations Are Immunogenic in Epithelial Cancer.
      Mutant p53-specific T cells were isolated from patients with metastatic epithelial cancers.
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2019-022
  81. EMBO Rep. 2019 Feb 12. pii: e44948. [Epub ahead of print]
    YAP1-LATS2 feedback loop dictates senescent or malignant cell fate to maintain tissue homeostasis.
    Chunbo He, Xiangmin Lv, Cong Huang, Guohua Hua, Bowen Ma, Xingcheng Chen, Peter C Angeletti, Jixin Dong, Jin Zhou, Zhengfeng Wang, Bo R Rueda, John S Davis, Cheng Wang.
      Dysfunction of the homeostasis-maintaining systems in specific cell types or tissues renders the organism susceptible to a range of diseases, including cancers. One of the emerging mechanisms for maintaining tissue homeostasis is cellular senescence. Here, we report that the Hippo pathway plays a critical role in controlling the fate of ovarian cells. Hyperactivation of Yes-associated protein 1 (YAP1), the major effector of the Hippo pathway, induces senescence in cultured primary human ovarian surface epithelial cells (hOSEs). Large tumor suppressor 2 (LATS2), the primary upstream negative regulator of YAP1, is elevated in both YAP1-induced and natural replicative-triggered senescence. Deletion of LATS2 in hOSEs prevents these cells from natural replicative and YAP1-induced senescence. Most importantly, loss of LATS2 switches ovarian cells from YAP-induced senescence to malignant transformation. Our results demonstrate that LATS2 and YAP1, two major components of the Hippo/YAP signaling pathway, form a negative feedback loop to control YAP1 activity and prevent ovarian cells from malignant transformation. Human cancer genomic data extracted from TCGA datasets further confirm the clinical relevance of our finding.
    Keywords:  YAP1‐LATS2 feedback loop; cellular senescence; the Hippo pathway; tissue homeostasis; tumorigenesis
    DOI:  https://doi.org/10.15252/embr.201744948
  82. Med Res Rev. 2019 Feb 12.
    Dimethyl fumarate, a two-edged drug: Current status and future directions.
    Nathaniel Edward Bennett Saidu, Niloufar Kavian, Karen Leroy, Claus Jacob, Carole Nicco, Frédéric Batteux, Jérôme Alexandre.
      Dimethyl fumarate (DMF) is a fumaric acid ester registered for the treatment of relapsing-remitting multiple sclerosis (RRMS). It induces protein succination leading to inactivation of cysteine-rich proteins. It was first shown to possess cytoprotective and antioxidant effects in noncancer models, which appeared related to the induction of the nuclear factor erythroid 2 (NF-E2)-related factor 2 (NRF2) pathway. DMF also displays antitumor activity in several cellular and mice models. Recently, we showed that the anticancer mechanism of DMF is dose-dependent and is paradoxically related to the decrease in the nuclear translocation of NRF2. Some other studies performed indicate also the potential role of DMF in cancers, which are dependent on the NRF2 antioxidant and cellular detoxification program, such as KRAS-mutated lung adenocarcinoma. It, however, seems that DMF has multiple biological effects as it has been shown to also inhibit the transcription factor nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), thus blocking downstream targets that may be involved in the development and progression of inflammatory cascades leading to various disease processes, including tumors, lymphomas, diabetic retinopathy, arthritis, and psoriasis. Herein, we present the current status and future directions of the use of DMF in various diseases models with particular emphases on its targeting of specific intracellular signal transduction cascades in cancer; to shed some light on its possible mode of action.
    Keywords:  DJ-1; cancer; dimethyl fumarate; immunomodulation; nuclear factor erythroid 2 (NF-E2)-related factor 2; oxidative stress; succinic-GSH
    DOI:  https://doi.org/10.1002/med.21567
  83. Ann Transl Med. 2018 Dec;6(24): 471
    Amino acid disorders.
    Ermal Aliu, Shibani Kanungo, Georgianne L Arnold.
      Amino acids serve as key building blocks and as an energy source for cell repair, survival, regeneration and growth. Each amino acid has an amino group, a carboxylic acid, and a unique carbon structure. Human utilize 21 different amino acids; most of these can be synthesized endogenously, but 9 are "essential" in that they must be ingested in the diet. In addition to their role as building blocks of protein, amino acids are key energy source (ketogenic, glucogenic or both), are building blocks of Kreb's (aka TCA) cycle intermediates and other metabolites, and recycled as needed. A metabolic defect in the metabolism of tyrosine (homogentisic acid oxidase deficiency) historically defined Archibald Garrod as key architect in linking biochemistry, genetics and medicine and creation of the term 'Inborn Error of Metabolism' (IEM). The key concept of a single gene defect leading to a single enzyme dysfunction, leading to "intoxication" with a precursor in the metabolic pathway was vital to linking genetics and metabolic disorders and developing screening and treatment approaches as described in other chapters in this issue. Amino acid disorders also led to the evolution of the field of metabolic nutrition and offending amino acid restricted formula and foods. This review will discuss the more common disorders caused by inborn errors in amino acid metabolism.
    Keywords:  Phenylketonuria (PKU); amino acids; dietary protein; intoxication; metabolic formula
    DOI:  https://doi.org/10.21037/atm.2018.12.12
  84. Cell Death Dis. 2019 Feb 15. 10(3): 162
    NETO2 promotes invasion and metastasis of gastric cancer cells via activation of PI3K/Akt/NF-κB/Snail axis and predicts outcome of the patients.
    Jun-Yan Liu, Lei Jiang, Tao He, Jia-Jia Liu, Jun-Yan Fan, Xian-Hui Xu, Bo Tang, Yan Shi, Yong-Liang Zhao, Feng Qian, Yan Wang, You-Hong Cui, Pei-Wu Yu.
      Aberrant expression of neuropilin and tolloid-like 2 (NETO2) has been observed during the progression of some human carcinomas. However, the expression pattern and clinical relevance of NETO2 in gastric cancer (GC) remain to be elucidated. In this study, we found that NETO2 expression was higher in GC tissues compared with paired non-cancerous tissues. Moreover, the expression of NETO2 was positively correlated with clinical stage, invasion depth, lymph node metastasis, and tumor size, but inversely correlated with overall and disease-free survival rates. Cox regression analysis identified NETO2 as an independent prognostic indicator for GC patients. Overexpression of NETO2 facilitated migration and invasion of GC cells in vitro and metastasis in vivo in association with induction of epithelial-mesenchymal transition. Conversely, knockdown of NETO2 had the opposite effects. Mechanistically, silencing NETO2 reduced the phosphorylation of PI3K, AKT, and NF-κB p65 as well as the expression of Snail, whereas NETO2 overexpression achieved the opposite results. Furthermore, we identified TNFRSF12A as a mediator for NETO2 to activate PI3K/AKT/NF-κB/Snail axis. Collectively, our results demonstrate that NETO2 promotes invasion and metastasis of GC cells and represents a novel prognostic indicator as well as a potential therapeutic target in GC.
    DOI:  https://doi.org/10.1038/s41419-019-1388-5
  85. Ann Transl Med. 2018 Dec;6(24): 472
    Organic acid disorders.
    Jessica Ramsay, Jacob Morton, Marie Norris, Shibani Kanungo.
      Organic acids (OAs) are intermediary products of several amino acid catabolism or degradation via multiple biochemical pathways for energy production. Vitamins or co-factors are often quintessential elements in such degradation pathways and OA metabolism. OAs that result from enzyme defects in these pathways can be identified in body fluids utilizing gas chromatography-mass spectrometry techniques (GC/MS). OAs are silent contributor to acid base imbalance and can affect nitrogen balance and recycling. Since OA production occurs in distal steps of a specific amino acid catabolism, offending amino acid accumulation is not characteristic. OA disorders as inborn errors of metabolism (IEM) are included in differential diagnosis of metabolic acidosis, as the common mnemonic MUDPILES taught in medical schools. High anion gap metabolic acidosis with hyperammonemia is a characteristic OA biochemical finding. VOMIT (valine, odd chain fatty acids, methionine, isoleucine, and threonine) is a smart acronym and a common clinical presentation of OA disorders and can present as early life-threatening illness, prior to Newborn Screening results availability. Easy identification and available medical formula make the field of metabolic nutrition vital for management of OA disorders. Treatment strategies also involve cofactor/vitamin utilization to aid specific pathways and disorder management. Optimal metabolic control and regular monitoring is key to long-term management and prevention of morbidity, disability and mortality. Prompt utilization of acute illness protocol (AIP) or emergency protocol and disorder specific education of family members or caregivers, primary care physicians and local emergency health care facilities; cautiously addressing common childhood illnesses in patients with OA disorders, can help avoid poor short- and long-term morbidity, disability and mortality outcomes.
    Keywords:  Organic acids (OAs); high anion gap metabolic acidosis; hyperammonemia; neutropenia; valine, odd chain fatty acids, methionine, isoleucine, and threonine (VOMIT)
    DOI:  https://doi.org/10.21037/atm.2018.12.39
  86. Nature. 2019 Jan 30.
    Deacylative transformations of ketones via aromatization-promoted C-C bond activation.
    Yan Xu, Xiaotian Qi, Pengfei Zheng, Carlo C Berti, Peng Liu, Guangbin Dong.
      Carbon-hydrogen (C-H) and carbon-carbon (C-C) bonds are the main constituents of organic matter. The recent advancement of C-H functionalization technology has vastly expanded our toolbox for organic synthesis1. In contrast, C-C activation methods that allow editing of the molecular skeleton remain limited2-. So far, a number of methods have appeared for catalytic C-C activation, particularly with ketone substrates, which are typically promoted either by ring-strain release as a thermodynamic driving force4,6 or using directing groups5,7 to control the reaction outcome. Although effective, these strategies require highly strained ketone substrates or those containing a pre-installed directing group, or are limited to more specialist substrate classes5. Here we report a general C-C activation mode driven by aromatization of a pre-aromatic intermediate formed in situ. This reaction is suitable for various ketone substrates, is catalysed by an iridium/phosphine combination, and is promoted by a hydrazine reagent and 1,3-dienes. Specifically, the acyl group is removed from the ketone, transformed to a pyrazole, and the resulting alkyl fragment undergoes various transformations. These include the deacetylation of methyl ketones, carbenoid-free formal homologation of aliphatic linear ketones and deconstructive pyrazole synthesis from cyclic ketones. Given that ketones are prevalent in feedstock chemicals, natural products and pharmaceuticals, these transformations could offer strategic bond disconnections in the synthesis of complex bioactive molecules.
    DOI:  https://doi.org/10.1038/s41586-019-0926-8
  87. Front Cell Dev Biol. 2019 ;7 3
    Emerging Roles in the Biogenesis of Cytochrome c Oxidase for Members of the Mitochondrial Carrier Family.
    Oluwaseun B Ogunbona, Steven M Claypool.
      The mitochondrial carrier family (MCF) is a group of transport proteins that are mostly localized to the inner mitochondrial membrane where they facilitate the movement of various solutes across the membrane. Although these carriers represent potential targets for therapeutic application and are repeatedly associated with human disease, research on the MCF has not progressed commensurate to their physiologic and pathophysiologic importance. Many of the 53 MCF members in humans are orphans and lack known transport substrates. Even for the relatively well-studied members of this family, such as the ADP/ATP carrier and the uncoupling protein, there exist fundamental gaps in our understanding of their biological roles including a clear rationale for the existence of multiple isoforms. Here, we briefly review this important family of mitochondrial carriers, provide a few salient examples of their diverse metabolic roles and disease associations, and then focus on an emerging link between several distinct MCF members, including the ADP/ATP carrier, and cytochrome c oxidase biogenesis. As the ADP/ATP carrier is regarded as the paradigm of the entire MCF, its newly established role in regulating translation of the mitochondrial genome highlights that we still have a lot to learn about these metabolite transporters.
    Keywords:  ADP/ATP carrier; cytochrome c oxidase; mitochondrial carrier family; mitochondrial translation; respiratory supercomplexes; solute carrier family
    DOI:  https://doi.org/10.3389/fcell.2019.00003
  88. FEBS J. 2019 Feb 15.
    Mitochondrial metabolism is inhibited by the HIF1α-MYC-PGC-1β axis in BRAF V600E thyroid cancer.
    Yanyan Gao, Fang Yang, Xiu-An Yang, Li Zhang, Huixin Yu, Xian Cheng, Shichen Xu, Jie Pan, Kun Wang, Peifeng Li.
      BRAF V600E is the most common mutation identified in thyroid cancers. However, the relationship between BRAF V600E and metabolic reprogramming in thyroid cancer is unclear. Here, we investigate the mechanism of metabolic reprogramming in BRAF V600E thyroid cancer by constructing BRAF V600E-overexpressing and BRAF-knockdown thyroid cell lines for use in mitochondrial respiration and glycolysis experiments. Western blot and RT-qPCR were performed to measure the level of metabolism-related proteins, and various approaches were used to investigate transcriptional regulation. In thyroid cancer cells, the overexpression of BRAF V600E inhibited OXPHOS gene expression and mitochondrial respiration but enhanced aerobic glycolysis. Clinical thyroid cancer samples carrying the BRAF V600E mutation had suppressed levels of PGC-1β but increased expression of HIF1α. Our results show that BRAF V600E reduced mitochondrial respiration by decreasing the expression of PGC-1β. In addition, HIF1α, which is a target of BRAF V600E, was found to regulate the expression of PGC-1β via MYC. Furthermore, glycolysis-related enzymes, such as LDHA and PKM2, were upregulated in BRAF V600E mutant thyroid cancer specimens, thereby promoting glycolysis. MEK1/2 inhibitor treatment enhanced the specific dependence of BRAF V600E mutant thyroid cancer on mitochondrial respiration. These results indicate that in thyroid cancer, the BRAF V600E mutation alters the HIF1α-MYC-PGC-1β axis, causing mitochondrial respiration to be inhibited and aerobic glycolysis to be enhanced. This article is protected by copyright. All rights reserved.
    Keywords:  BRAF V600E; Metabolic reprogramming; Mitochondrial biogenesis; Thyroid cancer; Warburg effect
    DOI:  https://doi.org/10.1111/febs.14786
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