bims-camemi Biomed news
on Mitochondrial metabolism in cancer
Issue of 2018‒12‒09
twenty-four papers selected by
Christian Frezza
University of Cambridge, MRC Cancer Unit

  1. Cell. 2018 Nov 29. pii: S0092-8674(18)31253-4. [Epub ahead of print]175(6): 1546-1560.e17
    Zheng Y, Lin TY, Lee G, Paddock MN, Momb J, Cheng Z, Li Q, Fei DL, Stein BD, Ramsamooj S, Zhang G, Blenis J, Cantley LC.
      Mammalian folate metabolism is comprised of cytosolic and mitochondrial pathways with nearly identical core reactions, yet the functional advantages of such an organization are not well understood. Using genome-editing and biochemical approaches, we find that ablating folate metabolism in the mitochondria of mammalian cell lines results in folate degradation in the cytosol. Mechanistically, we show that QDPR, an enzyme in tetrahydrobiopterin metabolism, moonlights to repair oxidative damage to tetrahydrofolate (THF). This repair capacity is overwhelmed when cytosolic THF hyperaccumulates in the absence of mitochondrially produced formate, leading to THF degradation. Unexpectedly, we also find that the classic antifolate methotrexate, by inhibiting its well-known target DHFR, causes even more extensive folate degradation in nearly all tested cancer cell lines. These findings shed light on design features of folate metabolism, provide a biochemical basis for clinically observed folate deficiency in QDPR-deficient patients, and reveal a hitherto unknown and unexplored cellular effect of methotrexate.
    Keywords:  folate; formate; metabolism; methotrexate; mitochondria; one-carbon
  2. Nat Commun. 2018 Dec 03. 9(1): 5132
    Bahat A, Goldman A, Zaltsman Y, Khan DH, Halperin C, Amzallag E, Krupalnik V, Mullokandov M, Silberman A, Erez A, Schimmer AD, Hanna JH, Gross A.
      The role of mitochondria dynamics and its molecular regulators remains largely unknown during naïve-to-primed pluripotent cell interconversion. Here we report that mitochondrial MTCH2 is a regulator of mitochondrial fusion, essential for the naïve-to-primed interconversion of murine embryonic stem cells (ESCs). During this interconversion, wild-type ESCs elongate their mitochondria and slightly alter their glutamine utilization. In contrast, MTCH2-/- ESCs fail to elongate their mitochondria and to alter their metabolism, maintaining high levels of histone acetylation and expression of naïve pluripotency markers. Importantly, enforced mitochondria elongation by the pro-fusion protein Mitofusin (MFN) 2 or by a dominant negative form of the pro-fission protein dynamin-related protein (DRP) 1 is sufficient to drive the exit from naïve pluripotency of both MTCH2-/- and wild-type ESCs. Taken together, our data indicate that mitochondria elongation, governed by MTCH2, plays a critical role and constitutes an early driving force in the naïve-to-primed pluripotency interconversion of murine ESCs.
  3. J Cell Physiol. 2018 Dec 04.
    Qi Z, Huang Z, Xie F, Chen L.
      Mitochondria play a key role in the maintenance of neuronal function by continuously providing energy. Here, we will give a detailed review about the recent developments in regards to dynamin-related protein 1 (Drp1) induced unbalanced mitochondrial dynamics, excessive mitochondrial division, and neuronal injury in neural system dysfunctions and neurodegenerative diseases, including the Drp1 knockout induced mice embryonic death, the dysfunction of the Drp1-dependent mitochondrial division induced neuronal cell apoptosis and impaired neuronal axonal transportation, the abnormal interaction between Drp1 and amyloid β (Aβ) in Alzheimer's disease (AD), the mutant Huntingtin (Htt) in Huntington's disease (HD), and the Drp1-associated pathogenesis of other neurodegenerative diseases such as Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS). Drp1 is required for mitochondrial division determining the size, shape, distribution, and remodeling as well as maintaining of mitochondrial integrity in mammalian cells. In addition, increasing reports indicate that the Drp1 is involved in some cellular events of neuronal cells causing some neural system dysfunctions and neurodegenerative diseases, including impaired mitochondrial dynamics, apoptosis, and several posttranslational modification induced increased mitochondrial divisions. Recent studies also revealed that the Drp1 can interact with Aβ, phosphorylated τ, and mutant Htt affecting the mitochondrial shape, size, distribution, axonal transportation, and energy production in the AD and HD neuronal cells. These changes can affect the health of mitochondria and the function of synapses causing neuronal injury and eventually leading to the dysfunction of memory, cognitive impairment, resting tremor, posture instability, involuntary movements, and progressive muscle atrophy and paralysis in patients.
    Keywords:  dynamin-related protein 1; mitochondrial dynamics; neural system dysfunctions; neurodegenerative diseases
  4. Am J Physiol Endocrinol Metab. 2018 12 04.
    Bond ST, Moody SC, Liu Y, Civelek M, Villanueva CJ, Gregorevic P, Kingwell BA, Hevener AL, Lusis AJ, Henstridge DC, Calkin AC, Drew BG.
      Mitochondrial dynamics refers to the constant remodelling of mitochondrial populations by multiple cellular pathways which help maintain mitochondrial health and function. Disruptions to mitochondrial dynamics often leads to mitochondrial dysfunction, which is frequently associated with disease in rodents and humans. Consistent with this, obesity is associated with reduced mitochondrial function in white adipose tissue, partly via alterations in mitochondrial dynamics. Several proteins are known to regulate mitochondrial dynamics including the E3 ubiquitin ligase MARCH5; however, the role of these proteins in adipocytes has been poorly studied. Here, we show that MARCH5 is regulated by PPARγ during adipogenesis and is correlated with fat mass across a panel of genetically diverse mouse strains, in ob/ob mice, and in humans. Furthermore, manipulation of MARCH5 expression both in vitro and in vivo alters mitochondrial function, affects cellular metabolism and leads to differential regulation of several metabolic genes. Thus, our data demonstrate a link between mitochondrial dynamics and metabolism which defines MARCH5 as a critical link between these interconnected pathways.
    Keywords:  March5; PPAR gamma; adipose tissue; lipid metabolism; mitochondria
  5. J Biomed Sci. 2018 Nov 30. 25(1): 87
    Guan R, Zou W, Dai X, Yu X, Liu H, Chen Q, Teng W.
      Mitochondria autophagy, termed as mitophagy, is a mechanism of specific autophagic elimination of mitochondria. Mitophagy controls the quality and the number of mitochondria, eliminating dysfunctional or excessive mitochondria that can generate reactive oxygen species (ROS) and cause cell death. Mitochondria are centrally implicated in neuron and tissue injury after stroke, due to the function of supplying adenosine triphosphate (ATP) to the tissue, regulating oxidative metabolism during the pathologic process, and contribution to apoptotic cell death after stroke. As a catabolic mechanism, mitophagy links numbers of a complex network of mitochondria, and affects mitochondrial dynamic process, fusion and fission, reducing mitochondrial production of ROS, mediated by the mitochondrial permeability transition pore (MPTP). The precise nature of mitophagy's involvement in stroke, and its underlying molecular mechanisms, have yet to be fully clarified. This review aims to provide a comprehensive overview of the integration of mitochondria with mitophagy, also to introduce and discuss recent advances in the understanding of the potential role, and possible signaling pathway, of mitophagy in the pathological processes of both hemorrhagic and ischemic stroke. The author also provides evidence to explain the dual role of mitophagy in stroke.
    Keywords:  Mitochondria; Mitochondria autophagy; Stroke
  6. J Pineal Res. 2018 Dec 05. e12542
    Zhang Y, Wang Y, Xu J, Tian F, Hu S, Chen Y, Fu Z.
      Optic atrophy 1 (OPA1)-related mitochondrial fusion and mitophagy are vital to sustain mitochondrial homeostasis under stress conditions. However, no study has confirmed whether OPA1-related mitochondrial fusion/mitophagy is activated by melatonin and, consequently, attenuates cardiomyocyte death and mitochondrial stress in the setting of cardiac ischemia reperfusion (I/R) injury. Our results indicated that OPA1, mitochondrial fusion and mitophagy were significantly repressed by I/R injury, accompanied by infarction area expansion, heart dysfunction, myocardial inflammation, and cardiomyocyte oxidative stress. However, melatonin treatment maintained myocardial function and cardiomyocyte viability, and these effects were highly dependent on OPA1-related mitochondrial fusion/mitophagy. At the molecular level, OPA1-related mitochondrial fusion/mitophagy, which was normalized by melatonin, substantially rectified the excessive mitochondrial fission, promoted mitochondria energy metabolism, sustained mitochondrial function and blocked cardiomyocyte caspase-9-involved mitochondrial apoptosis. However, genetic approaches with cardiac-specific knockout of OPA1 abolished the beneficial effects of melatonin on cardiomyocyte survival and mitochondrial homeostasis in vivo and in vitro. Furthermore, we demonstrated that melatonin affected OPA1 stabilization via the AMPK signaling pathway and that blockade of AMPK repressed OPA1 expression and compromised the cardioprotective action of melatonin. Overall, our results confirm that OPA1-related mitochondrial fusion/mitophagy is actually modulated by melatonin in the setting of cardiac I/R injury. Moreover, manipulation of the AMPK-OPA1-mitochondrial fusion/mitophagy axis via melatonin may be a novel therapeutic approach to reduce cardiac I/R injury. This article is protected by copyright. All rights reserved.
    Keywords:  Melatonin; OPA1 and AMPK signaling pathway; mitochondrial fusion; mitophagy; myocardial ischemia reperfusion injury
  7. J Clin Invest. 2018 Dec 04. pii: 120606. [Epub ahead of print]
    Park H, He A, Tan M, Johnson JM, Dean JM, Pietka TA, Chen Y, Zhang X, Hsu FF, Razani B, Funai K, Lodhi IJ.
      Peroxisomes perform essential functions in lipid metabolism, including fatty acid oxidation and plasmalogen synthesis. Here, we describe a role for peroxisomal lipid metabolism in mitochondrial dynamics in brown and beige adipocytes. Adipose tissue peroxisomal biogenesis was induced in response to cold exposure through activation of the thermogenic co-regulator PRDM16. Adipose-specific knockout of the peroxisomal biogenesis factor Pex16 (Pex16-AKO) in mice impaired cold tolerance, decreased energy expenditure, and increased diet-induced obesity. Pex16 deficiency blocked cold-induced mitochondrial fission, decreased mitochondrial copy number, and caused mitochondrial dysfunction. Adipose-specific knockout of the peroxisomal beta-oxidation enzyme acyl CoA oxidase 1 (Acox1-AKO) was not sufficient to affect adiposity, thermogenesis or mitochondrial copy number, but knockdown of the plasmalogen synthetic enzyme glyceronephosphate O-acyltransferase (GNPAT) recapitulated the effects of Pex16 inactivation on mitochondrial morphology and function. Plasmalogens are present in mitochondria and decreased with Pex16 inactivation. Their dietary supplementation increased mitochondrial copy number, improved mitochondrial function, and rescued thermogenesis in Pex16-AKO mice. These findings support a surprising interaction between peroxisomes and mitochondria to regulate mitochondrial dynamics and thermogenesis.
    Keywords:  Adipose tissue; Cell Biology; Metabolism; Mitochondria
  8. EMBO J. 2018 Nov 30. pii: e99435. [Epub ahead of print]
    Marchi S, Corricelli M, Branchini A, Vitto VAM, Missiroli S, Morciano G, Perrone M, Ferrarese M, Giorgi C, Pinotti M, Galluzzi L, Kroemer G, Pinton P.
      Although mitochondria play a multifunctional role in cancer progression and Ca2+ signaling is remodeled in a wide variety of tumors, the underlying mechanisms that link mitochondrial Ca2+ homeostasis with malignant tumor formation and growth remain elusive. Here, we show that phosphorylation at the N-terminal region of the mitochondrial calcium uniporter (MCU) regulatory subunit MICU1 leads to a notable increase in the basal mitochondrial Ca2+ levels. A pool of active Akt in the mitochondria is responsible for MICU1 phosphorylation, and mitochondrion-targeted Akt strongly regulates the mitochondrial Ca2+ content. The Akt-mediated phosphorylation impairs MICU1 processing and stability, culminating in reactive oxygen species (ROS) production and tumor progression. Thus, our data reveal the crucial role of the Akt-MICU1 axis in cancer and underscore the strategic importance of the association between aberrant mitochondrial Ca2+ levels and tumor development.
    Keywords:  Akt; MICU1; calcium; cancer; mitochondria
  9. Am J Physiol Lung Cell Mol Physiol. 2018 Dec 06.
    Schleifer G, Marutani E, Ferrari M, Sharma R, Skinner O, Goldberger O, Grange RMH, Peneyra K, Malhotra R, Wepler M, Ichinose F, Bloch D, Mootha V, Zapol WM.
      Hypoxic pulmonary vasoconstriction (HPV) is a physiological vasomotor response that maintains systemic oxygenation by matching perfusion to ventilation during alveolar hypoxia. Although mitochondria appear to play an essential role in HPV, the impact of mitochondrial dysfunction on HPV remains incompletely defined. Mice lacking the mitochondrial complex I (CI) subunit Ndufs4 (Ndufs4-/-) develop a fatal progressive encephalopathy and serve as a model for Leigh syndrome, the most common mitochondrial disease in children. Breathing normobaric 11% O2 prevents neurological disease and improves survival in Ndufs4-/- mice. In this study, we found that either genetic Ndufs4 deficiency or pharmacological inhibition of CI using piericidin A impaired the ability of left mainstem bronchus occlusion (LMBO) to induce HPV. In mice breathing air, the partial pressure of arterial oxygen (PaO2) during LMBO was lower in Ndufs4-/- and in piericidin A-treated mice than in matched controls. Impairment of HPV in air-breathing Ndufs4-/- mice was not a result of nonspecific dysfunction of the pulmonary vascular contractile apparatus or pulmonary inflammation. In Ndufs4 deficient mice, three weeks of breathing 11% O2 restored HPV in response to LMBO. Compared to Ndufs4-/- mice breathing air, chronic hypoxia improved systemic oxygenation during LMBO. The results of this study show that, when breathing air, mice with a congenital Ndufs4 deficiency or chemically-inhibited CI function have impaired HPV. Our study raises the possibility that patients with inborn errors of mitochondrial function may also have defects in HPV.
    Keywords:  Hypoxic pulmonary vasoconstriction; Leigh syndrome; complex I; mice; mitochondria
  10. Nat Commun. 2018 Nov 30. 9(1): 5111
    Bleck CKE, Kim Y, Willingham TB, Glancy B.
      Mapping biological circuit connectivity has revolutionized our understanding of structure-function relationships. Although connectomic analyses have primarily focused on neural systems, electrical connectivity within muscle mitochondrial networks was recently demonstrated to provide a rapid mechanism for cellular energy distribution. However, tools to evaluate organelle connectivity with high spatial fidelity within single cells are currently lacking. Here, we developed a framework to quantitatively assess mitochondrial network connectivity and interactions with cellular sites of energy storage, utilization, and calcium cycling in cardiac, oxidative, and glycolytic muscle. We demonstrate that mitochondrial network configuration, individual mitochondrial size and shape, and the junctions connecting mitochondria within each network are consistent with the differing contraction demands of each muscle type. Moreover, mitochondria-lipid droplet interaction analyses suggest that individual mitochondria within networks may play specialized roles regarding energy distribution and calcium cycling within the cell and reveal the power of connectomic analyses of organelle interactions within single cells.
  11. Cell Metab. 2018 Nov 20. pii: S1550-4131(18)30679-X. [Epub ahead of print]
    Chouchani ET, Kazak L, Spiegelman BM.
      Brown and beige adipocytes can catabolize stored energy to generate heat, and this distinct capacity for thermogenesis could be leveraged as a therapy for metabolic diseases like obesity and type 2 diabetes. Thermogenic adipocytes drive heat production through close coordination of substrate supply with the mitochondrial oxidative machinery and effectors that control the rate of substrate oxidation. Together, this apparatus affords these adipocytes with tremendous capacity to drive thermogenesis. The best characterized thermogenic effector is uncoupling protein 1 (UCP1). Importantly, additional mechanisms for activating thermogenesis beyond UCP1 have been identified and characterized to varying extents. Acute regulation of these thermogenic pathways has been an active area of study, and numerous regulatory factors have been uncovered in recent years. Here we will review the evidence for regulators of heat production in thermogenic adipocytes in the context of the thermodynamic and kinetic principles that govern their therapeutic utility.
    Keywords:  UCP1; beige fat; brown fat; creatine; diabetes; mitochondria; obesity; redox metabolism; thermogenesis; uncoupling
  12. J Clin Invest. 2018 Dec 04. pii: 122035. [Epub ahead of print]
    Saito T, Nah J, Oka SI, Mukai R, Monden Y, Maejima Y, Ikeda Y, Sciarretta S, Liu T, Li H, Baljinnyam E, Fraidenraich D, Fritzky L, Zhai P, Ichinose S, Isobe M, Hsu CP, Kundu M, Sadoshima J.
      Energy stress, such as ischemia, induces mitochondrial damage and death in the heart. Degradation of damaged mitochondria by mitophagy is essential for the maintenance of healthy mitochondria and survival. Here we show that mitophagy during myocardial ischemia was mediated predominantly through autophagy characterized by Rab9-associated autophagosomes, rather than the well-characterized form of autophagy that is dependent upon the Atg-conjugation system and LC3. This form of mitophagy played an essential role in protecting the heart against ischemia and was mediated by a protein complex consisting of Ulk1, Rab9, Rip1 and Drp1. This complex allowed recruitment of trans-Golgi membranes associated with Rab9 to damaged mitochondria through Ser179 phosphorylation of Rab9 by Ulk1 and Ser616 phosphorylation of Drp1 by Rip1. Knock-in of Rab9 (S179A) abolished mitophagy and exacerbated injury in response to myocardial ischemia without affecting conventional autophagy. Mitophagy mediated through the Ulk1-Rab9-Rip1-Drp1 pathway protected the heart against ischemia by maintaining healthy mitochondria.
    Keywords:  Autophagy; Cardiology; Cell Biology; Heart failure
  13. Cell Rep. 2018 Dec 04. pii: S2211-1247(18)31777-7. [Epub ahead of print]25(10): 2904-2918.e8
    Wortham M, Benthuysen JR, Wallace M, Savas JN, Mulas F, Divakaruni AS, Liu F, Albert V, Taylor BL, Sui Y, Saez E, Murphy AN, Yates JR, Metallo CM, Sander M.
      Pancreatic β cell physiology changes substantially throughout life, yet the mechanisms that drive these changes are poorly understood. Here, we performed comprehensive in vivo quantitative proteomic profiling of pancreatic islets from juvenile and 1-year-old mice. The analysis revealed striking differences in abundance of enzymes controlling glucose metabolism. We show that these changes in protein abundance are associated with higher activities of glucose metabolic enzymes involved in coupling factor generation as well as increased activity of the coupling factor-dependent amplifying pathway of insulin secretion. Nutrient tracing and targeted metabolomics demonstrated accelerated accumulation of glucose-derived metabolites and coupling factors in islets from 1-year-old mice, indicating that age-related changes in glucose metabolism contribute to improved glucose-stimulated insulin secretion with age. Together, our study provides an in-depth characterization of age-related changes in the islet proteome and establishes metabolic rewiring as an important mechanism for age-associated changes in β cell function.
    Keywords:  SILAM MudPIT mass spectrometry; TCA cycle; aging; amplifying pathway; insulin secretion; isotope tracing; quantitative proteomics; triggering pathway; β cell; β cell maturation
  14. EMBO J. 2018 Nov 30. pii: e99384. [Epub ahead of print]
    Safiulina D, Kuum M, Choubey V, Gogichaishvili N, Liiv J, Hickey MA, Cagalinec M, Mandel M, Zeb A, Liiv M, Kaasik A.
      The Parkinson's disease-associated protein kinase PINK1 and ubiquitin ligase Parkin coordinate the ubiquitination of mitochondrial proteins, which marks mitochondria for degradation. Miro1, an atypical GTPase involved in mitochondrial trafficking, is one of the substrates tagged by Parkin after mitochondrial damage. Here, we demonstrate that a small pool of Parkin interacts with Miro1 before mitochondrial damage occurs. This interaction does not require PINK1, does not involve ubiquitination of Miro1 and also does not disturb Miro1 function. However, following mitochondrial damage and PINK1 accumulation, this initial pool of Parkin becomes activated, leading to the ubiquitination and degradation of Miro1. Knockdown of Miro proteins reduces Parkin translocation to mitochondria and suppresses mitophagic removal of mitochondria. Moreover, we demonstrate that Miro1 EF-hand domains control Miro1's ubiquitination and Parkin recruitment to damaged mitochondria, and they protect neurons from glutamate-induced mitophagy. Together, our results suggest that Miro1 functions as a calcium-sensitive docking site for Parkin on mitochondria.
    Keywords:  Parkin; calcium homeostasis; miro proteins; mitophagy; neuron
  15. J Cell Sci. 2018 Dec 03. pii: jcs.221655. [Epub ahead of print]
    Vigié P, Cougouilles E, Bhatia-Kiššová I, Salin B, Blancard C, Camougrand N.
      Mitophagy, the selective degradation of mitochondria by autophagy, is a central process essential to maintain cell homeostasis. It is implicated in the clearance of superfluous or damaged mitochondria and requires specific proteins and regulators to perform. In yeast, Atg32, an outer mitochondrial membrane protein, interacts with the ubiquitin-like Atg8 protein, promoting the recruitment of mitochondria to the phagophore and their sequestration within autophagosomes. Atg8 is anchored to the phagophore and autophagosome membranes thanks to a phosphatidylethanolamine tail. In yeast, several phosphatidylethanolamine synthesis pathways have been characterized, but their contribution to autophagy and mitophagy are unknown. Through different approaches, we show that Psd1, the mitochondrial phosphatidylserine decarboxylase, is involved only in mitophagy induction in nitrogen starvation, whereas Psd2, located in vacuole/Golgi apparatus/endosome membranes, is required preferentially for mitophagy induction in the stationary phase of growth but also to a lesser extent for nitrogen starvation-induced mitophagy. Our results suggest that Δpsd1 mitophagy defect in nitrogen starvation may be due to a failure of Atg8 recruitment to mitochondria.
    Keywords:  Mitophagy; Phosphatidylethanolamine; Yeast
  16. Nat Commun. 2018 Nov 30. 9(1): 5099
    Rice CM, Davies LC, Subleski JJ, Maio N, Gonzalez-Cotto M, Andrews C, Patel NL, Palmieri EM, Weiss JM, Lee JM, Annunziata CM, Rouault TA, Durum SK, McVicar DW.
      Neutrophils are a vital component of immune protection, yet in cancer they may promote tumour progression, partly by generating reactive oxygen species (ROS) that disrupts lymphocyte functions. Metabolically, neutrophils are often discounted as purely glycolytic. Here we show that immature, c-Kit+ neutrophils subsets can engage in oxidative mitochondrial metabolism. With limited glucose supply, oxidative neutrophils use mitochondrial fatty acid oxidation to support NADPH oxidase-dependent ROS production. In 4T1 tumour-bearing mice, mitochondrial fitness is enhanced in splenic neutrophils and is driven by c-Kit signalling. Concordantly, tumour-elicited oxidative neutrophils are able to maintain ROS production and T cell suppression when glucose utilisation is restricted. Consistent with these findings, peripheral blood neutrophils from patients with cancer also display increased immaturity, mitochondrial content and oxidative phosphorylation. Together, our data suggest that the glucose-restricted tumour microenvironment induces metabolically adapted, oxidative neutrophils to maintain local immune suppression.
  17. PLoS Comput Biol. 2018 Dec 05. 14(12): e1006640
    Ghosh S, Tran K, Delbridge LMD, Hickey AJR, Hanssen E, Crampin EJ, Rajagopal V.
      Recent electron microscopy data have revealed that cardiac mitochondria are not arranged in crystalline columns but are organised with several mitochondria aggregated into columns of varying sizes often spanning the cell cross-section. This raises the question-how does the mitochondrial arrangement affect the metabolite distributions within cardiomyocytes and their impact on force dynamics? Here we employed finite element modelling of cardiac bioenergetics, using computational meshes derived from electron microscope images, to address this question. Our results indicate that heterogeneous mitochondrial distributions can lead to significant spatial variation across the cell in concentrations of inorganic phosphate, creatine (Cr) and creatine phosphate (PCr). However, our model predicts that sufficient activity of the creatine kinase (CK) system, coupled with rapid diffusion of Cr and PCr, maintains near uniform ATP and ADP ratios across the cell cross sections. This homogenous distribution of ATP and ADP should also evenly distribute force production and twitch duration with contraction. These results suggest that the PCr shuttle, and associated enzymatic reactions, act to maintain uniform force dynamics in the cell despite the heterogeneous mitochondrial organization. However, our model also predicts that under hypoxia-activity of mitochondrial CK enzyme and diffusion of high-energy phosphate compounds may be insufficient to sustain uniform ATP/ADP distribution and hence force generation.
  18. Med Oncol. 2018 Nov 30. 36(1): 11
    Miyake K, Baba Y, Ishimoto T, Hiyoshi Y, Iwatsuki M, Miyamoto Y, Yoshida N, Watanabe M, Ogata Y, Nagayama M, Silsirivanit A, Kobayashi D, Araki N, Baba H.
      Isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) are key metabolic enzymes that convert isocitrate to α-ketoglutarate. Somatic point mutations in IDH1/2 confer a gain-of-function in cancer cells, resulting in overproduction of an oncometabolite, 2-hydroxyglutarate (2HG). 2HG interferes with cellular metabolism and epigenetic regulation, contributing to oncogenesis. Given that IDH1 and IDH2 are attracting attention as promising therapeutic targets, better evaluation of the incidence of IDH1 and IDH2 mutations and 2HG level in human cancers is clinically important. This is the first study to assess their incidence in esophageal squamous cell carcinomas (ESCCs). First, we established pyrosequencing assays for IDH1 and IDH2 mutations and revealed that these mutations were absent in 10 ESCC cell lines and 96 ESCC tissues. Second, utilizing IDH1 and IDH2 overexpression vectors, we demonstrated that LC-MS/MS assays can accurately evaluate 2HG level and found that some ESCC cases presented a high level of 2HG. In conclusion, IDH1 or IDH2 mutations play a limited role in the development of ESCC. 2HG is potentially synthesized to high levels in the absence of IDH1 and IDH2 mutations, and this may correlate with progression of ESCCs.
    Keywords:  2-Hydroxyglutarate; Esophageal squamous cell carcinoma; Isocitrate dehydrogenase; Oncometabolite; α-Ketoglutaric acid
  19. J Cell Physiol. 2018 Dec 04.
    Zhou XL, Wu X, Xu QR, Zhu RR, Xu H, Li YY, Liu S, Huang H, Xu X, Wan L, Wu QC, Liu JC.
      Mitochondrial quality control is a new target for myocardial protection. Notch signaling plays an important role in heart development, maturation, and repair. However, the role of Notch in the myocardial mitochondrial quality control remains elusive. In this study, we isolated myocardial cells from rats and established myocardial ischemia reperfusion injury (IRI) model. We modulated Notch1 expression level in myocardial cells via infection with recombinant adenoviruses Ad-N1ICD and Ad-shN1ICD. We found that IR reduced myocardial cells viability, but Notch1 overexpression increased the viability of myocardial cells exposed to IRI. In addition, Notch1 overexpression improved ATP production, increased mitochondrial fusion and decreased mitochondrial fission, and inhibited mitophagy in myocardial cells exposed to IRI. However, N1ICD knockdown led to opposite effects. The myocardial protection role of Notch1 was related to the inhibition of Pink1 expression and Mfn2 and Parkin phosphorylation. In conclusion, Notch1 exerts myocardial protection and this is correlated with the maintenance of mitochondrial quality control and the inhibition of Pink1/Mfn2/Parkin signaling.
    Keywords:  Mitochondrial quality control; Notch1; mitophagy; myocardial protection
  20. Ann Nutr Metab. 2018 ;73 Suppl 5 5-14
    Cynober L.
      BACKGROUND: Glutamate is a non-essential amino acid at the crossroads of nitrogen and energy metabolism. Glutamate metabolism is characterized by reactions that may be anabolic or catabolic in nature depending on the tissue (i.e., glutamate dehydrogenase, transaminases), and it can also be either the precursor or the metabolite of glutamine. Unlike glutamine, which is the form of interorgan ammonia transport, glutamate metabolism is mostly compartmentalized within the cells, its interorgan exchanges being limited to a flux from liver to muscle.SUMMARY: Glutamate catabolism is extremely intense in the splanchnic area, such that after a meal (rich in proteins) almost no glutamate appears in the systemic circulation. However, this process is saturable as after glutamate loading at a high dose level, glutamate appears dose-dependently in the circulation. This systemic glutamate -appearance is blunted if glutamate is co-ingested with a carbohydrate source. Key Messages: The underlying reason for this highly specific metabolism is that glutamate plays a key role in nitrogen homeostasis, and the organism does all it can to limit the bioavailability of glutamate, which can be neurotoxic in excess. As glutamate is never eaten alone, its bioavailability will be limited if not negligible, and no adverse effects are to be expected in adult humans.
    Keywords:  Administration; Glutamate; Interorgan exchanges; Metabolism; Muscle; Pharmacokinetics; Splanchnic extraction
  21. Dev Cell. 2018 Dec 03. pii: S1534-5807(18)30928-6. [Epub ahead of print]47(5): 592-607.e6
    Becher J, Simula L, Volpe E, Procaccini C, La Rocca C, D'Acunzo P, Cianfanelli V, Strappazzon F, Caruana I, Nazio F, Weber G, Gigantino V, Botti G, Ciccosanti F, Borsellino G, Campello S, Mandolesi G, De Bardi M, Fimia GM, D'Amelio M, Ruffini F, Furlan R, Centonze D, Martino G, Braghetta P, Chrisam M, Bonaldo P, Matarese G, Locatelli F, Battistini L, Cecconi F.
      Regulatory T cells (Treg) are necessary to maintain immunological tolerance and are key players in the control of autoimmune disease susceptibility. Expression of the transcription factor FOXP3 is essential for differentiation of Treg cells and indispensable for their suppressive function. However, there is still a lack of knowledge about the mechanisms underlying its regulation. Here, we demonstrate that pro-autophagy protein AMBRA1 is also a key modulator of T cells, regulating the complex network that leads to human Treg differentiation and maintenance. Indeed, through its ability to interact with the phosphatase PP2A, AMBRA1 promotes the stability of the transcriptional activator FOXO3, which, in turn, triggers FOXP3 transcription. Furthermore, we found that AMBRA1 plays a significant role in vivo by regulating Treg cell induction in mouse models of both tumor growth and multiple sclerosis, thus highlighting the role of AMBRA1 in the control of immune homeostasis.
    Keywords:  PP2A; autophagy; experimental autoimmune encephalomyelitis; immune surveillance; multiple sclerosis; regulatory T cell
  22. Bioessays. 2018 Dec 04. e1800180
    Speijer D.
      Aspects of peroxisome evolution, uncoupling, carnitine shuttles, supercomplex formation, and missing neuronal fatty acid oxidation (FAO) are linked to reactive oxygen species (ROS) formation in respiratory chains. Oxidation of substrates with high FADH2 /NADH (F/N) ratios (e.g., FAs) initiate ROS formation in Complex I due to insufficient availability of its electron acceptor (Q) and reverse electron transport from QH2 , e.g., during FAO or glycerol-3-phosphate shuttle use. Here it is proposed that the Q-cycle of Complex III contributes to enhanced ROS formation going from low F/N ratio substrates (glucose) to high F/N substrates. This contribution is twofold: 1) Complex III uses Q as substrate, thus also competing with Complex I; 2) Complex III itself will produce more ROS under these conditions. I link this scenario to the universally observed Complex III dimerization. The Q-cycle of Complex III thus again illustrates the tension between efficient ATP generation and endogenous ROS formation. This model can explain recent findings concerning succinate and ROS-induced uncoupling.
    Keywords:  FADH2/NADH ratio; Q-cycle; beta-oxidation; carnitine; peroxisomes; reverse electron transport (RET); symbiogenesis
  23. Biophys J. 2018 Nov 10. pii: S0006-3495(18)31224-4. [Epub ahead of print]
    Yu H, Xue C, Long M, Jia H, Xue G, Du S, Coello Y, Ishibashi T.
      Regulation of transcription elongation is one of the key mechanisms employed to control gene expression. The single-subunit mitochondrial RNA polymerase (mtRNAP) transcribes mitochondrial genes, such as those related to ATP synthesis. We investigated how mitochondrial transcription elongation factor (TEFM) enhances mtRNAP transcription elongation using a single-molecule optical-tweezers transcription assay, which follows transcription dynamics in real time and allows the separation of pause-free elongation from transcriptional pauses. We found that TEFM enhances the stall force of mtRNAP. Although TEFM does not change the pause-free elongation rate, it enhances mtRNAP transcription elongation by reducing the frequency of long-lived pauses and shortening their durations. Furthermore, we demonstrate how mtRNAP passes through the conserved sequence block II, which is the key sequence for the switch between DNA replication and transcription in mitochondria. Our findings elucidate how both TEFM and mitochondrial genomic DNA sequences directly control the transcription elongation dynamics of mtRNAP.
  24. Nature. 2018 12;564(7734): 47-48
    Joffin N, Scherer PE.
    Keywords:  Diabetes; Metabolism; Obesity