bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2019‒02‒03
fifty papers selected by
Christian Frezza,

  1. Polyunsaturated Fatty Acid Desaturation Is a Mechanism for Glycolytic NAD+ Recycling.
  2. Adipocyte MTERF4 regulates non-shivering adaptive thermogenesis and sympathetic-dependent glucose homeostasis.
  3. SR-mitochondria communication in adult cardiomyocytes: A close relationship where the Ca2+ has a lot to say.
  4. Withaferin A-mediated apoptosis in breast cancer cells is associated with alterations in mitochondrial dynamics.
  5. A Selective and Cell-Permeable Mitochondrial Calcium Uniporter (MCU) Inhibitor Preserves Mitochondrial Bioenergetics after Hypoxia/Reoxygenation Injury.
  6. Obesity-dependent CDK1 signaling stimulates mitochondrial respiration at complex I in pancreatic β-cells.
  7. FOXK1 and FOXK2 regulate aerobic glycolysis.
  8. Vitamin B12 , folate, and the methionine remethylation cycle-biochemistry, pathways, and regulation.
  9. Mitochondrial dynamics in exercise physiology.
  10. Metabolic and Organelle Morphology Defects in Mice and Human Patients Define Spinocerebellar Ataxia Type 7 as a Mitochondrial Disease.
  11. Role of mitochondrial Ca2+ homeostasis in cardiac muscles.
  12. Prostate Cancer-specific Hallmarks of Amino Acids Metabolism: Towards a Paradigm of Precision Medicine.
  13. Drp1 phosphorylation is indispensable for steroidogenesis in Leydig cells.
  14. Functional role of PGAM5 multimeric assemblies and their polymerization into filaments.
  15. Loss of SLC25A11 causes suppression of NSCLC and melanoma tumor formation.
  16. L-Arginine Synthesis from L-Citrulline in Myeloid Cells Drives Host Defense against Mycobacteria In Vivo.
  17. Wheat mitochondrial respiration shifts from the TCA cycle to the GABA shunt under salt stress.
  18. AKT methylation by SETDB1 promotes AKT kinase activity and oncogenic functions.
  19. PKG1-modified TSC2 regulates mTORC1 activity to counter adverse cardiac stress.
  20. Regulation of Dendritic Cell Immune Function and Metabolism by Cellular Nutrient Sensor Mammalian Target of Rapamycin (mTOR).
  21. Multicolor Flow Cytometry-based Quantification of Mitochondria and Lysosomes in T Cells.
  22. Gut intraepithelial T cells calibrate metabolism and accelerate cardiovascular disease.
  23. Targeting the Vulnerability of Glutathione Metabolism in ARID1A-Deficient Cancers.
  24. SIRT5-mediated SDHA desuccinylation promotes clear cell renal cell carcinoma tumorigenesis.
  25. Mitochondria as a Target for Mitigating Sarcopenia.
  26. Alpha-lipoic acid suppresses Nε-(carboxymethyl) lysine-induced epithelial mesenchymal transition in HK-2 human renal proximal tubule cells.
  27. Mitochondrial fusion supports increased oxidative phosphorylation during cell proliferation.
  28. Autophagy modulates lipid metabolism to maintain metabolic flexibility for Lkb1-deficient Kras-driven lung tumorigenesis.
  29. Post-translational Regulation of FNIP1 Creates a Rheostat for the Molecular Chaperone Hsp90.
  30. Immune control by amino acid catabolism during tumorigenesis and therapy.
  31. Restraining Cancer Cells by Dual-Metabolic Inhibitions with a Mitochondrion-Targeted Platinum(II) Complex.
  32. The type III intermediate filament vimentin regulates organelle distribution and modulates autophagy.
  33. The mitochondrial heme metabolon: Insights into the complex(ity) of heme synthesis and distribution.
  34. New interfaces on MiD51 for Drp1 recruitment and regulation.
  35. Metabolic Checkpoints in Differentiation of Helper T Cells in Tissue Inflammation.
  36. Dimerization of MICU Proteins Controls Ca2+ Influx through the Mitochondrial Ca2+ Uniporter.
  37. MAP kinase and autophagy pathways cooperate to maintain RAS mutant cancer cell survival.
  38. Ascorbic acid-induced TET activation mitigates adverse hydroxymethylcystosine loss in renal cell carcinoma.
  39. Glucose starvation induces resistance to metformin through the elevation of mitochondrial multidrug resistance protein1.
  40. Extranuclear DNA accumulates in aged cells and contributes to senescence and inflammation.
  41. Autophagy in endothelial cells and tumor angiogenesis.
  42. Itaconate: the poster child of metabolic reprogramming in macrophage function.
  43. AIBP-mediated cholesterol efflux instructs hematopoietic stem and progenitor cell fate.
  44. CRISPR-Based Tools in Immunity.
  45. Snapshot: Implications for mTOR in Aging-related Ischemia/Reperfusion Injury.
  46. Central Carbon Metabolism Regulates Macrophage Antitumor Activity.
  47. Mechanisms of Mitochondrial DNA Deletion Formation.
  48. Inhibition of polyamine synthesis and uptake reduces tumor progression and prolongs survival in mouse models of neuroblastoma.
  49. SETDB1-mediated methylation of Akt promotes its K63-linked ubiquitination and activation leading to tumorigenesis.
  50. Control of mTOR signaling by ubiquitin.
  1. Cell Metab. 2019 Jan 14. pii: S1550-4131(18)30806-4. [Epub ahead of print]
    Polyunsaturated Fatty Acid Desaturation Is a Mechanism for Glycolytic NAD+ Recycling.
    Wondong Kim, Amy Deik, Clicerio Gonzalez, Maria Elena Gonzalez, Feifei Fu, Michele Ferrari, Claire L Churchhouse, Jose C Florez, Suzanne B R Jacobs, Clary B Clish, Eugene P Rhee.
      The reactions catalyzed by the delta-5 and delta-6 desaturases (D5D/D6D), key enzymes responsible for highly unsaturated fatty acid (HUFA) synthesis, regenerate NAD+ from NADH. Here, we show that D5D/D6D provide a mechanism for glycolytic NAD+ recycling that permits ongoing glycolysis and cell viability when the cytosolic NAD+/NADH ratio is reduced, analogous to lactate fermentation. Although lesser in magnitude than lactate production, this desaturase-mediated NAD+ recycling is acutely adaptive when aerobic respiration is impaired in vivo. Notably, inhibition of either HUFA synthesis or lactate fermentation increases the other, underscoring their interdependence. Consistent with this, a type 2 diabetes risk haplotype in SLC16A11 that reduces pyruvate transport (thus limiting lactate production) increases D5D/D6D activity in vitro and in humans, demonstrating a chronic effect of desaturase-mediated NAD+ recycling. These findings highlight key biologic roles for D5D/D6D activity independent of their HUFA end products and expand the current paradigm of glycolytic NAD+ regeneration.
    Keywords:  FADS1-3; NAD(+) recycling; SLC16A11; delta-5-desaturase; delta-6-desaturase; highly unsaturated fatty acids; polyunsaturated fatty acids
    DOI:  https://doi.org/10.1016/j.cmet.2018.12.023
  2. Biochim Biophys Acta Mol Basis Dis. 2019 Jan 25. pii: S0925-4439(19)30025-0. [Epub ahead of print]
    Adipocyte MTERF4 regulates non-shivering adaptive thermogenesis and sympathetic-dependent glucose homeostasis.
    Anna Castillo, Maria Vilà, Inés Pedriza, Rosario Pardo, Yolanda Cámara, Edgar Martín, Daniel Beiroa, Javier Torres-Torronteras, Marta Oteo, Miguel A Morcillo, Ramon Martí, Rafael Simó, Rubén Nogueiras, Josep A Villena.
      In humans, low brown adipose tissue (BAT) mass and activity have been associated with increased adiposity and fasting glucose levels, suggesting that defective BAT-dependent thermogenesis could contribute to the development of obesity and/or type 2 diabetes. The thermogenic function of BAT relies on a vast network of mitochondria exclusively equipped with UCP1. Mitochondrial biogenesis is exquisitely regulated by a well-defined network of transcription factors that coordinate the expression of nuclear genes required for the formation of functional mitochondria. However, less is known about the mitochondrial factors that control the expression of the genes encoded by the mitochondrial genome. Here, we have studied the role of mitochondrial transcription termination factor-4 (MTERF4) in BAT by using a new mouse model devoid of MTERF4 specifically in adipocytes (MTERF4-FAT-KO mice). Lack of MTERF4 in BAT leads to reduced OxPhos mitochondrial protein levels and impaired assembly of OxPhos complexes I, III and IV due to deficient translation of mtDNA-encoded proteins. As a result, brown adipocytes lacking MTERF4 exhibit impaired respiratory capacity. MTERF4-FAT-KO mice show a blunted thermogenic response and are unable to maintain body temperature when exposed to cold. Despite impaired BAT function, MTERF4-FAT-KO mice do not develop obesity or insulin resistance. Still, MTERF4-FAT-KO mice became resistant to the insulin-sensitizing effects of β3-specific adrenergic receptor agonists. Our results demonstrate that MTERF4 regulates mitochondrial protein translation and is essential for proper BAT thermogenic activity. Our study also supports the notion that pharmacological activation of BAT is a plausible therapeutic target for the treatment of insulin resistance.
    Keywords:  Brown adipose tissue; Glucose homeostasis; Mitochondrial biogenesis; Mitochondrial transcription termination factor 4; Non-shivering adaptive thermogenesis; β(3)-adrenoreceptor agonist
    DOI:  https://doi.org/10.1016/j.bbadis.2019.01.025
  3. Arch Biochem Biophys. 2019 Jan 24. pii: S0003-9861(18)30832-4. [Epub ahead of print]663 259-268
    SR-mitochondria communication in adult cardiomyocytes: A close relationship where the Ca2+ has a lot to say.
    Sergio De la Fuente, Shey-Shing Sheu.
      In adult cardiomyocytes, T-tubules, junctional sarcoplasmic reticulum (jSR), and mitochondria juxtapose each other and form a unique and highly repetitive functional structure along the cell. The close apposition between jSR and mitochondria creates high Ca2+ microdomains at the contact sites, increasing the efficiency of the excitation-contraction-bioenergetics coupling, where the Ca2+ transfer from SR to mitochondria plays a critical role. The SR-mitochondria contacts are established through protein tethers, with mitofusin 2 the most studied SR-mitochondrial "bridge", albeit controversial. Mitochondrial Ca2+ uptake is further optimized with the mitochondrial Ca2+ uniporter preferentially localized in the jSR-mitochondria contact sites and the mitochondrial Na+/Ca2+ exchanger localized away from these sites. Despite all these unique features facilitating the privileged transport of Ca2+ from SR to mitochondria in adult cardiomyocytes, the question remains whether mitochondrial Ca2+ concentrations oscillate in synchronicity with cytosolic Ca2+ transients during heartbeats. Proper Ca2+ transfer controls not only the process of mitochondrial bioenergetics, but also of mitochondria-mediated cell death, autophagy/mitophagy, mitochondrial fusion/fission dynamics, reactive oxygen species generation, and redox signaling, among others. Our review focuses specifically on Ca2+ signaling between SR and mitochondria in adult cardiomyocytes. We discuss the physiological and pathological implications of this SR-mitochondrial Ca2+ signaling, research gaps, and future trends.
    Keywords:  Calcium; Heart; Mitochondria; Mitochondrial Ca(2+) uniporter; Mitofusin 2; SR-Mitochondria contacts
    DOI:  https://doi.org/10.1016/j.abb.2019.01.026
  4. Mitochondrion. 2019 Jan 24. pii: S1567-7249(18)30225-3. [Epub ahead of print]
    Withaferin A-mediated apoptosis in breast cancer cells is associated with alterations in mitochondrial dynamics.
    Anuradha Sehrawat, Suman K Samanta, Eun-Ryeong Hahm, Claudette St Croix, Simon Watkins, Shivendra V Singh.
      Withaferin A (WA), a steroidal lactone derived from a medicinal plant (Withania somnifera), inhibits cancer development in transgenic and chemically-induced rodent models of breast cancer but the underlying mechanism is not fully grasped. We have shown previously that WA treatment causes apoptotic cell death in human breast cancer cells that is preceded by inhibition of complex III of the mitochondrial electron transport chain. This study extends these observations to now demonstrate alterations in mitochondrial dynamics in WA-induced apoptosis. Assembly of complex III was decreased in MCF-7 and SUM159 cells but not in MDA-MB-231 as determined by native blue gel electrophoresis. Because WA is a Michael acceptor (electrophile), we explored the possibility of whether it covalently modifies cysteine residue(s) in ubiquinol-cytochrome c reductase, Rieske iron-sulfur polypeptide 1 (UQCRFS1). Covalent modification of cysteine in UQCRFS1 was not observed after WA treatment. Instead, WA treatment inhibited chemically-induced mitochondrial fusion and decreased the mitochondrial volume, and this effect was accompanied by a decrease in the expression of proteins involved in fusion process, including mitofusin1, mitofusin2, and full-length optic atrophy protein 1 (OPA1). A loss of volume in fragmented mitochondria also occurred in WA-exposed cells when compared to vehicle-treated control. WA treatment also caused a decrease in protein level of mitochondrial fission-regulating protein dynamin-related protein 1 (DRP1). Functional studies revealed that DRP1 deficiency and OPA1 knockdown attenuated apoptotic potential of WA. Taken together, these results indicate that WA not only alters Complex III assembly but also inhibits mitochondrial dynamics in breast cancer cells.
    Keywords:  Apoptosis; Breast cancer; Chemoprevention; Mitochondrial dynamics; Withaferin A
    DOI:  https://doi.org/10.1016/j.mito.2019.01.003
  5. ACS Cent Sci. 2019 Jan 23. 5(1): 153-166
    A Selective and Cell-Permeable Mitochondrial Calcium Uniporter (MCU) Inhibitor Preserves Mitochondrial Bioenergetics after Hypoxia/Reoxygenation Injury.
    Joshua J Woods, Neeharika Nemani, Santhanam Shanmughapriya, Akshay Kumar, MengQi Zhang, Sarah R Nathan, Manfred Thomas, Edmund Carvalho, Karthik Ramachandran, Subramanya Srikantan, Peter B Stathopulos, Justin J Wilson, Muniswamy Madesh.
      Mitochondrial Ca2+ (mCa2+) uptake mediated by the mitochondrial calcium uniporter (MCU) plays a critical role in signal transduction, bioenergetics, and cell death, and its dysregulation is linked to several human diseases. In this study, we report a new ruthenium complex Ru265 that is cell-permeable, minimally toxic, and highly potent with respect to MCU inhibition. Cells treated with Ru265 show inhibited MCU activity without any effect on cytosolic Ca2+ dynamics and mitochondrial membrane potential (ΔΨm). Dose-dependent studies reveal that Ru265 is more potent than the currently employed MCU inhibitor Ru360. Site-directed mutagenesis of Cys97 in the N-terminal domain of human MCU ablates the inhibitory activity of Ru265, suggesting that this matrix-residing domain is its target site. Additionally, Ru265 prevented hypoxia/reoxygenation injury and subsequent mitochondrial dysfunction, demonstrating that this new inhibitor is a valuable tool for studying the functional role of the MCU in intact biological models.
    DOI:  https://doi.org/10.1021/acscentsci.8b00773
  6. J Biol Chem. 2019 Jan 30. pii: jbc.RA118.006085. [Epub ahead of print]
    Obesity-dependent CDK1 signaling stimulates mitochondrial respiration at complex I in pancreatic β-cells.
    Trillian Gregg, Sophia M Sdao, Rashpal S Dhillon, Jarred W Rensvold, Sophie L Lewandowski, David J Pagliarini, John M Denu, Matthew J Merrins.
      β-cell mitochondria play a central role in coupling glucose metabolism with insulin secretion. Here, we identified a metabolic function of cyclin-dependent kinase 1 (CDK1)/cyclin B1 - the activation of mitochondrial respiratory complex I - that is active in quiescent adult β-cells and hyperactive in β-cells from obese (ob/ob) mice. In wild-type islets, respirometry revealed that 65% of complex I flux and 49% of state 3 respiration is sensitive to CDK1 inhibition. Islets from ob/ob mice expressed more cyclin B1 and exhibited a higher sensitivity to CDK1 blockade, which reduced complex I flux by 76% and state 3 respiration by 79%. The ensuing reduction in mitochondrial NADH utilization, measured with 2-photon NAD(P)H fluorescence lifetime imaging (FLIM), was matched in the cytosol by a lag in citrate cycling, as shown with a FRET reporter targeted to β-cells. Moreover, time-resolved measurements revealed that in ob/ob islets, where complex I flux dominates respiration, CDK1 inhibition is sufficient to restrict the duty cycle of ATP/ADP and calcium oscillations, the parameter that dynamically encodes β-cell glucose sensing. Direct complex I inhibition with rotenone mimicked the restrictive effects of CDK1 inhibition on mitochondrial respiration, NADH turnover, ATP/ADP, and calcium influx. These findings identify complex I as a critical mediator of obesity-associated metabolic remodeling in β-cells, and implicate CDK1 as a regulator of complex I that enhances β-cell glucose sensing.
    Keywords:  Complex I; RO-3306; calcium; cyclin B1; cyclin-dependent kinase 1 (CDK1); insulin secretion; mitochondrial metabolism; ob/ob mice; obesity; pancreatic beta cell
    DOI:  https://doi.org/10.1074/jbc.RA118.006085
  7. Nature. 2019 Jan 30.
    FOXK1 and FOXK2 regulate aerobic glycolysis.
    Valentina Sukonina, Haixia Ma, Wei Zhang, Stefano Bartesaghi, Santhilal Subhash, Mikael Heglind, Håvard Foyn, Matthias J Betz, Daniel Nilsson, Martin E Lidell, Jennifer Naumann, Saskia Haufs-Brusberg, Henrik Palmgren, Tanmoy Mondal, Muheeb Beg, Mark P Jedrychowski, Kjetil Taskén, Alexander Pfeifer, Xiao-Rong Peng, Chandrasekhar Kanduri, Sven Enerbäck.
      Adaptation to the environment and extraction of energy are essential for survival. Some species have found niches and specialized in using a particular source of energy, whereas others-including humans and several other mammals-have developed a high degree of flexibility1. A lot is known about the general metabolic fates of different substrates but we still lack a detailed mechanistic understanding of how cells adapt in their use of basic nutrients2. Here we show that the closely related fasting/starvation-induced forkhead transcription factors FOXK1 and FOXK2 induce aerobic glycolysis by upregulating the enzymatic machinery required for this (for example, hexokinase-2, phosphofructokinase, pyruvate kinase, and lactate dehydrogenase), while at the same time suppressing further oxidation of pyruvate in the mitochondria by increasing the activity of pyruvate dehydrogenase kinases 1 and 4. Together with suppression of the catalytic subunit of pyruvate dehydrogenase phosphatase 1 this leads to increased phosphorylation of the E1α regulatory subunit of the pyruvate dehydrogenase complex, which in turn inhibits further oxidation of pyruvate in the mitochondria-instead, pyruvate is reduced to lactate. Suppression of FOXK1 and FOXK2 induce the opposite phenotype. Both in vitro and in vivo experiments, including studies of primary human cells, show how FOXK1 and/or FOXK2 are likely to act as important regulators that reprogram cellular metabolism to induce aerobic glycolysis.
    DOI:  https://doi.org/10.1038/s41586-019-0900-5
  8. J Inherit Metab Dis. 2018 Dec 27.
    Vitamin B12 , folate, and the methionine remethylation cycle-biochemistry, pathways, and regulation.
    D Sean Froese, Brian Fowler, Matthias R Baumgartner.
      Vitamin B12 (cobalamin, Cbl) is a nutrient essential to human health. Due to its complex structure and dual cofactor forms, Cbl undergoes a complicated series of absorptive and processing steps before serving as cofactor for the enzymes methylmalonyl-CoA mutase and methionine synthase. Methylmalonyl-CoA mutase is required for the catabolism of certain (branched-chain) amino acids into an anaplerotic substrate in the mitochondrion, and dysfunction of the enzyme itself or in production of its cofactor adenosyl-Cbl result in an inability to successfully undergo protein catabolism with concomitant mitochondrial energy disruption. Methionine synthase catalyzes the methyl-Cbl dependent (re)methylation of homocysteine to methionine within the methionine cycle; a reaction required to produce this essential amino acid and generate S-adenosylmethionine, the most important cellular methyl-donor. Disruption of methionine synthase has wide-ranging implications for all methylation-dependent reactions, including epigenetic modification, but also for the intracellular folate pathway, since methionine synthase uses 5-methyltetrahydrofolate as a one-carbon donor. Folate-bound one-carbon units are also required for deoxythymidine monophosphate and de novo purine synthesis; therefore, the flow of single carbon units to each of these pathways must be regulated based on cellular needs. This review provides an overview on Cbl metabolism with a brief description of absorption and intracellular metabolic pathways. It also provides a description of folate-mediated one-carbon metabolism and its intersection with Cbl at the methionine cycle. Finally, a summary of recent advances in understanding of how both pathways are regulated is presented.
    Keywords:  folate; hyperhomocysteinemia; methionine cycle; methylmalonic acidemia; one-carbon metabolism; vitamin B12
    DOI:  https://doi.org/10.1002/jimd.12009
  9. Pflugers Arch. 2019 Feb 01.
    Mitochondrial dynamics in exercise physiology.
    Tomohiro Tanaka, Akiyuki Nishimura, Kazuhiro Nishiyama, Takumi Goto, Takuro Numaga-Tomita, Motohiro Nishida.
      A growing body of evidence suggests that exercise shows pleiotropic effects on the maintenance of systemic homeostasis through mitochondria. Dysregulation of mitochondrial dynamism is associated with metabolic inflexibility, resulting in many of the metabolic diseases and aging. Studies have suggested that exercise prevents and delays the progression of mitochondrial dysfunction by improving mitochondrial metabolism, biogenesis, and quality control. Exercise modulates functions of mitochondrial dynamics-regulating proteins through post-translational modification mechanisms. In this review, we discuss the putative mechanisms underlying maintenance of mitochondrial homeostasis by exercise, especially focusing on the post-translational modifications of several signaling proteins contributing to mitochondrial biogenesis, autophagy or mitophagy flux, and fission/fusion cycle. We also introduce novel small molecules that can potentially mimic exercise therapy through preserving mitochondrial dynamism. These recent advancements in the field of mitochondrial biology may lead to a greater understanding of exercise signaling.
    Keywords:  Drug design; Metabolism; Mitochondrial dynamics; Quality control; Redox biology
    DOI:  https://doi.org/10.1007/s00424-019-02258-3
  10. Cell Rep. 2019 Jan 29. pii: S2211-1247(19)30037-3. [Epub ahead of print]26(5): 1189-1202.e6
    Metabolic and Organelle Morphology Defects in Mice and Human Patients Define Spinocerebellar Ataxia Type 7 as a Mitochondrial Disease.
    Jacqueline M Ward, Colleen A Stoyas, Pawel M Switonski, Farid Ichou, Weiwei Fan, Brett Collins, Christopher E Wall, Isaac Adanyeguh, Chenchen Niu, Bryce L Sopher, Chizuru Kinoshita, Richard S Morrison, Alexandra Durr, Alysson R Muotri, Ronald M Evans, Fanny Mochel, Albert R La Spada.
      Spinocerebellar ataxia type 7 (SCA7) is a retinal-cerebellar degenerative disorder caused by CAG-polyglutamine (polyQ) repeat expansions in the ataxin-7 gene. As many SCA7 clinical phenotypes occur in mitochondrial disorders, and magnetic resonance spectroscopy of patients revealed altered energy metabolism, we considered a role for mitochondrial dysfunction. Studies of SCA7 mice uncovered marked impairments in oxygen consumption and respiratory exchange. When we examined cerebellar Purkinje cells in mice, we observed mitochondrial network abnormalities, with enlarged mitochondria upon ultrastructural analysis. We developed stem cell models from patients and created stem cell knockout rescue systems, documenting mitochondrial morphology defects, impaired oxidative metabolism, and reduced expression of nicotinamide adenine dinucleotide (NAD+) production enzymes in SCA7 models. We observed NAD+ reductions in mitochondria of SCA7 patient NPCs using ratiometric fluorescent sensors and documented alterations in tryptophan-kynurenine metabolism in patients. Our results indicate that mitochondrial dysfunction, stemming from decreased NAD+, is a defining feature of SCA7.
    Keywords:  Purkinje cell; ataxin-7; induced pluripotent stem cells; mitochondria; mouse model; nicotinamide adenine dinucleotide; oxidative metabolism; polyglutamine; spinocerebellar ataxia; trinucleotide repeat
    DOI:  https://doi.org/10.1016/j.celrep.2019.01.028
  11. Arch Biochem Biophys. 2019 Jan 23. pii: S0003-9861(18)30834-8. [Epub ahead of print]663 276-287
    Role of mitochondrial Ca2+ homeostasis in cardiac muscles.
    Jessica L Cao, Stephanie M Adaniya, Michael W Cypress, Yuta Suzuki, Yoichiro Kusakari, Bong Sook Jhun, Jin O-Uchi.
      Recent discoveries of the molecular identity of mitochondrial Ca2+ influx/efflux mechanisms have placed mitochondrial Ca2+ transport at center stage in views of cellular regulation in various cell-types/tissues. Indeed, mitochondria in cardiac muscles also possess the molecular components for efficient uptake and extraction of Ca2+. Over the last several years, multiple groups have taken advantage of newly available molecular information about these proteins and applied genetic tools to delineate the precise mechanisms for mitochondrial Ca2+ handling in cardiomyocytes and its contribution to excitation-contraction/metabolism coupling in the heart. Though mitochondrial Ca2+ has been proposed as one of the most crucial secondary messengers in controlling a cardiomyocyte's life and death, the detailed mechanisms of how mitochondrial Ca2+ regulates physiological mitochondrial and cellular functions in cardiac muscles, and how disorders of this mechanism lead to cardiac diseases remain unclear. In this review, we summarize the current controversies and discrepancies regarding cardiac mitochondrial Ca2+ signaling that remain in the field to provide a platform for future discussions and experiments to help close this gap.
    DOI:  https://doi.org/10.1016/j.abb.2019.01.027
  12. Biochim Biophys Acta Rev Cancer. 2019 Jan 29. pii: S0304-419X(18)30199-9. [Epub ahead of print]
    Prostate Cancer-specific Hallmarks of Amino Acids Metabolism: Towards a Paradigm of Precision Medicine.
    Vladislav Strmiska, Petr Michalek, Tomas Eckschlager, Marie Stiborova, Vojtech Adam, Sona Krizkova, Zbynek Heger.
      So far multiple differences in prostate cancer-specific amino acids metabolism have been discovered. Moreover, some attempts to utilize these alterations for prostate cancer diagnosis and treatment have been made. The prostate cancer metabolism and biosynthesis of amino acids are particularly focused on anaplerosis more than on energy production. Other crucial requirements on amino acids pool come from the serine, one‑carbon cycle, glycine synthesis pathway and folate metabolism forming major sources of interproducts for synthesis of nucleobases necessary for rapidly proliferating cells. Considering the lack of some amino acids biosynthetic pathways and/or their extraordinary importance for prostate cancer cells, there is a widespread potential for targeted therapeutic applications with no effect on non-malignant cells. This review summarizes the up-to-date knowledge of the importance of amino acids for prostate cancer pathogenesis with a special emphasis on potential applications of metabolic variabilities in the new oncologic paradigm of precision medicine.
    Keywords:  Mitochondria; Personalized Medicine; Prostate; Sarcosine; Serine; Warburg effect
    DOI:  https://doi.org/10.1016/j.bbcan.2019.01.001
  13. Endocrinology. 2019 Jan 25.
    Drp1 phosphorylation is indispensable for steroidogenesis in Leydig cells.
    Ji-Eun Park, Yoon-Jae Kim, Seung Gee Lee, Ji Young Kim, Jin-Yong Chung, Seon-Yong Jeong, Hyongjong Koh, Jeanho Yun, Hwan Tae Park, Young Hyun Yoo, Jong-Min Kim.
      The initial steps of steroidogenesis occur in the mitochondria. Dynamic changes in the mitochondria are associated with their fission and fusion. Therefore, understanding the cellular and molecular relationship between steroidogenesis and mitochondrial dynamics is important. The hypothesis of the present study is that mitochondrial fission and fusion are closely associated with steroid hormone synthesis in the testicular Leydig cells. Steroid hormone production, induced by dibutyryl cyclic-adenosine monophosphate (dbcAMP) in Leydig cells, was accompanied by increased mitochondrial mass. Mitochondrial elongation increased during the dbcAMP-induced steroid production, whereas mitochondrial fragmentation reduced. Among the mitochondrial-shaping proteins, the level of Drp1 was altered in response to dbcAMP stimulation. The increase in Drp1 Ser 637 phosphorylation correlated with steroid hormone production in the MA-10 Leydig cells as well as in the primary adult rat Leydig cells. Drp1 was differentially expressed in the Leydig cells during testicular development. Finally, gonadotropin administration altered the status of Drp1 phosphorylation in the Leydig cells of immature rat testes. Overall, mitochondrial dynamics is directly linked to steroidogenesis, and Drp1 plays an important regulatory role during steroidogenesis. This study shows that Drp1 level is regulated by cAMP and that its phosphorylation via PKA activation plays a decisive role in mitochondrial shaping by offering an optimal environment for steroid hormone biosynthesis in the Leydig cells. Therefore, it is suggested that PKA-mediated Drp1 ser 637 phosphorylation is indispensable for steroidogenesis in the Leydig cells, and this phosphorylation results in mitochondrial elongation via the relative attenuation of mitochondrial fission during steroidogenesis.
    DOI:  https://doi.org/10.1210/en.2019-00029
  14. Nat Commun. 2019 Jan 31. 10(1): 531
    Functional role of PGAM5 multimeric assemblies and their polymerization into filaments.
    Karen Ruiz, Tarjani M Thaker, Christopher Agnew, Lakshmi Miller-Vedam, Raphael Trenker, Clara Herrera, Maria Ingaramo, Daniel Toso, Adam Frost, Natalia Jura.
      PGAM5 is a mitochondrial protein phosphatase whose genetic ablation in mice results in mitochondria-related disorders, including neurodegeneration. Functions of PGAM5 include regulation of mitophagy, cell death, metabolism and aging. However, mechanisms regulating PGAM5 activation and signaling are poorly understood. Using electron cryo-microscopy, we show that PGAM5 forms dodecamers in solution. We also present a crystal structure of PGAM5 that reveals the determinants of dodecamer formation. Furthermore, we observe PGAM5 dodecamer assembly into filaments both in vitro and in cells. We find that PGAM5 oligomerization into a dodecamer is not only essential for catalytic activation, but this form also plays a structural role on mitochondrial membranes, which is independent of phosphatase activity. Together, these findings suggest that modulation of the oligomerization of PGAM5 may be a regulatory switch of potential therapeutic interest.
    DOI:  https://doi.org/10.1038/s41467-019-08393-w
  15. EBioMedicine. 2019 Jan 24. pii: S2352-3964(19)30045-3. [Epub ahead of print]
    Loss of SLC25A11 causes suppression of NSCLC and melanoma tumor formation.
    Jae-Seon Lee, Ho Lee, Soohyun Lee, Joon Hee Kang, Seon-Hyeong Lee, Seul-Gi Kim, Eunae Sandra Cho, Nam Hee Kim, Jong In Yook, Soo-Youl Kim.
      BACKGROUND: Fast growing cancer cells require greater amounts of ATP than normal cells. Although glycolysis was suggested as a source of anabolic metabolism based on lactate production, the main source of ATP to support cancer cell metabolism remains unidentified.METHODS: We have proposed that the oxoglutarate carrier SLC25A11 is important for ATP production in cancer by NADH transportation from the cytosol to mitochondria as a malate. We have examined not only changes of ATP and NADH but also changes of metabolites after SLC25A11 knock down in cancer cells.
    FINDINGS: The mitochondrial electron transport chain was functionally active in cancer cells. The cytosolic to mitochondrial NADH ratio was higher in non-small cell lung cancer (NSCLC) and melanoma cells than in normal cells. This was consistent with higher levels of the oxoglutarate carrier SLC25A11. Blocking malate transport by knockdown of SLC25A11 significantly impaired ATP production and inhibited the growth of cancer cells, which was not observed in normal cells. In in vivo experiments, heterozygote of SLC25A11 knock out mice suppressed KRASLA2 lung tumor formation by cross breeding.
    INTERPRETATION: Cancer cells critically depended on the oxoglutarate carrier SLC25A11 for transporting NADH from cytosol to mitochondria as a malate form for the purpose of ATP production. Therefore blocking SLC25A11 may have an advantage in stopping cancer growth by reducing ATP production. FUND: The Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of Science and ICT to SYK (NRF-2017R1A2B2003428).
    Keywords:  Cancer metabolism; Cancer therapeutic target; Malate aspartate shuttle; Oxoglutarate carrier; SLC25A11
    DOI:  https://doi.org/10.1016/j.ebiom.2019.01.036
  16. J Immunol. 2019 Feb 01. pii: ji1801569. [Epub ahead of print]
    L-Arginine Synthesis from L-Citrulline in Myeloid Cells Drives Host Defense against Mycobacteria In Vivo.
    Shannon M Lange, Melanie C McKell, Stephanie M Schmidt, Junfang Zhao, Rebecca R Crowther, Lisa C Green, Rebecca L Bricker, Eusondia Arnett, S Eleonore Köhler, Larry S Schlesinger, Kenneth D R Setchell, Joseph E Qualls.
      Immunonutrition as a therapeutic approach is rapidly gaining interest in the fight against infection. Targeting l-arginine metabolism is intriguing, considering this amino acid is the substrate for antimicrobial NO production by macrophages. The importance of l-arginine during infection is supported by the finding that inhibiting its synthesis from its precursor l-citrulline blunts host defense. During the first few weeks following pulmonary mycobacterial infection, we found a drastic increase in l-citrulline in the lung, even though serum concentrations were unaltered. This correlated with increased gene expression of the l-citrulline-generating (i.e., iNOS) and l-citrulline-using (i.e., Ass1) enzymes in key myeloid populations. Eliminating l-arginine synthesis from l-citrulline in myeloid cells via conditional deletion of either Ass1 or Asl resulted in increased Mycobacterium bovis bacillus Calmette-Guérin and Mycobacterium tuberculosis H37Rv burden in the lungs compared with controls. Our data illustrate the necessity of l-citrulline metabolism for myeloid defense against mycobacterial infection and highlight the potential for host-directed therapy against mycobacterial disease targeting this nutrient and/or its metabolic pathway.
    DOI:  https://doi.org/10.4049/jimmunol.1801569
  17. New Phytol. 2019 Jan 28.
    Wheat mitochondrial respiration shifts from the TCA cycle to the GABA shunt under salt stress.
    M Hafiz Che-Othman, Richard P Jacoby, A Harvey Millar, Nicolas L Taylor.
      Mitochondrial respiration and tricarboxylic acid (TCA) cycle activity are required during salt stress in plants to provide ATP and reductants for adaptive processes such as ion exclusion, compatible solute synthesis and reactive oxygen species (ROS) detoxification. However, there is a poor mechanistic understanding of how salinity affects mitochondrial metabolism, particularly respiratory substrate source. To determine the mechanism of respiratory changes under salt stress in wheat leaves, we conducted an integrated analysis of metabolite content, respiratory rate, and targeted protein abundance measurements. Also, we investigate the direct effect of salt on mitochondrial enzyme activities. Salt treated wheat leaves exhibit higher respiration rate and extensive metabolite changes. The activity of the TCA cycle enzymes pyruvate dehydrogenase complex and the 2-oxoglutarate dehydrogenase complex were shown to be directly salt sensitive. Multiple lines of evidence showed that the γ-aminobutyric acid (GABA) shunt was activated under salt treatment. During salt exposure, key metabolic enzymes required for the cyclic operation of the TCA cycle are physiochemically inhibited by salt. This inhibition is overcome by increased GABA shunt activity, which provides an alternative carbon source for mitochondria that bypasses salt-sensitive enzymes to facilitate the increased respiration of wheat leaves. This article is protected by copyright. All rights reserved.
    Keywords:  Mitochondria; Pyruvate Dehydrogenase; SRM Mass Spectrometry; Salinity; Sodium Chloride; Wheat; γ-aminobutyric acid (GABA) Shunt
    DOI:  https://doi.org/10.1111/nph.15713
  18. Nat Cell Biol. 2019 Feb;21(2): 226-237
    AKT methylation by SETDB1 promotes AKT kinase activity and oncogenic functions.
    Jianping Guo, Xiangpeng Dai, Benoit Laurent, Nana Zheng, Wenjian Gan, Jian Zhang, Ailan Guo, Min Yuan, Pengda Liu, John M Asara, Alex Toker, Yang Shi, Pier Paolo Pandolfi, Wenyi Wei.
      Aberrant activation of AKT disturbs the proliferation, survival and metabolic homeostasis of various human cancers. Thus, it is critical to understand the upstream signalling pathways governing AKT activation. Here, we report that AKT undergoes SETDB1-mediated lysine methylation to promote its activation, which is antagonized by the Jumonji-family demethylase KDM4B. Notably, compared with wild-type mice, mice harbouring non-methylated mutant Akt1 not only exhibited reduced body size but were also less prone to carcinogen-induced skin tumours, in part due to reduced AKT activation. Mechanistically, the interaction of phosphatidylinositol (3,4,5)-trisphosphate with AKT facilitates its interaction with SETDB1 for subsequent AKT methylation, which in turn sustains AKT phosphorylation. Pathologically, genetic alterations, including SETDB1 amplification, aberrantly promote AKT methylation to facilitate its activation and oncogenic functions. Thus, AKT methylation is an important step, synergizing with PI3K signalling to control AKT activation. This suggests that targeting SETDB1 signalling could be a potential therapeutic strategy for combatting hyperactive AKT-driven cancers.
    DOI:  https://doi.org/10.1038/s41556-018-0261-6
  19. Nature. 2019 Jan 30.
    PKG1-modified TSC2 regulates mTORC1 activity to counter adverse cardiac stress.
    Mark J Ranek, Kristen M Kokkonen-Simon, Anna Chen, Brittany L Dunkerly-Eyring, Miguel Pinilla Vera, Christian U Oeing, Chirag H Patel, Taishi Nakamura, Guangshuo Zhu, Djahida Bedja, Masayuki Sasaki, Ronald J Holewinski, Jennifer E Van Eyk, Jonathan D Powell, Dong Ik Lee, David A Kass.
      The mechanistic target of rapamycin complex-1 (mTORC1) coordinates regulation of growth, metabolism, protein synthesis and autophagy1. Its hyperactivation contributes to disease in numerous organs, including the heart1,2, although broad inhibition of mTORC1 risks interference with its homeostatic roles. Tuberin (TSC2) is a GTPase-activating protein and prominent intrinsic regulator of mTORC1 that acts through modulation of RHEB (Ras homologue enriched in brain). TSC2 constitutively inhibits mTORC1; however, this activity is modified by phosphorylation from multiple signalling kinases that in turn inhibits (AMPK and GSK-3β) or stimulates (AKT, ERK and RSK-1) mTORC1 activity3-9. Each kinase requires engagement of multiple serines, impeding analysis of their role in vivo. Here we show that phosphorylation or gain- or loss-of-function mutations at either of two adjacent serine residues in TSC2 (S1365 and S1366 in mice; S1364 and S1365 in humans) can bidirectionally control mTORC1 activity stimulated by growth factors or haemodynamic stress, and consequently modulate cell growth and autophagy. However, basal mTORC1 activity remains unchanged. In the heart, or in isolated cardiomyocytes or fibroblasts, protein kinase G1 (PKG1) phosphorylates these TSC2 sites. PKG1 is a primary effector of nitric oxide and natriuretic peptide signalling, and protects against heart disease10-13. Suppression of hypertrophy and stimulation of autophagy in cardiomyocytes by PKG1 requires TSC2 phosphorylation. Homozygous knock-in mice that express a phosphorylation-silencing mutation in TSC2 (TSC2(S1365A)) develop worse heart disease and have higher mortality after sustained pressure overload of the heart, owing to mTORC1 hyperactivity that cannot be rescued by PKG1 stimulation. However, cardiac disease is reduced and survival of heterozygote Tsc2S1365A knock-in mice subjected to the same stress is improved by PKG1 activation or expression of a phosphorylation-mimicking mutation (TSC2(S1365E)). Resting mTORC1 activity is not altered in either knock-in model. Therefore, TSC2 phosphorylation is both required and sufficient for PKG1-mediated cardiac protection against pressure overload. The serine residues identified here provide a genetic tool for bidirectional regulation of the amplitude of stress-stimulated mTORC1 activity.
    DOI:  https://doi.org/10.1038/s41586-019-0895-y
  20. Front Immunol. 2018 ;9 3145
    Regulation of Dendritic Cell Immune Function and Metabolism by Cellular Nutrient Sensor Mammalian Target of Rapamycin (mTOR).
    Julia P Snyder, Eyal Amiel.
      Dendritic cell (DC) activation is characterized by an acute increase in glucose metabolic flux that is required to fuel the high anabolic rates associated with DC activation. Inhibition of glycolysis significantly attenuates most aspects of DC immune effector function including antigen presentation, inflammatory cytokine production, and T cell stimulatory capacity. The cellular nutrient sensor mammalian/mechanistic Target of Rapamycin (mTOR) is an important upstream regulator of glycolytic metabolism and plays a central role in coordinating DC metabolic changes and immune responses. Because mTOR signaling can be activated by a variety of immunological stimuli, including signaling through the Toll-like Receptor (TLR) family of receptors, mTOR is involved in orchestrating many aspects of the DC metabolic response to microbial stimuli. It has become increasingly clear that mTOR's role in promoting or attenuating inflammatory processes in DCs is highly context-dependent and varies according to specific cellular subsets and the immunological conditions being studied. This review will address key aspects of the complex role of mTOR in regulating DC metabolism and effector function.
    Keywords:  dendritic cell (DC); glycolysis; immune metabolism; mTOR; metabolism regulation
    DOI:  https://doi.org/10.3389/fimmu.2018.03145
  21. J Vis Exp. 2019 Jan 09.
    Multicolor Flow Cytometry-based Quantification of Mitochondria and Lysosomes in T Cells.
    Chin-Wen Wei, Tyng-An Zhou, Ivan L Dzhagalov, Chia-Lin Hsu.
      T cells utilize different metabolic programs to match their functional needs during differentiation and proliferation. Mitochondria are crucial cellular components responsible for supplying cell energy; however, excess mitochondria also produce reactive oxygen species (ROS) that could cause cell death. Therefore, the number of mitochondria must constantly be adjusted to fit the needs of the cells. This dynamic regulation is achieved in part through the function of lysosomes that remove surplus/damaged organelles and macromolecules. Hence, cellular mitochondrial and lysosomal contents are key indicators to evaluate the metabolic adjustment of cells. With the development of probes for organelles, well-characterized lysosome or mitochondria-specific dyes have become available in various formats to label cellular lysosomes and mitochondria. Multicolor flow cytometry is a common tool to profile cell phenotypes, and has the capability to be integrated with other assays. Here, we present a detailed protocol of how to combine organelle-specific dyes with surface markers staining to measure the amount of lysosomes and mitochondria in different T cell populations on a flow cytometer.
    DOI:  https://doi.org/10.3791/58844
  22. Nature. 2019 Jan 30.
    Gut intraepithelial T cells calibrate metabolism and accelerate cardiovascular disease.
    Shun He, Florian Kahles, Sara Rattik, Manfred Nairz, Cameron S McAlpine, Atsushi Anzai, Daniel Selgrade, Ashley M Fenn, Christopher T Chan, John E Mindur, Colin Valet, Wolfram C Poller, Lennard Halle, Noemi Rotllan, Yoshiko Iwamoto, Gregory R Wojtkiewicz, Ralph Weissleder, Peter Libby, Carlos Fernández-Hernando, Daniel J Drucker, Matthias Nahrendorf, Filip K Swirski.
      The biochemical response to food intake must be precisely regulated. Because ingested sugars and fats can feed into many anabolic and catabolic pathways1, how our bodies handle nutrients depends on strategically positioned metabolic sensors that link the intrinsic nutritional value of a meal with intermediary metabolism. Here we describe a subset of immune cells-integrin β7+ natural gut intraepithelial T lymphocytes (natural IELs)-that is dispersed throughout the enterocyte layer of the small intestine and that modulates systemic metabolism. Integrin β7- mice that lack natural IELs are metabolically hyperactive and, when fed a high-fat and high-sugar diet, are resistant to obesity, hypercholesterolaemia, hypertension, diabetes and atherosclerosis. Furthermore, we show that protection from cardiovascular disease in the absence of natural IELs depends on the enteroendocrine-derived incretin GLP-12, which is normally controlled by IELs through expression of the GLP-1 receptor. In this metabolic control system, IELs modulate enteroendocrine activity by acting as gatekeepers that limit the bioavailability of GLP-1. Although the function of IELs may prove advantageous when food is scarce, present-day overabundance of diets high in fat and sugar renders this metabolic checkpoint detrimental to health.
    DOI:  https://doi.org/10.1038/s41586-018-0849-9
  23. Cancer Cell. 2019 Jan 16. pii: S1535-6108(18)30581-6. [Epub ahead of print]
    Targeting the Vulnerability of Glutathione Metabolism in ARID1A-Deficient Cancers.
    Hideaki Ogiwara, Kazuaki Takahashi, Mariko Sasaki, Takafumi Kuroda, Hiroshi Yoshida, Reiko Watanabe, Ami Maruyama, Hideki Makinoshima, Fumiko Chiwaki, Hiroki Sasaki, Tomoyasu Kato, Aikou Okamoto, Takashi Kohno.
      ARID1A encodes an SWI/SNF chromatin-remodeling factor and is frequently mutated in various cancers. This study demonstrates that ARID1A-deficient cancer cells are specifically vulnerable to inhibition of the antioxidant glutathione (GSH) and the glutamate-cysteine ligase synthetase catalytic subunit (GCLC), a rate-limiting enzyme for GSH synthesis. Inhibition of GCLC markedly decreased GSH in ARID1A-deficient cancer cells, leading to apoptotic cell death triggered by excessive amounts of reactive oxygen species. The vulnerability of ARID1A-deficient cancer cells results from low basal levels of GSH due to impaired expression of SLC7A11. The SLC7A11-encoded cystine transporter supplies cells with cysteine, a key source of GSH, and its expression is enhanced by ARID1A-mediated chromatin remodeling. Thus, ARID1A-deficient cancers are susceptible to synthetic lethal targeting of GCLC.
    Keywords:  APR-246; ARID1A; GCLC; SWI/SNF chromatin-remodeling complex; glutathione; ovarian cancer; ovarian clear cell carcinoma; reactive oxygen species; synthetic lethality; vulnerability
    DOI:  https://doi.org/10.1016/j.ccell.2018.12.009
  24. Free Radic Biol Med. 2019 Jan 28. pii: S0891-5849(18)32214-7. [Epub ahead of print]
    SIRT5-mediated SDHA desuccinylation promotes clear cell renal cell carcinoma tumorigenesis.
    Yuanzhen Ma, Yijun Qi, Lei Wang, Zhaoxu Zheng, Yue Zhang, Junfang Zheng.
      Metabolic reprogramming is a prominent feature of clear cell renal cell carcinoma (ccRCC). Protein succinylation influences cell metabolism, but its effects on ccRCC tumorigenesis remain largely uncharacterized. In this study, we investigated the lysine succinylome of ccRCC tissues by using tandem mass tag labeling, affinity enrichment, liquid chromatography-tandem mass spectrometry and integrated bioinformatics analyses. Proteins involved in metabolic process, the tricarboxylic acid (TCA) cycle, oxidation-reduction and transport processes were subject to succinylation. A total of 135 sites in 102 proteins were differentially succinylated between ccRCC and adjacent normal tissues. Succinate dehydrogenase complex subunit A (SDHA), which is involved in both the TCA cycle and oxidative phosphorylation, was desuccinylated at lysine 547 in ccRCC. SDHA desuccinylation by mimetic mutation (K547R) suppressed its activity through the inhibition of succinate dehydrogenase 5 (SDH5) binding, further promoted ccRCC cell proliferation. The desuccinylase sirtuin5 (SIRT5) was found to interact with SDHA, and SIRT5 silencing led to the hypersuccinylation and reactivation of SDHA. SIRT5 was also found to be upregulated in ccRCC tissues, and its silencing inhibited ccRCC cell proliferation. This indicates that SIRT5 promotes ccRCC tumorigenesis through inhibiting SDHA succinylation. This is the first quantitative study of lysine succinylome in ccRCC, through which we identified succinylation in core enzymes as a novel mechanism regulating various ccRCC metabolic pathways. These results expand our understanding about the mechanisms of ccRCC tumorigenesis and highlight succinylation as a novel therapeutic target for ccRCC.
    Keywords:  Clear cell renal cell carcinoma; Desuccinylation; SDHA; SIRT5; Tumorigenesis
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2019.01.030
  25. Front Physiol. 2018 ;9 1883
    Mitochondria as a Target for Mitigating Sarcopenia.
    Paul M Coen, Robert V Musci, J Matthew Hinkley, Benjamin F Miller.
      Sarcopenia is the loss of muscle mass, strength, and physical function that is characteristic of aging. The progression of sarcopenia is gradual but may be accelerated by periods of muscle loss during physical inactivity secondary to illness or injury. The loss of mobility and independence and increased comorbidities associated with sarcopenia represent a major healthcare challenge for older adults. Mitochondrial dysfunction and impaired proteostatic mechanisms are important contributors to the complex etiology of sarcopenia. As such, interventions that target improving mitochondrial function and proteostatic maintenance could mitigate or treat sarcopenia. Exercise is currently the only effective option to treat sarcopenia and does so, in part, by improving mitochondrial energetics and protein turnover. Exercise interventions also serve as a discovery tool to identify molecular targets for development of alternative therapies to treat sarcopenia. In summary, we review the evidence linking mitochondria and proteostatic maintenance to sarcopenia and discuss the therapeutic potential of interventions addressing these two factors to mitigate sarcopenia.
    Keywords:  aging; exercise; mitochondria; sarcopenia; skeletal muscle; treatment
    DOI:  https://doi.org/10.3389/fphys.2018.01883
  26. Free Radic Res. 2018 Dec;52(11-12): 1387-1397
    Alpha-lipoic acid suppresses Nε-(carboxymethyl) lysine-induced epithelial mesenchymal transition in HK-2 human renal proximal tubule cells.
    Mei-Chen Lo, Ming-Hong Chen, Yu-Ting Hsueh, Yung-Ting Kuo, Horng-Mo Lee.
      Nε-(carboxymethyl) lysine (CML) plays causal roles in diabetic complications. In the present study, we investigated whether CML-induced HIF-1α accumulation and epithelial-mesenchymal transition (EMT) in HK-2 renal proximal tubular epithelial cells. Treatment with CML-BSA increased reactive oxygen species (ROS) production reduced the mitochondrial membrane potential and induced mitochondrial fragmentation. Pre-treatment of cells with antioxidant, α-lipoic acid, normalised the ROS production and restored the mitochondrial membrane potential. These changes were accompanied with morphological changes of epithelial mesenchymal transition. CML-BSA increased the protein level of hypoxia-inducible factor-1α (HIF-1α), and the EMT-associated transcription factor, TWIST. These effects were reversed by α-lipoic acid. CML-BSA increased the protein levels of mesenchymal-specific markers, including vimentin, α-smooth muscle actin, which were alleviated by pre-treatment with α-lipoic acid. Our data suggest that CML-BSA induces EMT through a ROS/HIF-1α/TWIST-dependent mechanism, and that α-lipoic acid may alleviate the CML-induced EMT in renal tubular cells.
    Keywords:  -(carboxymethyl) lysine; EMT; HIF-1α; TWIST; mitochondria
    DOI:  https://doi.org/10.1080/10715762.2018.1489129
  27. Elife. 2019 Jan 29. pii: e41351. [Epub ahead of print]8
    Mitochondrial fusion supports increased oxidative phosphorylation during cell proliferation.
    Cong-Hui Yao, Rencheng Wang, Yahui Wang, Che-Pei Kung, Jason D Weber, Gary J Patti.
      Proliferating cells often have increased glucose consumption and lactate excretion relative to the same cells in the quiescent state, a phenomenon known as the Warburg effect. Despite an increase in glycolysis, however, here we show that non-transformed mouse fibroblasts also increase oxidative phosphorylation (OXPHOS) by nearly two-fold and mitochondrial coupling efficiency by ~30% during proliferation. Both increases are supported by mitochondrial fusion. Impairing mitochondrial fusion by knocking down mitofusion-2 (Mfn2) was sufficient to attenuate proliferation, while overexpressing Mfn2 increased proliferation. Interestingly, impairing mitochondrial fusion decreased OXPHOS but did not deplete ATP levels. Instead, inhibition caused cells to transition from excreting aspartate to consuming it. Transforming fibroblasts with the Ras oncogene induced mitochondrial biogenesis, which further elevated OXPHOS. Notably, transformed fibroblasts continued to have elongated mitochondria and their proliferation remained sensitive to inhibition of Mfn2. Our results suggest that cell proliferation requires increased OXPHOS as supported by mitochondrial fusion.
    Keywords:  cancer; cancer biology; cell biology; cell proliferation; human; metabolism; mitochondrial fusion; mouse; oxidative phosphorylation; warburg effect
    DOI:  https://doi.org/10.7554/eLife.41351
  28. Genes Dev. 2019 Feb 01. 33(3-4): 150-165
    Autophagy modulates lipid metabolism to maintain metabolic flexibility for Lkb1-deficient Kras-driven lung tumorigenesis.
    Vrushank Bhatt, Khoosheh Khayati, Zhixian Sherrie Hu, Amy Lee, Wali Kamran, Xiaoyang Su, Jessie Yanxiang Guo.
      Loss of tumor suppressor liver kinase B1 (LKB1) promotes cancer cell proliferation but also leads to decreased metabolic plasticity in dealing with energy crises. Autophagy is a protective process involving self-cannibalization to maintain cellular energy homeostasis during nutrient deprivation. We developed a mouse model for Lkb1-deficient lung cancer with conditional deletion of essential autophagy gene Atg7 to test whether autophagy compensates for LKB1 loss for tumor cells to survive energy crises. We found that autophagy ablation was synthetically lethal during Lkb1-deficient lung tumorigenesis in both tumor initiation and tumor growth. We further found that autophagy deficiency causes defective intracellular recycling, which limits amino acids to support mitochondrial energy production in starved cancer cells and causes autophagy-deficient cells to be more dependent on fatty acid oxidation (FAO) for energy production, leading to reduced lipid reserve and energy crisis. Our findings strongly suggest that autophagy inhibition could be a strategy for treating LKB1-deficient lung tumors.
    Keywords:  LKB1; autophagy; energy metabolism; lipid metabolism; non-small cell lung cancer
    DOI:  https://doi.org/10.1101/gad.320481.118
  29. Cell Rep. 2019 Jan 29. pii: S2211-1247(19)30027-0. [Epub ahead of print]26(5): 1344-1356.e5
    Post-translational Regulation of FNIP1 Creates a Rheostat for the Molecular Chaperone Hsp90.
    Rebecca A Sager, Mark R Woodford, Sarah J Backe, Alan M Makedon, Alexander J Baker-Williams, Bryanna T DiGregorio, David R Loiselle, Timothy A Haystead, Natasha E Zachara, Chrisostomos Prodromou, Dimitra Bourboulia, Laura S Schmidt, W Marston Linehan, Gennady Bratslavsky, Mehdi Mollapour.
      The molecular chaperone Hsp90 stabilizes and activates client proteins. Co-chaperones and post-translational modifications tightly regulate Hsp90 function and consequently lead to activation of clients. However, it is unclear whether this process occurs abruptly or gradually in the cellular context. We show that casein kinase-2 phosphorylation of the co-chaperone folliculin-interacting protein 1 (FNIP1) on priming serine-938 and subsequent relay phosphorylation on serine-939, 941, 946, and 948 promotes its gradual interaction with Hsp90. This leads to incremental inhibition of Hsp90 ATPase activity and gradual activation of both kinase and non-kinase clients. We further demonstrate that serine/threonine protein phosphatase 5 (PP5) dephosphorylates FNIP1, allowing the addition of O-GlcNAc (O-linked N-acetylglucosamine) to the priming serine-938. This process antagonizes phosphorylation of FNIP1, preventing its interaction with Hsp90, and consequently promotes FNIP1 lysine-1119 ubiquitination and proteasomal degradation. These findings provide a mechanism for gradual activation of the client proteins through intricate crosstalk of post-translational modifications of the co-chaperone FNIP1.
    Keywords:  BHD; Birt-Hogg-Dubé syndrome; FNIP1; Hsp90; O-GlcNAcylation; PP5; co-chaperone; folliculin-interacting protein 1; heat shock protein 90; serine/threonine protein phosphatase 5
    DOI:  https://doi.org/10.1016/j.celrep.2019.01.018
  30. Nat Rev Cancer. 2019 Jan 29.
    Immune control by amino acid catabolism during tumorigenesis and therapy.
    Henrique Lemos, Lei Huang, George C Prendergast, Andrew L Mellor.
      Immune checkpoints arise from physiological changes during tumorigenesis that reprogramme inflammatory, immunological and metabolic processes in malignant lesions and local lymphoid tissues, which constitute the immunological tumour microenvironment (TME). Improving clinical responses to immune checkpoint blockade will require deeper understanding of factors that impact local immune balance in the TME. Elevated catabolism of the amino acids tryptophan (Trp) and arginine (Arg) is a common TME hallmark at clinical presentation of cancer. Cells catabolizing Trp and Arg suppress effector T cells and stabilize regulatory T cells to suppress immunity in chronic inflammatory diseases of clinical importance, including cancers. Processes that induce Trp and Arg catabolism in the TME remain incompletely defined. Indoleamine 2,3 dioxygenase (IDO) and arginase 1 (ARG1), which catabolize Trp and Arg, respectively, respond to inflammatory cues including interferons and transforming growth factor-β (TGFβ) cytokines. Dying cells generate inflammatory signals including DNA, which is sensed to stimulate the production of type I interferons via the stimulator of interferon genes (STING) adaptor. Thus, dying cells help establish local conditions that suppress antitumour immunity to promote tumorigenesis. Here, we review evidence that Trp and Arg catabolism contributes to inflammatory processes that promote tumorigenesis, impede immune responses to therapy and might promote neurological comorbidities associated with cancer.
    DOI:  https://doi.org/10.1038/s41568-019-0106-z
  31. Angew Chem Int Ed Engl. 2019 Jan 28.
    Restraining Cancer Cells by Dual-Metabolic Inhibitions with a Mitochondrion-Targeted Platinum(II) Complex.
    Kun Wang, Chengcheng Zhu, Yafeng He, Zhenqin Zhang, Wen Zhou, Nafees Muhammad, Yan Guo, Xiaoyong Wang, Zijian Guo.
      Cancer cells usually adapt metabolic phenotypes to chemotherapeutics. A defensive strategy against this flexibility is to modulate signaling pathways relevant to cancer bioenergetics. A triphenylphosphonium-modified terpyridine platinum(II) complex (TTP) was designed to inhibit thioredoxin reductase (TrxR) and multiple metabolisms of cancer cells. TTP exhibits enhanced cytotoxicity against cisplatin-insensitive human ovarian cancer cells in a caspase-3-independent way, and shows preferential inhibition on mitochondrial TrxR. The morphology and function of mitochondria are severely damaged, and the levels of mitochondrial and cellular reactive oxygen species are decreased. As a result, TTP exerts strong inhibition to both mitochondrial and glycolytic bioenergetics, inducing cancer cells to enter into a hypometabolic state.
    Keywords:  anticancer drug; metabolism; mitochondrion; platinum(II) complex; thioredoxin reductase
    DOI:  https://doi.org/10.1002/anie.201900387
  32. PLoS One. 2019 ;14(1): e0209665
    The type III intermediate filament vimentin regulates organelle distribution and modulates autophagy.
    Olga Biskou, Victor Casanova, Kirsty M Hooper, Sadie Kemp, Graham P Wright, Jack Satsangi, Peter G Barlow, Craig Stevens.
      The cytoskeletal protein vimentin plays a key role in positioning of organelles within the cytosol and has been linked to the regulation of numerous cellular processes including autophagy, however, how vimentin regulates autophagy remains relatively unexplored. Here we report that inhibition of vimentin using the steroidal lactone Withaferin A (WFA) causes vimentin to aggregate, and this is associated with the relocalisation of organelles including autophagosomes and lysosomes from the cytosol to a juxtanuclear location. Vimentin inhibition causes autophagosomes to accumulate, and we demonstrate this results from modulation of mechanistic target of rapamycin (mTORC1) activity, and disruption of autophagosome-lysosome fusion. We suggest that vimentin plays a physiological role in autophagosome and lysosome positioning, thus identifying vimentin as a key factor in the regulation of mTORC1 and autophagy.
    DOI:  https://doi.org/10.1371/journal.pone.0209665
  33. Mol Genet Metab. 2019 Jan 17. pii: S1096-7192(18)30634-6. [Epub ahead of print]
    The mitochondrial heme metabolon: Insights into the complex(ity) of heme synthesis and distribution.
    Robert B Piel, Harry A Dailey, Amy E Medlock.
      Heme is an essential cofactor in metazoans that is also toxic in its free state. Heme is synthesized by most metazoans and must be delivered to all cellular compartments for incorporation into a variety of hemoproteins. The heme biosynthesis enzymes have been proposed to exist in a metabolon, a protein complex consisting of interacting enzymes in a metabolic pathway. Metabolons enhance the function of enzymatic pathways by creating favorable microenvironments for pathway enzymes and intermediates, facilitating substrate transport, and providing a scaffold for interactions with other pathways, signaling molecules, or organelles. Herein we detail growing evidence for a mitochondrial heme metabolon and discuss its implications for the study of heme biosynthesis and cellular heme homeostasis.
    Keywords:  Anemia; Heme; Heme Biosynthesis; Metabolon; Porphyria
    DOI:  https://doi.org/10.1016/j.ymgme.2019.01.006
  34. PLoS One. 2019 ;14(1): e0211459
    New interfaces on MiD51 for Drp1 recruitment and regulation.
    Jun Ma, Yujia Zhai, Ming Chen, Kai Zhang, Quan Chen, Xiaoyun Pang, Fei Sun.
      Mitochondrial fission is facilitated by dynamin-related protein Drp1 and a variety of its receptors. However, the molecular mechanism of how Drp1 is recruited to the mitochondrial surface by receptors MiD49 and MiD51 remains elusive. Here, we showed that the interaction between Drp1 and MiD51 is regulated by GTP binding and depends on the polymerization of Drp1. We identified two regions on MiD51 that directly bind to Drp1, and found that dimerization of MiD51, relevant to residue C452, is required for mitochondrial dynamics regulation. Our Results have suggested a multi-faceted regulatory mechanism for the interaction between Drp1 and MiD51 that illustrates the potentially complicated and tight regulation of mitochondrial fission.
    DOI:  https://doi.org/10.1371/journal.pone.0211459
  35. Front Immunol. 2018 ;9 3036
    Metabolic Checkpoints in Differentiation of Helper T Cells in Tissue Inflammation.
    Suyasha Roy, Zaigham Abbas Rizvi, Amit Awasthi.
      Naïve CD4+ T cell differentiate into effector and regulatory subsets of helper T (Th) cells in various pathophysiological conditions and modulate tissue inflammation in autoimmune diseases. While cytokines play a key role in determining the fate of Th cells differentiation, metabolites, and metabolic pathways profoundly influence Th cells fate and their functions. Emerging literature suggests that interplay between metabolic pathways and cytokines potentiates T cell differentiation and functions in tissue inflammation in autoimmune diseases. Metabolic pathways, which are essential for the differentiation and functions of Th cell subsets, are regulated by cytokines, nutrients, growth factors, local oxygen levels, co-activation receptors, and metabolites. Dysregulation of metabolic pathways not only alters metabolic regulators in Th cells but also affect the outcome of tissue inflammation in autoimmune and allergic diseases. Understanding the modulation of metabolic pathways during T cells differentiation may potentially lead to a therapeutic strategy for immune-modulation of autoimmune and allergic diseases. In this review, we summarize the role of metabolic checkpoints and their crosstalk with different master transcription factors and signaling molecules in differentiation and function of Th subsets, which may potentially unravel novel therapeutic interventions for tissue inflammation and autoimmune disorders.
    Keywords:  T cell; checkpoint; cytokines; inflammation; metabolism; transcription factor
    DOI:  https://doi.org/10.3389/fimmu.2018.03036
  36. Cell Rep. 2019 Jan 29. pii: S2211-1247(19)30031-2. [Epub ahead of print]26(5): 1203-1212.e4
    Dimerization of MICU Proteins Controls Ca2+ Influx through the Mitochondrial Ca2+ Uniporter.
    Yangfei Xing, Mingfei Wang, Jia Wang, Zhenzhen Nie, Guangyan Wu, Xue Yang, Yuequan Shen.
      The mitochondrial Ca2+ uniporter complex (MCUC) is responsible for Ca2+ influx into the mitochondrial matrix, playing critical roles in various mitochondrial functions. Eukaryotic MCUC consists of multiple subunits, and its Ca2+ influx activity is controlled by regulatory subunits, including mitochondrial Ca2+ uptake 1 (MICU1) and its paralogs (MICU2 and MICU3). However, the underlying mechanism remains unclear. Here, we determined multiple crystal structures of MICU2 and MICU3 from Homo sapiens. Our data demonstrate that distinct MICU protein N-domains determine the specific type of MICU dimers that perform the opposing roles in mitochondrial Ca2+ uptake at low cytosolic Ca2+ levels. In contrast, at high cytosolic Ca2+ levels, all MICU proteins undergo dimer rearrangement induced by Ca2+ binding, which releases the suppression of the MCUC pore-forming subunit and promotes the influx of large amounts of Ca2+. Altogether, our results elucidate the delicate mechanism of mitochondrial Ca2+ uptake regulation by MICU proteins.
    Keywords:  MCU; MCUC; MICU; calcium; mitochondria; mitochondrial Ca(2+) uniporter; mitochondrial Ca(2+) uptake; structure
    DOI:  https://doi.org/10.1016/j.celrep.2019.01.022
  37. Proc Natl Acad Sci U S A. 2019 Feb 01. pii: 201817494. [Epub ahead of print]
    MAP kinase and autophagy pathways cooperate to maintain RAS mutant cancer cell survival.
    Chih-Shia Lee, Liam C Lee, Tina L Yuan, Sirisha Chakka, Christof Fellmann, Scott W Lowe, Natasha J Caplen, Frank McCormick, Ji Luo.
      Oncogenic mutations in the small GTPase KRAS are frequently found in human cancers, and, currently, there are no effective targeted therapies for these tumors. Using a combinatorial siRNA approach, we analyzed a panel of KRAS mutant colorectal and pancreatic cancer cell lines for their dependency on 28 gene nodes that represent canonical RAS effector pathways and selected stress response pathways. We found that RAF node knockdown best differentiated KRAS mutant and KRAS WT cancer cells, suggesting RAF kinases are key oncoeffectors for KRAS addiction. By analyzing all 376 pairwise combination of these gene nodes, we found that cotargeting the RAF, RAC, and autophagy pathways can improve the capture of KRAS dependency better than targeting RAF alone. In particular, codepletion of the oncoeffector kinases BRAF and CRAF, together with the autophagy E1 ligase ATG7, gives the best therapeutic window between KRAS mutant cells and normal, untransformed cells. Distinct patterns of RAS effector dependency were observed across KRAS mutant cell lines, indicative of heterogeneous utilization of effector and stress response pathways in supporting KRAS addiction. Our findings revealed previously unappreciated complexity in the signaling network downstream of the KRAS oncogene and suggest rational target combinations for more effective therapeutic intervention.
    Keywords:  KRAS; MAPK; RAF; autophagy; siRNA
    DOI:  https://doi.org/10.1073/pnas.1817494116
  38. J Clin Invest. 2019 Jan 31. pii: 98747. [Epub ahead of print]
    Ascorbic acid-induced TET activation mitigates adverse hydroxymethylcystosine loss in renal cell carcinoma.
    Niraj Shenoy, Tushar D Bhagat, John C Cheville, Christine Lohse, Sanchari Bhattacharyya, Alexander Tischer, Venkata Machha, Shanisha Gordon-Mitchell, Gaurav S Choudhary, Li-Fan Wong, LouAnn Gross, Emily Ressegue, Bradley C Leibovich, Stephen A Boorjian, Ulrich Steidl, Xiaosheng Wu, Kith Pradhan, Benjamin Gartrell, Beamon Agarwal, Lance Pagliaro, Masako Suzuki, John M Greally, Dinesh Rakheja, R Houston Thompson, Katalin Susztak, Thomas Witzig, Yiyu Zou, Amit Verma.
      Although ccRCC has been shown to have widespread aberrant cytosine methylation and loss of hydroxymethylation (5hmC), the prognostic impact and therapeutic targeting of this epigenetic aberrancy has not been fully explored. Analysis of 576 primary ccRCC samples demonstrated that loss of 5hmC was significantly associated with aggressive clinicopathologic features and was an independent adverse prognostic factor. Loss of 5hmC also predicted reduced progression free survival after resection of non-metastatic disease. The loss of 5hmC in ccRCC was not due to mutational or transcriptional inactivation of TET enzymes, but by their functional inactivation by l-2-hydroxyglutarate (L2HG) that was overexpressed due to the deletion and under-expression of l-2-hydroxyglutarate dehydrogenase (L2HGDH). Ascorbic acid (AA) reduced methylation and restored genome wide 5hmC levels via TET activation. Fluorescence quenching of the recombinant TET-2 protein was unaffected by L2HG in the presence of AA. Pharmacologic AA treatment led to reduced growth of ccRCC in vitro and reduced tumor growth in vivo, with increased intratumoral 5hmC. These data demonstrate that reduced 5hmC is associated with reduced survival in ccRCC and provide a preclinical rationale for exploring the therapeutic potential of high dose AA in ccRCC.
    Keywords:  Cancer; Oncology
    DOI:  https://doi.org/10.1172/JCI98747
  39. Cancer Sci. 2019 Jan 28.
    Glucose starvation induces resistance to metformin through the elevation of mitochondrial multidrug resistance protein1.
    Sung-Hyun Hwang, Myung-Chul Kim, Sumin Ji, Yeseul Yang, Yeji Jeong, Yongbaek Kim.
      Metformin, a drug for type 2 diabetes mellitus, has shown therapeutic effects for various cancers. However, it had no beneficial effects on survival rate of human malignant mesothelioma (HMM) patients. This study was performed to elucidate the underlying mechanism of metformin resistance in HMM cells. Glucose starved HMM cells had enhanced resistance to metformin demonstrated by decreased apoptosis and autophagy and increased cell survival. These cells showed abnormalities in mitochondria such as decreased ATP synthesis, morphological elongation, altered mitochondrial permeability transition pore and hyperpolarization of mitochondrial membrane potential (MMP). Intriguingly Mdr1 was significantly upregulated in mitochondria, but not in cell membrane. The upregulated mitochondrial Mdr1 was reversed by treatment with CCCP, a MMP depolarization inducer. Furthermore, apoptosis and autophagy was increased in MDR1 KO HMM cells cultured under glucose starvation with metformin treatment. The data suggest that mitochondrial Mdr1 plays a critical role in the chemoresistance to metformin in HMM cells, which could be a potential target for improving its therapeutic efficacy. This article is protected by copyright. All rights reserved.
    Keywords:  Drug resistance; Glucose starvation; MDR1; Metformin; Mitochondria
    DOI:  https://doi.org/10.1111/cas.13952
  40. Aging Cell. 2019 Jan 31. e12901
    Extranuclear DNA accumulates in aged cells and contributes to senescence and inflammation.
    Yuk Yuen Lan, James M Heather, Thomas Eisenhaure, Christopher Stuart Garris, David Lieb, Raktima Raychowdhury, Nir Hacohen.
      Systemic inflammation is central to aging-related conditions. However, the intrinsic factors that induce inflammation are not well understood. We previously identified a cell-autonomous pathway through which damaged nuclear DNA is trafficked to the cytosol where it activates innate cytosolic DNA sensors that trigger inflammation. These results led us to hypothesize that DNA released after cumulative damage contributes to persistent inflammation in aging cells through a similar mechanism. Consistent with this notion, we found that older cells harbored higher levels of extranuclear DNA compared to younger cells. Extranuclear DNA was exported by a leptomycin B-sensitive process, degraded through the autophagosome-lysosomal pathway and triggered innate immune responses through the DNA-sensing cGAS-STING pathway. Patient cells from the aging diseases ataxia and progeria also displayed extranuclear DNA accumulation, increased pIRF3 and pTBK1, and STING-dependent p16 expression. Removing extranuclear DNA in old cells using DNASE2A reduced innate immune responses and senescence-associated (SA) β-gal enzyme activity. Cells and tissues of Dnase2a- / - mice with defective DNA degradation exhibited slower growth, higher activity of β-gal, or increased expression of HP-1β and p16 proteins, while Dnase2a- / - ;Sting- / - cells and tissues were rescued from these phenotypes, supporting a role for extranuclear DNA in senescence. We hypothesize a direct role for excess DNA in aging-related inflammation and in replicative senescence, and propose DNA degradation as a therapeutic approach to remove intrinsic DNA and revert inflammation associated with aging.
    Keywords:  Dnase2a; STING pathway; cellular senescence; extranuclear DNA; inflammation; premature aging
    DOI:  https://doi.org/10.1111/acel.12901
  41. Cell Death Differ. 2019 Jan 28.
    Autophagy in endothelial cells and tumor angiogenesis.
    Marco B Schaaf, Diede Houbaert, Odeta Meçe, Patrizia Agostinis.
      In mammalian cells, autophagy is the major pathway for the degradation and recycling of obsolete and potentially noxious cytoplasmic materials, including proteins, lipids, and whole organelles, through the lysosomes. Autophagy maintains cellular and tissue homeostasis and provides a mechanism to adapt to extracellular cues and metabolic stressors. Emerging evidence unravels a critical function of autophagy in endothelial cells (ECs), the major components of the blood vasculature, which delivers nutrients and oxygen to the parenchymal tissue. EC-intrinsic autophagy modulates the response of ECs to various metabolic stressors and has a fundamental role in redox homeostasis and EC plasticity. In recent years moreover, genetic evidence suggests that autophagy regulates pathological angiogenesis, a hallmark of solid tumors. In the hypoxic, nutrient-deprived, and pro-angiogenic tumor microenvironment, heightened autophagy in the blood vessels is emerging as a critical mechanism enabling ECs to dynamically accommodate their higher bioenergetics demands to the extracellular environment and connect with other components of the tumor stroma through paracrine signaling. In this review, we provide an overview of the major cellular mechanisms regulated by autophagy in ECs and discuss their potential role in tumor angiogenesis, tumor growth, and response to anticancer therapy.
    DOI:  https://doi.org/10.1038/s41418-019-0287-8
  42. Nat Rev Immunol. 2019 Jan 31.
    Itaconate: the poster child of metabolic reprogramming in macrophage function.
    Luke A J O'Neill, Maxim N Artyomov.
      Itaconate is one of the best examples of the consequences of metabolic reprogramming during immunity. It is made by diverting aconitate away from the tricarboxylic acid cycle during inflammatory macrophage activation. The main reason macrophages exhibit this response currently appears to be for an anti-inflammatory effect, with itaconate connecting cell metabolism, oxidative and electrophilic stress responses and immune responses. A role for itaconate in the regulation of type I interferons during viral infection has also been described, as well as in M2 macrophage function under defined circumstances. Finally, macrophage-specific itaconate production has also been shown to have a pro-tumour effect. All of these studies point towards itaconate being a critical immunometabolite that could have far-reaching consequences for immunity, host defence and tumorigenesis.
    DOI:  https://doi.org/10.1038/s41577-019-0128-5
  43. Science. 2019 Jan 31. pii: eaav1749. [Epub ahead of print]
    AIBP-mediated cholesterol efflux instructs hematopoietic stem and progenitor cell fate.
    Qilin Gu, Xiaojie Yang, Jie Lv, Jiaxiong Zhang, Bo Xia, Jun-Dae Kim, Ruoyu Wang, Feng Xiong, Shu Meng, Thomas P Clements, Bhavna Tandon, Daniel S Wagner, Miguel F Diaz, Pamela L Wenzel, Yury I Miller, David Traver, John P Cooke, Wenbo Li, Leonard I Zon, Kaifu Chen, Yongping Bai, Longhou Fang.
      Hypercholesterolemia, the driving force of atherosclerosis, accelerates the expansion and mobilization of hematopoietic stem and progenitor cells (HSPCs). The molecular determinants connecting hypercholesterolemia with hematopoiesis are unclear. Here we report that a somite-derived pro-hematopoietic cue, AIBP, orchestrates HSPC emergence from the hemogenic endothelium, a type of specialized endothelium manifesting hematopoietic potential. Mechanistically, AIBP-mediated cholesterol efflux activates endothelial Srebp2, the master transcription factor for cholesterol biosynthesis, which in turn transactivates Notch and promotes HSPC emergence. Srebp2 inhibition impairs hypercholesterolemia-induced HSPC expansion. Srebp2 activation and Notch upregulation are associated with HSPC expansion in hypercholesterolemic human subjects. Genome-wide ChIP-seq, RNA-seq, and ATAC-seq indicate that Srebp2 trans-regulates Notch pathway genes required for hematopoiesis. Our studies outline an AIBP-regulated Srebp2-dependent paradigm for HSPC emergence in development and HPSC expansion in atherosclerotic cardiovascular disease.
    DOI:  https://doi.org/10.1126/science.aav1749
  44. Annu Rev Immunol. 2019 Jan 30.
    CRISPR-Based Tools in Immunity.
    Dimitre R Simeonov, Alexander Marson.
      CRISPR technology has opened a new era of genome interrogation and genome engineering. Discovered in bacteria, where it protects against bacteriophage by cleaving foreign nucleic acid sequences, the CRISPR system has been repurposed as an adaptable tool for genome editing and multiple other applications. CRISPR's ease of use, precision, and versatility have led to its widespread adoption, accelerating biomedical research and discovery in human cells and model organisms. Here we review CRISPR-based tools and discuss how they are being applied to decode the genetic circuits that control immune function in health and disease. Genetic variation in immune cells can affect autoimmune disease risk, infectious disease pathogenesis, and cancer immunotherapies. CRISPR provides unprecedented opportunities for functional mechanistic studies of coding and noncoding genome sequence function in immunity. Finally, we discuss the potential of CRISPR technology to engineer synthetic cellular immunotherapies for a wide range of human diseases. Expected final online publication date for the Annual Review of Immunology Volume 37 is April 26, 2019 Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
    DOI:  https://doi.org/10.1146/annurev-immunol-042718-041522
  45. Aging Dis. 2019 Feb;10(1): 116-133
    Snapshot: Implications for mTOR in Aging-related Ischemia/Reperfusion Injury.
    Dong Liu, Liqun Xu, Xiaoyan Zhang, Changhong Shi, Shubin Qiao, Zhiqiang Ma, Jiansong Yuan.
      Aging may aggravate the damage and dysfunction of different components of multiorgan and thus increasing multiorgan ischemia/reperfusion (IR) injury. IR injury occurs in many organs and tissues, which is a major cause of morbidity and mortality worldwide. The kinase mammalian target of rapamycin (mTOR), an atypical serine/threonine protein kinase, involves in the pathophysiological process of IR injury. In this review, we first briefly introduce the molecular features of mTOR, the association between mTOR and aging, and especially its role on autophagy. Special focus is placed on the roles of mTOR during ischemic and IR injury. We then clarify the association between mTOR and conditioning phenomena. Following this background, we expand our discussion to potential future directions of research in this area. Collectively, information reviewed herein will serve as a comprehensive reference for the actions of mTOR in IR injury and may be significant for the design of future research and increase the potential of mTOR as a therapeutic target.
    Keywords:  Aging; Autophagy; Ischemia/reperfusion injury; mTOR
    DOI:  https://doi.org/10.14336/AD.2018.0501
  46. Cancer Discov. 2019 Feb 01.
    Central Carbon Metabolism Regulates Macrophage Antitumor Activity.
      CpG rewires macrophage metabolism to bypass inhibitory CD47 signals and enhance antitumor activity.
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2019-015
  47. Trends Genet. 2019 Jan 25. pii: S0168-9525(19)30002-2. [Epub ahead of print]
    Mechanisms of Mitochondrial DNA Deletion Formation.
    Nadee Nissanka, Michal Minczuk, Carlos T Moraes.
      Mitochondrial DNA (mtDNA) encodes a subset of genes which are essential for oxidative phosphorylation. Deletions in the mtDNA can ablate a number of these genes and result in mitochondrial dysfunction, which is associated with bona fide mitochondrial disorders. Although mtDNA deletions are thought to occur as a result of replication errors or following double-strand breaks, the exact mechanism(s) behind deletion formation have yet to be determined. In this review we discuss the current knowledge about the fate of mtDNA following double-strand breaks, including the molecular players which mediate the degradation of linear mtDNA fragments and possible mechanisms of recircularization. We propose that mtDNA deletions formed from replication errors versus following double-strand breaks can be mediated by separate pathways.
    Keywords:  double-strand breaks; mitochondrial DNA; mitochondrial DNA deletions; replication
    DOI:  https://doi.org/10.1016/j.tig.2019.01.001
  48. Sci Transl Med. 2019 Jan 30. pii: eaau1099. [Epub ahead of print]11(477):
    Inhibition of polyamine synthesis and uptake reduces tumor progression and prolongs survival in mouse models of neuroblastoma.
    Laura D Gamble, Stefania Purgato, Jayne Murray, Lin Xiao, Denise M T Yu, Kimberley M Hanssen, Federico M Giorgi, Daniel R Carter, Andrew J Gifford, Emanuele Valli, Giorgio Milazzo, Alvin Kamili, Chelsea Mayoh, Bing Liu, Georgina Eden, Sara Sarraf, Sophie Allan, Simone Di Giacomo, Claudia L Flemming, Amanda J Russell, Belamy B Cheung, Andre Oberthuer, Wendy B London, Matthias Fischer, Toby N Trahair, Jamie I Fletcher, Glenn M Marshall, David S Ziegler, Michael D Hogarty, Mark R Burns, Giovanni Perini, Murray D Norris, Michelle Haber.
      Amplification of the MYCN oncogene is associated with an aggressive phenotype and poor outcome in childhood neuroblastoma. Polyamines are highly regulated essential cations that are frequently elevated in cancer cells, and the rate-limiting enzyme in polyamine synthesis, ornithine decarboxylase 1 (ODC1), is a direct transcriptional target of MYCN. Treatment of neuroblastoma cells with the ODC1 inhibitor difluoromethylornithine (DFMO), although a promising therapeutic strategy, is only partially effective at impeding neuroblastoma cell growth due to activation of compensatory mechanisms resulting in increased polyamine uptake from the surrounding microenvironment. In this study, we identified solute carrier family 3 member 2 (SLC3A2) as the key transporter involved in polyamine uptake in neuroblastoma. Knockdown of SLC3A2 in neuroblastoma cells reduced the uptake of the radiolabeled polyamine spermidine, and DFMO treatment increased SLC3A2 protein. In addition, MYCN directly increased polyamine synthesis and promoted neuroblastoma cell proliferation by regulating SLC3A2 and other regulatory components of the polyamine pathway. Inhibiting polyamine uptake with the small-molecule drug AMXT 1501, in combination with DFMO, prevented or delayed tumor development in neuroblastoma-prone mice and extended survival in rodent models of established tumors. Our findings suggest that combining AMXT 1501 and DFMO with standard chemotherapy might be an effective strategy for treating neuroblastoma.
    DOI:  https://doi.org/10.1126/scitranslmed.aau1099
  49. Nat Cell Biol. 2019 Feb;21(2): 214-225
    SETDB1-mediated methylation of Akt promotes its K63-linked ubiquitination and activation leading to tumorigenesis.
    Guihua Wang, Jie Long, Yuan Gao, Weina Zhang, Fei Han, Chuan Xu, Li Sun, Shun-Chin Yang, Jingqin Lan, Zhenlin Hou, Zhen Cai, Guoxiang Jin, Che-Chia Hsu, Yu-Hui Wang, Junbo Hu, Tsai-Yu Chen, Hongyu Li, Min Gyu Lee, Hui-Kuan Lin.
      The serine/threonine kinase Akt plays a central role in cell proliferation, survival and metabolism, and its hyperactivation is linked to cancer progression. Here we report that Akt undergoes K64 methylation by SETDB1, which is crucial for cell membrane recruitment, phosphorylation and activation of Akt following growth factor stimulation. Furthermore, we reveal an adaptor function of histone demethylase JMJD2A, which is important for recognizing Akt K64 methylation and recruits E3 ligase TRAF6 and Skp2-SCF to the Akt complex, independently of its demethylase activity, thereby initiating K63-linked ubiquitination, cell membrane recruitment and activation of Akt. Notably, the cancer-associated Akt mutant E17K displays enhanced K64 methylation, leading to its hyper-phosphorylation and activation. SETDB1-mediated Akt K64 methylation is upregulated and correlated with Akt hyperactivation in non-small-cell lung carcinoma (NSCLC), promotes tumour development and predicts poor outcome. Collectively, these findings reveal complicated layers of Akt activation regulation coordinated by SETDB1-mediated Akt K64 methylation to drive tumorigenesis.
    DOI:  https://doi.org/10.1038/s41556-018-0266-1
  50. Oncogene. 2019 Jan 31.
    Control of mTOR signaling by ubiquitin.
    Yao Jiang, Siyuan Su, Yanqiong Zhang, Jiayi Qian, Pengda Liu.
      The evolutionarily conserved mTOR signaling pathway plays essential roles in cell growth, proliferation, metabolism and responses to cellular stresses. Hyperactivation of the mTOR signaling is observed in virtually all solid tumors and has been an attractive drug target. In addition to changes at genetic levels, aberrant activation of the mTOR signaling is also a result from dysregulated posttranslational modifications on key pathway members, such as phosphorylation that has been extensively studied. Emerging evidence also supports a critical role for ubiquitin-mediated modifications in dynamically regulating the mTOR signaling pathway, while a comprehensive review for relevant studies is missing. In this review, we will summarize characterized ubiquitination events on major mTOR signaling components, their modifying E3 ubiquitin ligases, deubiquitinases and corresponding pathophysiological functions. We will also reveal methodologies that have been used to identify E3 ligases or DUBs to facilitate the search for yet-to-be discovered ubiquitin-mediated regulatory mechanisms in mTOR signaling. We hope that our review and perspectives provide rationales and strategies to target ubiquitination for inhibiting mTOR signaling to treat human diseases.
    DOI:  https://doi.org/10.1038/s41388-019-0713-x
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