bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2019‒07‒21
37 papers selected by
Christian Frezza
University of Cambridge, MRC Cancer Unit


  1. Cell Rep. 2019 Jul 16. pii: S2211-1247(19)30831-9. [Epub ahead of print]28(3): 759-772.e10
    Jesinkey SR, Madiraju AK, Alves TC, Yarborough OH, Cardone RL, Zhao X, Parsaei Y, Nasiri AR, Butrico G, Liu X, Molina AJ, Rountree AM, Neal AS, Wolf DM, Sterpka J, Philbrick WM, Sweet IR, Shirihai OH, Kibbey RG.
      Mechanisms coordinating pancreatic β cell metabolism with insulin secretion are essential for glucose homeostasis. One key mechanism of β cell nutrient sensing uses the mitochondrial GTP (mtGTP) cycle. In this cycle, mtGTP synthesized by succinyl-CoA synthetase (SCS) is hydrolyzed via mitochondrial PEPCK (PEPCK-M) to make phosphoenolpyruvate, a high-energy metabolite that integrates TCA cycling and anaplerosis with glucose-stimulated insulin secretion (GSIS). Several strategies, including xenotopic overexpression of yeast mitochondrial GTP/GDP exchanger (GGC1) and human ATP and GTP-specific SCS isoforms, demonstrated the importance of the mtGTP cycle. These studies confirmed that mtGTP triggers and amplifies normal GSIS and rescues defects in GSIS both in vitro and in vivo. Increased mtGTP synthesis enhanced calcium oscillations during GSIS. mtGTP also augmented mitochondrial mass, increased insulin granule number, and membrane proximity without triggering de-differentiation or metabolic fragility. These data highlight the importance of the mtGTP signal in nutrient sensing, insulin secretion, mitochondrial maintenance, and β cell health.
    Keywords:  MIMOSA; PEPCK-M; anaplerosis; insulin secretion; metabolic flux; mitochondrial GTP; oxidative phosphorylation; phosphoenolpyruvate; stable isotope; succinyl-CoA synthetase
    DOI:  https://doi.org/10.1016/j.celrep.2019.06.058
  2. Cell Metab. 2019 Jul 09. pii: S1550-4131(19)30317-1. [Epub ahead of print]
    Bi J, Ichu TA, Zanca C, Yang H, Zhang W, Gu Y, Chowdhry S, Reed A, Ikegami S, Turner KM, Zhang W, Villa GR, Wu S, Quehenberger O, Yong WH, Kornblum HI, Rich JN, Cloughesy TF, Cavenee WK, Furnari FB, Cravatt BF, Mischel PS.
      Advances in DNA sequencing technologies have reshaped our understanding of the molecular basis of cancer, providing a precise genomic view of tumors. Complementary biochemical and biophysical perspectives of cancer point toward profound shifts in nutrient uptake and utilization that propel tumor growth and major changes in the structure of the plasma membrane of tumor cells. The molecular mechanisms that bridge these fundamental aspects of tumor biology remain poorly understood. Here, we show that the lysophosphatidylcholine acyltransferase LPCAT1 functionally links specific genetic alterations in cancer with aberrant metabolism and plasma membrane remodeling to drive tumor growth. Growth factor receptor-driven cancers are found to depend on LPCAT1 to shape plasma membrane composition through enhanced saturated phosphatidylcholine content that is, in turn, required for the transduction of oncogenic signals. These results point to a genotype-informed strategy that prioritizes lipid remodeling pathways as therapeutic targets for diverse cancers.
    Keywords:  cancer dependency; cancer metabolism; gene amplification; growth factor signaling; membrane lipid remodeling
    DOI:  https://doi.org/10.1016/j.cmet.2019.06.014
  3. Mitochondrion. 2019 Jul 13. pii: S1567-7249(18)30204-6. [Epub ahead of print]
    Jaña F, Bustos G, Rivas J, Cruz P, Urra F, Basualto-Alarcón C, Sagredo E, Ríos M, Lovy A, Dong Z, Cerda O, Madesh M, Cárdenas C.
      Cytosolic calcium (cCa2+) entry into mitochondria is facilitated by the mitochondrial membrane potential (ΔΨm), an electrochemical gradient generated by the electron transport chain (ETC). Is has been assumed that as long as mutations that affect the ETC do not affect the ΔΨm, the mitochondrial Ca2+ (mCa2+) homeostasis remains normal. We show that knockdown of NDUFAF3 and SDHB reduce ETC activity altering mCa2+ efflux and influx rates while ΔΨm remains intact. Shifting the equilibrium toward lower [Ca2+]m accumulation renders cells resistant to death. Our findings reveal an unexpected relationship between complex I and II with the mCa2+ homeostasis independent of ΔΨm.
    Keywords:  Calcium flux; Cell death; Migration; Mitochondrial membrane potential
    DOI:  https://doi.org/10.1016/j.mito.2019.07.004
  4. Autophagy. 2019 Jul 18. 1-2
    Zhou B, Soukas AA.
      A wide variety of genetic, pharmacological and nutrient manipulations that extend lifespan in model organisms do so in a manner dependent upon increased autophagic flux. However, our recent findings suggest that when mitochondrial membrane integrity is compromised, macroautophagy/autophagy can be detrimental. In C. elegans lacking the serine/threonine kinase mechanistic target of rapamycin kinase complex 2 and its downstream effector SGK-1 (Serum- and Glucocorticoid-inducible Kinase homolog), lifespan is shortened in spite of increased levels of autophagy, whereas reducing autophagy restores normal lifespan. This is due to a concomitant defect in mitochondrial permeability in mutants defective in either SGK-1 or mechanistic target of rapamycin kinase complex 2, attributable to increased VDAC-1 (VDAC Voltage Dependent Anion Channel homolog) protein level. More generally, we find that induction of mitochondrial permeability reverses each and every tested paradigm of autophagy-dependent lifespan extension and, further, exacerbates ischemia-reperfusion injury. In this punctum, we discuss our finding that autophagy with increased mitochondrial permeability is a detrimental combination conserved from nematode to mammals.
    Keywords:  Aging; MTOR (mechanistic target of rapamycin kinase); MTOR complex 2 (MTORC2); SGK-1 (serum and glucocorticoid-regulated kinase); VDAC1 (voltage dependent anion channel 1); autophagy; ischemia/reperfusion injury; lifespan; mitochondrial permeability transition pore (mPTP)
    DOI:  https://doi.org/10.1080/15548627.2019.1644077
  5. Mol Cell. 2019 Jun 25. pii: S1097-2765(19)30441-1. [Epub ahead of print]
    Wang T, Cao Y, Zheng Q, Tu J, Zhou W, He J, Zhong J, Chen Y, Wang J, Cai R, Zuo Y, Wei B, Fan Q, Yang J, Wu Y, Yi J, Li D, Liu M, Wang C, Zhou A, Li Y, Wu X, Yang W, Chin YE, Chen G, Cheng J.
      Sirt3, as a major mitochondrial nicotinamide adenine dinucleotide (NAD)-dependent deacetylase, is required for mitochondrial metabolic adaption to various stresses. However, how to regulate Sirt3 activity responding to metabolic stress remains largely unknown. Here, we report Sirt3 as a SUMOylated protein in mitochondria. SUMOylation suppresses Sirt3 catalytic activity. SUMOylation-deficient Sirt3 shows elevated deacetylation on mitochondrial proteins and increased fatty acid oxidation. During fasting, SUMO-specific protease SENP1 is accumulated in mitochondria and quickly de-SUMOylates and activates Sirt3. SENP1 deficiency results in hyper-SUMOylation of Sirt3 and hyper-acetylation of mitochondrial proteins, which reduces mitochondrial metabolic adaption responding to fasting. Furthermore, we find that fasting induces SENP1 translocation into mitochondria to activate Sirt3. The studies on mice show that Sirt3 SUMOylation mutation reduces fat mass and antagonizes high-fat diet (HFD)-induced obesity via increasing oxidative phosphorylation and energy expenditure. Our results reveal that SENP1-Sirt3 signaling modulates Sirt3 activation and mitochondrial metabolism during metabolic stress.
    Keywords:  SENP1; SUMOylation; Sirt3; acetylation; metabolism; mitochondrion; obesity
    DOI:  https://doi.org/10.1016/j.molcel.2019.06.008
  6. Front Cell Dev Biol. 2019 ;7 100
    Vringer E, Tait SWG.
      Mitochondrial outer membrane permeabilization (MOMP) is essential to initiate mitochondrial apoptosis. Due to the disruption of mitochondrial outer membrane integrity, intermembrane space proteins, notably cytochrome c, are released into the cytosol whereupon they activate caspase proteases and apoptosis. Beyond its well-established apoptotic role, MOMP has recently been shown to display potent pro-inflammatory effects. These include mitochondrial DNA dependent activation of cGAS-STING signaling leading to a type I interferon response. Secondly, via an IAP-regulated mechanism, MOMP can engage pro-inflammatory NF-κB signaling. During cell death, apoptotic caspase activity inhibits mitochondrial dependent inflammation. Importantly, by engaging an immunogenic form of cell death, inhibiting caspase function can effectively inhibit tumorigenesis. Unexpectedly, these studies reveal mitochondria as inflammatory signaling hubs during cell death and demonstrate its potential for therapeutic exploitation.
    Keywords:  NF-κB; apoptosis; caspases; cell death; inflammation; interferon; mitochondria; mtDNA
    DOI:  https://doi.org/10.3389/fcell.2019.00100
  7. Sci Rep. 2019 Jul 18. 9(1): 10414
    Yetkin-Arik B, Vogels IMC, Neyazi N, van Duinen V, Houtkooper RH, van Noorden CJF, Klaassen I, Schlingemann RO.
      Formation of new blood vessels by differentiated endothelial tip cells, stalk cells, and phalanx cells during angiogenesis is an energy-demanding process. How these specialized endothelial cell phenotypes generate their energy, and whether there are differences between these phenotypes, is unknown. This may be key to understand their functions, as (1) metabolic pathways are essentially involved in the regulation of angiogenesis, and (2) a metabolic switch has been associated with angiogenic endothelial cell differentiation. With the use of Seahorse flux analyses, we studied metabolic pathways in tip cell and non-tip cell human umbilical vein endothelial cell populations. Our study shows that both tip cells and non-tip cells use glycolysis as well as mitochondrial respiration for energy production. However, glycolysis is significantly lower in tip cells than in non-tip cells. Additionally, tip cells have a higher capacity to respond to metabolic stress. Finally, in non-tip cells, blocking of mitochondrial respiration inhibits endothelial cell proliferation. In conclusion, our data demonstrate that tip cells are less glycolytic than non-tip cells and that both endothelial cell phenotypes can adapt their metabolism depending on microenvironmental circumstances. Our results suggest that a balanced involvement of metabolic pathways is necessary for both endothelial cell phenotypes for proper functioning during angiogenesis.
    DOI:  https://doi.org/10.1038/s41598-019-46503-2
  8. EMBO J. 2019 Jul 15. 38(14): e100978
    He X, Zhu Y, Zhang Y, Geng Y, Gong J, Geng J, Zhang P, Zhang X, Liu N, Peng Y, Wang C, Wang Y, Liu X, Wan L, Gong F, Wei C, Zhong H.
      Viral infection triggers the formation of mitochondrial antiviral signaling protein (MAVS) aggregates, which potently promote immune signaling. Autophagy plays an important role in controlling MAVS-mediated antiviral signaling; however, the exact molecular mechanism underlying the targeted autophagic degradation of MAVS remains unclear. Here, we investigated the mechanism by which RNF34 regulates immunity and mitophagy by targeting MAVS. RNF34 binds to MAVS in the mitochondrial compartment after viral infection and negatively regulates RIG-I-like receptor (RLR)-mediated antiviral immunity. Moreover, RNF34 catalyzes the K27-/K29-linked ubiquitination of MAVS at Lys 297, 311, 348, and 362 Arg, which serves as a recognition signal for NDP52-dependent autophagic degradation. Specifically, RNF34 initiates the K63- to K27-linked ubiquitination transition on MAVS primarily at Lys 311, which facilitates the autophagic degradation of MAVS upon RIG-I stimulation. Notably, RNF34 is required for the clearance of damaged mitochondria upon viral infection. Thus, we elucidated the mechanism by which RNF34-mediated autophagic degradation of MAVS regulates the innate immune response, mitochondrial homeostasis, and infection.
    Keywords:   MAVS ; RNF34; innate immune response; selective mitophagy; ubiquitination
    DOI:  https://doi.org/10.15252/embj.2018100978
  9. BMC Biol. 2019 Jul 18. 17(1): 57
    Stuani L, Sabatier M, Sarry JE.
      Changes in cell metabolism and metabolic adaptation are hallmark features of many cancers, including leukemia, that support biological processes involved into tumor initiation, growth, and response to therapeutics. The discovery of mutations in key metabolic enzymes has highlighted the importance of metabolism in cancer biology and how these changes might constitute an Achilles heel for cancer treatment. In this Review, we discuss the role of metabolic and mitochondrial pathways dysregulated in acute myeloid leukemia, and the potential of therapeutic intervention targeting these metabolic dependencies on the proliferation, differentiation, stem cell function and cell survival to improve patient stratification and outcomes.
    DOI:  https://doi.org/10.1186/s12915-019-0670-4
  10. Antioxid Redox Signal. 2019 Jul 15.
    Grossmann D, Berenguer-Escuder C, Bellet ME, Scheibner D, Bohler J, Massart F, Rapaport D, Skupin A, Fouquier d'Hérouël A, Sharma M, Ghelfi J, Rakovic A, Lichtner P, Antony P, Glaab E, May P, Dimmer KS, Fitzgerald JC, Gruenewald A, Krüger R.
      OBJECTIVE: The outer mitochondrial membrane protein Miro1 is a crucial player in mitochondrial dynamics and calcium homeostasis. Recent evidence indicated that Miro1 mediates calcium-induced mitochondrial shape transition (MiST), which is a prerequisite for the initiation of mitophagy. Moreover, altered Miro1 protein levels have emerged as a shared feature of monogenic and sporadic Parkinson's disease (PD), but, so far, no disease-associated variants in RHOT1 have been identified.RESULTS: Here, for the first time, we describe heterozygous RHOT1 mutations in two PD patients (het c.815G>A; het c.1348C>T) and identified mitochondrial phenotypes with reduced mitochondrial mass in patient-derived cellular models. Both mutations lead to decreased ER-mitochondrial contact sites and calcium dyshomeostasis. As a consequence, energy metabolism was impaired, which in turn lead to increased mitophagy.
    CONCLUSION: In summary, our data support the role of Miro1 in maintaining calcium homeostasis and mitochondrial quality control in PD.
    DOI:  https://doi.org/10.1089/ars.2018.7718
  11. J Clin Invest. 2019 Jul 15. pii: 127166. [Epub ahead of print]130
    Li T, Ju E, Gao SJ.
      Cytosolic arginine sensor for mTORC1 subunits 1 and 2 (CASTOR1 and CASTOR2) inhibit the mammalian target of rapamycin complex 1 (mTORC1) upon arginine deprivation. mTORC1 regulates cell proliferation, survival, and metabolism and is often dysregulated in cancers, indicating that cancer cells may regulate CASTOR1 and CASTOR2 to control mTORC1 signaling and promote tumorigenesis. mTORC1 is the most effective therapeutic target of Kaposi sarcoma, which is caused by infection with the Kaposi sarcoma-associated herpesvirus (KSHV). Hence, KSHV-induced cellular transformation is a suitable model for investigating mTORC1 regulation in cancer cells. Currently, the mechanism of KSHV activation of mTORC1 in KSHV-induced cancers remains unclear. We showed that KSHV suppressed CASTOR1 and CASTOR2 expression to activate the mTORC1 pathway. CASTOR1 or CASTOR2 overexpression and mTOR inhibitors abolished cell proliferation and colony formation in soft agar of KSHV-transformed cells by attenuating mTORC1 activation. Furthermore, the KSHV-encoded miRNA miR-K4-5p, and probably miR-K1-5p, directly targeted CASTOR1 to inhibit its expression. Knockdown of miR-K1-5p and -K4-5p restored CASTOR1 expression and thereby attenuated mTORC1 activation. Overexpression of CASTOR1 or CASTOR2 and mTOR inhibitors abolished the activation of mTORC1 and growth transformation induced by pre-miR-K1 and -K4. Our results define the mechanism of KSHV activation of the mTORC1 pathway and establish the scientific basis for targeting this pathway to treat KSHV-associated cancers.
    Keywords:  AIDS/HIV; Kaposi’s sarcoma; Molecular biology; Tumor suppressors; Virology
    DOI:  https://doi.org/10.1172/JCI127166
  12. Clin Epigenetics. 2019 Jul 18. 11(1): 104
    Sinton MC, Hay DC, Drake AJ.
      Non-alcoholic fatty liver disease (NAFLD) is estimated to affect 24% of the global adult population. NAFLD is a major risk factor for the development of cirrhosis and hepatocellular carcinoma, as well as being strongly associated with type 2 diabetes and cardiovascular disease. It has been proposed that up to 88% of obese adults have NAFLD, and with global obesity rates increasing, this disease is set to become even more prevalent. Despite intense research in this field, the molecular processes underlying the pathology of NAFLD remain poorly understood. Hepatic intracellular lipid accumulation may lead to dysregulated tricarboxylic acid (TCA) cycle activity and associated alterations in metabolite levels. The TCA cycle metabolites alpha-ketoglutarate, succinate and fumarate are allosteric regulators of the alpha-ketoglutarate-dependent dioxygenase family of enzymes. The enzymes within this family have multiple targets, including DNA and chromatin, and thus may be capable of modulating gene transcription in response to intracellular lipid accumulation through alteration of the epigenome. In this review, we discuss what is currently understood in the field and suggest areas for future research which may lead to the development of novel preventative or therapeutic interventions for NAFLD.
    Keywords:  Alpha-ketoglutarate-dependent dioxygenases; Metabolite; Mitochondria; Non-alcoholic fatty liver disease; TCA cycle
    DOI:  https://doi.org/10.1186/s13148-019-0702-5
  13. EMBO Rep. 2019 Jul 18. e47892
    Wang T, Xu YQ, Yuan YX, Xu PW, Zhang C, Li F, Wang LN, Yin C, Zhang L, Cai XC, Zhu CJ, Xu JR, Liang BQ, Schaul S, Xie PP, Yue D, Liao ZR, Yu LL, Luo L, Zhou G, Yang JP, He ZH, Du M, Zhou YP, Deng BC, Wang SB, Gao P, Zhu XT, Xi QY, Zhang YL, Shu G, Jiang QY.
      The conversion of skeletal muscle fiber from fast twitch to slow-twitch is important for sustained and tonic contractile events, maintenance of energy homeostasis, and the alleviation of fatigue. Skeletal muscle remodeling is effectively induced by endurance or aerobic exercise, which also generates several tricarboxylic acid (TCA) cycle intermediates, including succinate. However, whether succinate regulates muscle fiber-type transitions remains unclear. Here, we found that dietary succinate supplementation increased endurance exercise ability, myosin heavy chain I expression, aerobic enzyme activity, oxygen consumption, and mitochondrial biogenesis in mouse skeletal muscle. By contrast, succinate decreased lactate dehydrogenase activity, lactate production, and myosin heavy chain IIb expression. Further, by using pharmacological or genetic loss-of-function models generated by phospholipase Cβ antagonists, SUNCR1 global knockout, or SUNCR1 gastrocnemius-specific knockdown, we found that the effects of succinate on skeletal muscle fiber-type remodeling are mediated by SUNCR1 and its downstream calcium/NFAT signaling pathway. In summary, our results demonstrate succinate induces transition of skeletal muscle fiber via SUNCR1 signaling pathway. These findings suggest the potential beneficial use of succinate-based compounds in both athletic and sedentary populations.
    Keywords:  SUNCR1; aerobic exercise; fiber type; skeletal muscle; succinate
    DOI:  https://doi.org/10.15252/embr.201947892
  14. Cell Rep. 2019 Jul 16. pii: S2211-1247(19)30830-7. [Epub ahead of print]28(3): 581-589.e4
    Imanikia S, Sheng M, Castro C, Griffin JL, Taylor RC.
      The endoplasmic reticulum unfolded protein response (UPRER) is a cellular stress response that maintains homeostasis within the secretory pathway, regulates glucose and lipid metabolism, and influences longevity. To ask whether this role in lifespan determination depends upon metabolic intermediaries, we metabotyped C. elegans expressing the active form of the UPRER transcription factor XBP-1, XBP-1s, and found many metabolic changes. These included reduced levels of triglycerides and increased levels of oleic acid (OA), a monounsaturated fatty acid associated with lifespan extension in C. elegans. Here, we show that constitutive XBP-1s expression increases the activity of lysosomal lipases and upregulates transcription of the Δ9 desaturase FAT-6, which is required for the full lifespan extension induced by XBP-1s. Dietary OA supplementation increases the lifespan of wild-type, but not xbp-1s-expressing animals and enhances proteostasis. These results suggest that modulation of lipid metabolism by XBP-1s contributes to its downstream effects on protein homeostasis and longevity.
    Keywords:  C. elegans; aging; lipids; metabolism; monounsaturated; neurons; proteostasis; signaling
    DOI:  https://doi.org/10.1016/j.celrep.2019.06.057
  15. F1000Res. 2019 ;pii: F1000 Faculty Rev-998. [Epub ahead of print]8
    Papadopoli D, Boulay K, Kazak L, Pollak M, Mallette F, Topisirovic I, Hulea L.
      The mammalian/mechanistic target of rapamycin (mTOR) is a key component of cellular metabolism that integrates nutrient sensing with cellular processes that fuel cell growth and proliferation. Although the involvement of the mTOR pathway in regulating life span and aging has been studied extensively in the last decade, the underpinning mechanisms remain elusive. In this review, we highlight the emerging insights that link mTOR to various processes related to aging, such as nutrient sensing, maintenance of proteostasis, autophagy, mitochondrial dysfunction, cellular senescence, and decline in stem cell function.
    Keywords:  aging; lifespan; mTOR; mitochondria; nutrient sensing; proteostasis; senescence; stem cell
    DOI:  https://doi.org/10.12688/f1000research.17196.1
  16. Semin Cancer Biol. 2019 Jul 15. pii: S1044-579X(19)30007-0. [Epub ahead of print]
    Long M, McWilliams TG.
      Autophagy refers to an essential mechanism that evolved to sustain eukaryotic homeostasis and metabolism during instances of nutrient deprivation. During autophagy, intracellular cargo is encapsulated and delivered to the lysosome for elimination. Loss of basal autophagy in vivo negatively impacts cellular proteostasis, metabolism and tissue integrity. Accordingly, many drug development strategies are focused on modulating autophagic capacity in various pathophysiological states, from cancer to neurodegenerative disease. The role of autophagy in cancer is particularly complicated, as either augmenting or attenuating this process can have variable outcomes on cellular survival, proliferation and transformation. This complexity is compounded by the emergence of several selective autophagy pathways, which act to eliminate damaged or superfluous cellular components in a targeted fashion. The advent of sensitive tools to monitor autophagy pathways in vivo holds promise to clarify their importance in cancer pathophysiology. In this review, we provide an overview of autophagy in cancer biology and outline how the development of tools to study autophagy in vivo could enhance our understanding of its function for translational benefit.
    Keywords:  Autophagy; cancer; metabolism; organelles; tumour
    DOI:  https://doi.org/10.1016/j.semcancer.2019.05.016
  17. Aging Cell. 2019 Jul 16. e12994
    Lee G, Uddin MJ, Kim Y, Ko M, Yu I, Ha H.
      Aging is defined as changes in an organism over time. The proportion of the aged population is markedly increasing worldwide. The kidney, as an essential organ with a high energy requirement, is one of the most susceptible organs to aging. It is involved in glucose metabolism via gluconeogenesis, glucose filtration and reabsorption, and glucose utilization. Proximal tubular epithelial cells (PTECs) depend on lipid metabolism to meet the high demand for ATP. Recent studies have shown that aging-related kidney dysfunction is highly associated with metabolic changes in the kidney. Peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α), a transcriptional coactivator, plays a major role in the regulation of mitochondrial biogenesis, peroxisomal biogenesis, and glucose and lipid metabolism. PGC-1α is abundant in tissues, including kidney PTECs, which demand high energy. Many in vitro and in vivo studies have demonstrated that the activation of PGC-1α by genetic or pharmacological intervention prevents telomere shortening and aging-related changes in the skeletal muscle, heart, and brain. The activation of PGC-1α can also prevent kidney dysfunction in various kidney diseases. Therefore, a better understanding of the effect of PGC-1α activation in various organs on aging and kidney diseases may unveil a potential therapeutic strategy against kidney aging.
    Keywords:  PGC-1α; kidney aging; lipid metabolism; mitochondria; peroxisome
    DOI:  https://doi.org/10.1111/acel.12994
  18. BMC Biol. 2019 Jul 18. 17(1): 59
    Thaker SK, Ch'ng J, Christofk HR.
      This review discusses the current state of the viral metabolism field and gaps in knowledge that will be important for future studies to investigate. We discuss metabolic rewiring caused by viruses, the influence of oncogenic viruses on host cell metabolism, and the use of viruses as guides to identify critical metabolic nodes for cancer anabolism. We also discuss the need for more mechanistic studies identifying viral proteins responsible for metabolic hijacking and for in vivo studies of viral-induced metabolic rewiring. Improved technologies for detailed metabolic measurements and genetic manipulation will lead to important discoveries over the next decade.
    DOI:  https://doi.org/10.1186/s12915-019-0678-9
  19. Commun Biol. 2019 ;2 258
    MacDonald JA, Bothun AM, Annis SN, Sheehan H, Ray S, Gao Y, Ivanov AR, Khrapko K, Tilly JL, Woods DC.
      Mitochondria are well-characterized regarding their function in both energy production and regulation of cell death; however, the heterogeneity that exists within mitochondrial populations is poorly understood. Typically analyzed as pooled samples comprised of millions of individual mitochondria, there is little information regarding potentially different functionality across subpopulations of mitochondria. Herein we present a new methodology to analyze mitochondria as individual components of a complex and heterogeneous network, using a nanoscale and multi-parametric flow cytometry-based platform. We validate the platform using multiple downstream assays, including electron microscopy, ATP generation, quantitative mass-spectrometry proteomic profiling, and mtDNA analysis at the level of single organelles. These strategies allow robust analysis and isolation of mitochondrial subpopulations to more broadly elucidate the underlying complexities of mitochondria as these organelles function collectively within a cell.
    Keywords:  Biological techniques; Cell biology; Mitochondria
    DOI:  https://doi.org/10.1038/s42003-019-0513-4
  20. J Biol Chem. 2019 Jul 18. pii: jbc.RA118.006756. [Epub ahead of print]
    Dall M, Trammell SAJ, Asping M, Hassing AS, Agerholm M, Vienberg SG, Gillum MP, Larsen S, Treebak JT.
      Supplementation with nicotinamide adenine dinucleotide (NAD+) precursors such as nicotinamide riboside (NR) has been shown to enhance mitochondrial function in the liver and prevent hepatic lipid accumulation in high-fat diet (HFD)-fed rodents. Hepatocyte-specific knockout of the NAD+-synthesizing enzyme nicotinamide phosphoribosyltransferase (NAMPT) reduces liver NAD+ levels, but the metabolic phenotype of Nampt-deficient hepatocytes in mice is unknown. Here, we assessed Nampt's role in maintaining mitochondrial and metabolic functions in the mouse liver. Using the Cre-LoxP system, we generated hepatocyte-specific Nampt knockout (HNKO) mice, having a 50% reduction of liver NAD+ levels. We screened the HNKO mice for signs of metabolic dysfunction following 60% HFD feeding for 20 weeks +/- NR supplementation and found that NR increases hepatic NAD+ levels without affecting fat mass or glucose tolerance in HNKO or WT animals. High-resolution respirometry revealed that NR supplementation of the HNKO mice did not increase state III respiration, which was observed in WT mice following NR supplementation.  Mitochondrial oxygen consumption and fatty-acid oxidation was unaltered in primary HNKO hepatocytes. Mitochondria isolated from whole HNKO livers had only a 20% reduction in NAD+, suggesting that the mitochondrial NAD+ pool is less affected by HNKO than the whole-tissue pool. When stimulated with tryptophan in the presence of 15N-glutamine, HNKO hepatocytes had a higher 15N-NAD+ enrichment than WT hepatocytes, indicating that HNKO mice compensate through de novo NAD+ synthesis. We conclude that NAMPT-deficient hepatocytes can maintain substantial NAD+ levels and that the Nampt knockout has only minor consequences for mitochondrial function in the mouse liver.
    Keywords:  NAD biosynthesis; NAMPT; fatty acid metabolism; hepatocyte; mitochondrial metabolism; nicotinamide adenine dinucleotide (NAD); respiration; tryptophan metabolism
    DOI:  https://doi.org/10.1074/jbc.RA118.006756
  21. EMBO J. 2019 Jul 15. e100871
    Zhang X, Gibhardt CS, Will T, Stanisz H, Körbel C, Mitkovski M, Stejerean I, Cappello S, Pacheu-Grau D, Dudek J, Tahbaz N, Mina L, Simmen T, Laschke MW, Menger MD, Schön MP, Helms V, Niemeyer BA, Rehling P, Vultur A, Bogeski I.
      Reactive oxygen species (ROS) are emerging as important regulators of cancer growth and metastatic spread. However, how cells integrate redox signals to affect cancer progression is not fully understood. Mitochondria are cellular redox hubs, which are highly regulated by interactions with neighboring organelles. Here, we investigated how ROS at the endoplasmic reticulum (ER)-mitochondria interface are generated and translated to affect melanoma outcome. We show that TMX1 and TMX3 oxidoreductases, which promote ER-mitochondria communication, are upregulated in melanoma cells and patient samples. TMX knockdown altered mitochondrial organization, enhanced bioenergetics, and elevated mitochondrial- and NOX4-derived ROS. The TMX-knockdown-induced oxidative stress suppressed melanoma proliferation, migration, and xenograft tumor growth by inhibiting NFAT1. Furthermore, we identified NFAT1-positive and NFAT1-negative melanoma subgroups, wherein NFAT1 expression correlates with melanoma stage and metastatic potential. Integrative bioinformatics revealed that genes coding for mitochondrial- and redox-related proteins are under NFAT1 control and indicated that TMX1, TMX3, and NFAT1 are associated with poor disease outcome. Our study unravels a novel redox-controlled ER-mitochondria-NFAT1 signaling loop that regulates melanoma pathobiology and provides biomarkers indicative of aggressive disease.
    Keywords:  calcium; contact site; melanoma; mitochondria; redox
    DOI:  https://doi.org/10.15252/embj.2018100871
  22. Oncogene. 2019 Jul 15.
    Arnold JM, Gu F, Ambati CR, Rasaily U, Ramirez-Pena E, Joseph R, Manikkam M, San Martin R, Charles C, Pan Y, Chatterjee SS, Den Hollander P, Nagi C, Sikora AG, Rowley D, Putluri N, Karanam B, Mani SA, Sreekumar A.
      An improved understanding of the biochemical alterations that accompany tumor progression and metastasis is necessary to inform the next generation of diagnostic tools and targeted therapies. Metabolic reprogramming is known to occur during the epithelial-mesenchymal transition (EMT), a process that promotes metastasis. Here, we identify metabolic enzymes involved in extracellular matrix remodeling that are upregulated during EMT and are highly expressed in patients with aggressive mesenchymal-like breast cancer. Activation of EMT significantly increases production of hyaluronic acid, which is enabled by the reprogramming of glucose metabolism. Using genetic and pharmacological approaches, we show that depletion of the hyaluronic acid precursor UDP-glucuronic acid is sufficient to inhibit several mesenchymal-like properties including cellular invasion and colony formation in vitro, as well as tumor growth and metastasis in vivo. We found that depletion of UDP-glucuronic acid altered the expression of PPAR-gamma target genes and increased PPAR-gamma DNA-binding activity. Taken together, our findings indicate that the disruption of EMT-induced metabolic reprogramming affects hyaluronic acid production, as well as associated extracellular matrix remodeling and represents pharmacologically actionable target for the inhibition of aggressive mesenchymal-like breast cancer progression.
    DOI:  https://doi.org/10.1038/s41388-019-0885-4
  23. Proc Natl Acad Sci U S A. 2019 Jul 18. pii: 201906606. [Epub ahead of print]
    Wang H, Fedorov AA, Fedorov EV, Hunt DM, Rodgers A, Douglas HL, Garza-Garcia A, Bonanno JB, Almo SC, de Carvalho LPS.
      Mycobacterium tuberculosis (Mtb) is the etiological agent of tuberculosis. One-fourth of the global population is estimated to be infected with Mtb, accounting for ∼1.3 million deaths in 2017. As part of the immune response to Mtb infection, macrophages produce metabolites with the purpose of inhibiting or killing the bacterial cell. Itaconate is an abundant host metabolite thought to be both an antimicrobial agent and a modulator of the host inflammatory response. However, the exact mode of action of itaconate remains unclear. Here, we show that Mtb has an itaconate dissimilation pathway and that the last enzyme in this pathway, Rv2498c, also participates in l-leucine catabolism. Our results from phylogenetic analysis, in vitro enzymatic assays, X-ray crystallography, and in vivo Mtb experiments, identified Mtb Rv2498c as a bifunctional β-hydroxyacyl-CoA lyase and that deletion of the rv2498c gene from the Mtb genome resulted in attenuation in a mouse infection model. Altogether, this report describes an itaconate resistance mechanism in Mtb and an l-leucine catabolic pathway that proceeds via an unprecedented (R)-3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) stereospecific route in nature.
    Keywords:  Mycobacterium tuberculosis; carbon–carbon bond lyase; enzyme function; itaconate catabolism; leucine catabolism
    DOI:  https://doi.org/10.1073/pnas.1906606116
  24. Proc Natl Acad Sci U S A. 2019 Jul 16. pii: 201904523. [Epub ahead of print]
    Srivastava R, Cao Z, Nedeva C, Naim S, Bachmann D, Rabachini T, Gangoda L, Shahi S, Glab J, Menassa J, Osellame L, Nelson T, Fernandez-Marrero Y, Brown F, Wei A, Ke F, O'Reilly L, Doerflinger M, Allison C, Kueh A, Ramsay R, Smith BJ, Mathivanan S, Kaufmann T, Puthalakath H.
      BCL-2 family proteins regulate the mitochondrial apoptotic pathway. BOK, a multidomain BCL-2 family protein, is generally believed to be an adaptor protein similar to BAK and BAX, regulating the mitochondrial permeability transition during apoptosis. Here we report that BOK is a positive regulator of a key enzyme involved in uridine biosynthesis; namely, uridine monophosphate synthetase (UMPS). Our data suggest that BOK expression enhances UMPS activity, cell proliferation, and chemosensitivity. Genetic deletion of Bok results in chemoresistance to 5-fluorouracil (5-FU) in different cell lines and in mice. Conversely, cancer cells and primary tissues that acquire resistance to 5-FU down-regulate BOK expression. Furthermore, we also provide evidence for a role for BOK in nucleotide metabolism and cell cycle regulation. Our results have implications in developing BOK as a biomarker for 5-FU resistance and have the potential for the development of BOK-mimetics for sensitizing 5-FU-resistant cancers.
    Keywords:  Bok; UMPS; apoptosis; chemoresistance; metabolism
    DOI:  https://doi.org/10.1073/pnas.1904523116
  25. Curr Pharm Des. 2019 Jul 18.
    Kalvala AK, Khan I, Gundu C, Kumar A.
      Mitochondria are the central power stations of the cell involved with a myriad of cell signalling pathways that contributes for whole health status of the cell. It is well known fact not only mitochondrial genome encodes for mitochondrial proteins but also there are several mitochondrial specific proteins encoded by nuclear genome which regulates plethora of cell catabolic and anabolic process. Anterograde pathways includes nuclear gene encoded proteins and their specific transport into the mitochondria and regulation of mitochondrial homeostasis. The retrograde pathways include crosstalk between the mitochondria and cytoplasmic proteins. Indeed, ATP dependent and independent proteases are identified to be very critical in balancing anterograde to retrograde signalling and vice versa to maintain the cell viability or cell death. Different experimental studies conducted on silencing the genes of these proteases shown embryonic lethality, cancer cells death, increased hepatic glucose output, insulin tolerance, increased protein exclusion bodies, mitochondrial dysfunction, and defect in mitochondrial biogenesis, increased inflammation, Apoptosis etc. These experimental studies included from eubacteria to eukaryotes. Hence, many lines of theories proposed these proteases are conservative from eubacteria to eukaryotes. However, the regulation of these proteases at gene level is not clearly understood and still research is warranted. In this review, we articulated origin and regulation of these proteases and cross talk between the nucleus and mitochondria vice versa, and highlighted the role of these proteases in diabetes and diabetic complications and in human diseases.
    Keywords:  ATP dependent and Independent proteases; Diabetes; Mitochondrial dysfunction
    DOI:  https://doi.org/10.2174/1381612825666190718153901
  26. Elife. 2019 Jul 15. pii: e45873. [Epub ahead of print]8
    Sharma A, Oonthonpan L, Sheldon RD, Rauckhorst AJ, Zhu Z, Tompkins SC, Cho K, Grzesik WJ, Gray LR, Scerbo DA, Pewa AD, Cushing EM, Dyle MC, Cox JE, Adams C, Davies BS, Shields RK, Norris AW, Patti G, Zingman LV, Taylor EB.
      Metabolic cycles are a fundamental element of cellular and organismal function. Among the most critical in higher organisms is the Cori Cycle, the systemic cycling between lactate and glucose. Here, skeletal muscle-specific Mitochondrial Pyruvate Carrier (MPC) deletion in mice diverted pyruvate into circulating lactate. This switch disinhibited muscle fatty acid oxidation and drove Cori Cycling that contributed to increased energy expenditure. Loss of muscle MPC activity led to strikingly decreased adiposity with complete muscle mass and strength retention. Notably, despite decreasing muscle glucose oxidation, muscle MPC disruption increased muscle glucose uptake and whole-body insulin sensitivity. Furthermore, chronic and acute muscle MPC deletion accelerated fat mass loss on a normal diet after high fat diet-induced obesity. Our results illuminate the role of the skeletal muscle MPC as a whole-body carbon flux control point. They highlight the potential utility of decreasing muscle pyruvate utilization to ameliorate obesity and type 2 diabetes.
    Keywords:  cell biology; human biology; medicine; mouse
    DOI:  https://doi.org/10.7554/eLife.45873
  27. Trends Immunol. 2019 Jul 10. pii: S1471-4906(19)30127-9. [Epub ahead of print]
    Giovanelli P, Sandoval TA, Cubillos-Ruiz JR.
      Dendritic cells (DCs) are fundamental for the initiation and maintenance of immune responses against malignant cells. Despite the unique potential of DCs to elicit robust anticancer immunity, the tumor microenvironment poses a variety of challenges that hinder competent DC function and consequently inhibit the development of protective immune responses. Here, we discuss recent studies uncovering new molecular pathways and metabolic programs that tumors manipulate in DCs to disturb their homeostasis and evade immune control. We also examine certain state-of-the-art strategies that seek to improve DC function and elicit antitumor responses in hosts with cancer. Understanding and modulating DC metabolism and activity within tumors might help improve the efficacy of T cell-centric immunotherapies.
    Keywords:  cancer; dendritic cells; immunosuppression; immunotherapy; metabolism; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.it.2019.06.004
  28. EMBO Mol Med. 2019 Jul 17. e10968
    Kaur A, Gardiner EE.
      Autophagy, the process by which damaged or potentially cytotoxic cytosolic components are removed and destroyed by lysosomes, occurs to varying extents in all cells. Mitophagy describes an autophagic response that specifically targets damaged cytotoxic mitochondria for removal. This aggressive defense-first policy ("parking the bus" in footballing terms) serves to protect the intracellular environment from cytotoxic mitochondrial components and maintain intracellular homeostasis. While mitophagy pathways have been extensively studied (Harper et al, 2018), precisely how the selective removal of a damaged mitochondrion is achieved in healthy cells, as well as in cells exposed to high oxidative stress conditions, remains unclear. Work from Lee and colleagues (Lee et al, 2019) has evaluated the molecular basis of mitophagy in platelets and has outlined some new molecular events that help control this process.
    DOI:  https://doi.org/10.15252/emmm.201910968
  29. Nature. 2019 Jul 17.
    Matheoud D, Cannon T, Voisin A, Penttinen AM, Ramet L, Fahmy AM, Ducrot C, Laplante A, Bourque MJ, Zhu L, Cayrol R, Le Campion A, McBride HM, Gruenheid S, Trudeau LE, Desjardins M.
      Parkinson's disease is a neurodegenerative disorder with motor symptoms linked to the loss of dopaminergic neurons in the substantia nigra compacta. Although the mechanisms that trigger the loss of dopaminergic neurons are unclear, mitochondrial dysfunction and inflammation are thought to have key roles1,2. An early-onset form of Parkinson's disease is associated with mutations in the PINK1 kinase and PRKN ubiquitin ligase genes3. PINK1 and Parkin (encoded by PRKN) are involved in the clearance of damaged mitochondria in cultured cells4, but recent evidence obtained using knockout and knockin mouse models have led to contradictory results regarding the contributions of PINK1 and Parkin to mitophagy in vivo5-8. It has previously been shown that PINK1 and Parkin have a key role in adaptive immunity by repressing presentation of mitochondrial antigens9, which suggests that autoimmune mechanisms participate in the aetiology of Parkinson's disease. Here we show that intestinal infection with Gram-negative bacteria in Pink1-/- mice engages mitochondrial antigen presentation and autoimmune mechanisms that elicit the establishment of cytotoxic mitochondria-specific CD8+ T cells in the periphery and in the brain. Notably, these mice show a sharp decrease in the density of dopaminergic axonal varicosities in the striatum and are affected by motor impairment that is reversed after treatment with L-DOPA. These data support the idea that PINK1 is a repressor of the immune system, and provide a pathophysiological model in which intestinal infection acts as a triggering event in Parkinson's disease, which highlights the relevance of the gut-brain axis in the disease10.
    DOI:  https://doi.org/10.1038/s41586-019-1405-y
  30. Trends Cancer. 2019 Jul;pii: S2405-8033(19)30101-3. [Epub ahead of print]5(7): 411-425
    Smith EA, Hodges HC.
      Many malignancies display heterogeneous features that support cancer progression. Emerging high-resolution methods provide a view of heterogeneity that recognizes the influence of diverse cell types and cell states of the tumor microenvironment. Here we outline a hierarchical organization of tumor heterogeneity from a genomic perspective, summarize the origins of spatially patterned metabolic features, and review recent developments in single-cell and spatially resolved techniques for genome-wide study of multicellular tissues. We also discuss how integrating these approaches can yield new insights into human cancer and emerging immune therapies. Applying these technologies for the analysis of primary tumors, patient-derived xenografts, and in vitro systems holds great promise for understanding the hierarchical structure and environmental influences that underlie tumor ecosystems.
    Keywords:  epigenetics; genomics; hypoxia; in situ; metabolism; stroma
    DOI:  https://doi.org/10.1016/j.trecan.2019.05.009
  31. Cell Chem Biol. 2019 Jul 02. pii: S2451-9456(19)30206-5. [Epub ahead of print]
    Reckzeh ES, Karageorgis G, Schwalfenberg M, Ceballos J, Nowacki J, Stroet MCM, Binici A, Knauer L, Brand S, Choidas A, Strohmann C, Ziegler S, Waldmann H.
      Cancer cells sustain growth by altering their metabolism to accelerated aerobic glycolysis accompanied by increased glucose demand and employ glutamine as additional nutrient source. This metabolic adaptation induces upregulation of glucose transporters GLUT-1 and -3, and simultaneous targeting of both transporters and of glutamine metabolism may offer a promising approach to inhibit cancer cell growth. We describe the discovery of the very potent glucose uptake inhibitor Glutor, which targets glucose transporters GLUT-1, -2, and -3, attenuates glycolytic flux and potently and selectively suppresses growth of a variety of cancer cell lines. Co-treatment of colon cancer cells with Glutor and glutaminase inhibitor CB-839 very potently and synergistically inhibits cancer cell growth. Such a dual inhibition promises to be particularly effective because it targets the metabolic plasticity as well as metabolic rescue mechanisms in cancer cells.
    Keywords:  GLUT-1; GLUT-3; Warburg effect; co-treatment; glutaminase; metabolic plasticity; small molecule
    DOI:  https://doi.org/10.1016/j.chembiol.2019.06.005
  32. Nat Commun. 2019 Jul 18. 10(1): 3187
    Castets P, Rion N, Théodore M, Falcetta D, Lin S, Reischl M, Wild F, Guérard L, Eickhorst C, Brockhoff M, Guridi M, Ibebunjo C, Cruz J, Sinnreich M, Rudolf R, Glass DJ, Rüegg MA.
      Loss of innervation of skeletal muscle is a determinant event in several muscle diseases. Although several effectors have been identified, the pathways controlling the integrated muscle response to denervation remain largely unknown. Here, we demonstrate that PKB/Akt and mTORC1 play important roles in regulating muscle homeostasis and maintaining neuromuscular endplates after nerve injury. To allow dynamic changes in autophagy, mTORC1 activation must be tightly balanced following denervation. Acutely activating or inhibiting mTORC1 impairs autophagy regulation and alters homeostasis in denervated muscle. Importantly, PKB/Akt inhibition, conferred by sustained mTORC1 activation, abrogates denervation-induced synaptic remodeling and causes neuromuscular endplate degeneration. We establish that PKB/Akt activation promotes the nuclear import of HDAC4 and is thereby required for epigenetic changes and synaptic gene up-regulation upon denervation. Hence, our study unveils yet-unknown functions of PKB/Akt-mTORC1 signaling in the muscle response to nerve injury, with important implications for neuromuscular integrity in various pathological conditions.
    DOI:  https://doi.org/10.1038/s41467-019-11227-4
  33. Cell Death Differ. 2019 Jul 18.
    Chen PH, Wu J, Ding CC, Lin CC, Pan S, Bossa N, Xu Y, Yang WH, Mathey-Prevot B, Chi JT.
      Ferroptosis is a specialized iron-dependent cell death that is associated with lethal lipid peroxidation. Modulation of ferroptosis may have therapeutic potential since it has been implicated in various human diseases as well as potential antitumor activities. However, much remains unknown about the underlying mechanisms and genetic determinants of ferroptosis. Given the critical role of kinases in most biological processes and the availability of various kinase inhibitors, we sought to systemically identify kinases essential for ferroptosis. We performed a forward genetic-based kinome screen against ferroptosis in MDA-MB-231 cells triggered by cystine deprivation. This screen identified 34 essential kinases involved in TNFα and NF-kB signaling. Unexpectedly, the DNA damage response serine/threonine kinase ATM (mutated in Ataxia-Telangiectasia) was found to be essential for ferroptosis. The pharmacological or genetic inhibition of ATM consistently rescued multiple cancer cells from ferroptosis triggered by cystine deprivation or erastin. Instead of the canonical DNA damage pathways, ATM inhibition rescued ferroptosis by increasing the expression of iron regulators involved in iron storage (ferritin heavy and light chain, FTH1 and FTL) and export (ferroportin, FPN1). The coordinated changes of these iron regulators during ATM inhibition resulted in a lowering of labile iron and prevented the iron-dependent ferroptosis. Furthermore, we found that ATM inhibition enhanced the nuclear translocation of metal-regulatory transcription factor 1 (MTF1), responsible for regulating expression of Ferritin/FPN1 and ferroptosis protection. Genetic depletion of MTF-1 abolished the regulation of iron-regulatory elements by ATM and resensitized the cells to ferroptosis. Together, we have identified an unexpected ATM-MTF1-Ferritin/FPN1 regulatory axis as novel determinants of ferroptosis through regulating labile iron levels.
    DOI:  https://doi.org/10.1038/s41418-019-0393-7
  34. Cell Rep. 2019 Jul 16. pii: S2211-1247(19)30820-4. [Epub ahead of print]28(3): 746-758.e4
    Suzuki T, Muramatsu A, Saito R, Iso T, Shibata T, Kuwata K, Kawaguchi SI, Iwawaki T, Adachi S, Suda H, Morita M, Uchida K, Baird L, Yamamoto M.
      The Keap1-Nrf2 system plays a central role in the oxidative stress response; however, the identity of the reactive oxygen species sensor within Keap1 remains poorly understood. Here, we show that a Keap1 mutant lacking 11 cysteine residues retains the ability to target Nrf2 for degradation, but it is unable to respond to cysteine-reactive Nrf2 inducers. Of the 11 mutated cysteine residues, we find that 4 (Cys226/613/622/624) are important for sensing hydrogen peroxide. Our analyses of multiple mutant mice lines, complemented by MEFs expressing a series of Keap1 mutants, reveal that Keap1 uses the cysteine residues redundantly to set up an elaborate fail-safe mechanism in which specific combinations of these four cysteine residues can form a disulfide bond to sense hydrogen peroxide. This sensing mechanism is distinct from that used for electrophilic Nrf2 inducers, demonstrating that Keap1 is equipped with multiple cysteine-based sensors to detect various endogenous and exogenous stresses.
    Keywords:  Keap1; Nrf2; oxidative stress response; reactive cysteine residues
    DOI:  https://doi.org/10.1016/j.celrep.2019.06.047
  35. Autophagy. 2019 Jul 18.
    Pastore N, Ballabio A.
      Most essential physiological functions in mammals show a 24-h rhythmic pattern, which includes sleep-wake, feeding-non-feeding cycles and energy metabolism. Recent studies indicate that macroautophagy/autophagy also displays a robust circadian rhythmicity following the daily feeding pattern in adult mammals. We discovered that MiT-TFE transcription factors TFEB and TFE3, master regulators of autophagy and lysosomal biogenesis, are activated in a circadian manner and drive the expression of NR1D1/REV-ERBα, a key component of the core clockwork, thus revealing a molecular link between the nutrient-driven circadian cycle and the light-induced molecular clock. The dynamic balance between TFEB and TFE3 activation and NR1D1 expression is responsible for the modulation and oscillation of autophagy and metabolism genes.
    Keywords:  Autophagy; NR1D1/REV-ERBα; TFEB/TFE3; circadian rhythm; gene oscillation
    DOI:  https://doi.org/10.1080/15548627.2019.1645545
  36. Trends Cancer. 2019 Jul;pii: S2405-8033(19)30079-2. [Epub ahead of print]5(7): 396-399
    Dauer P, Lengyel E.
      Glycogen is a high-density glucose polymer, which provides organisms with an immediate source of glucose to support the cell's energy requirements. Epithelial cells primarily store energy as glycogen, but until recently it has not been reported as a major fuel source for cancer growth. Hypoxia, which occurs in many cancers, results in glycogen synthesis and increased survival under stressed conditions. Recently, glycogen mobilization has been shown to play a role in the maturation and immune activity of dendritic cells (DCs) and in the proliferation and metastatic efficiency of cancer cells aided by the tumor microenvironment (TME). These studies indicate that glycogen plays an important role in glucose homeostasis and contributes to key functions related to tumor aggressiveness and the survival of cancer cells.
    Keywords:  breast cancer; glycogen; metabolism; ovarian cancer
    DOI:  https://doi.org/10.1016/j.trecan.2019.05.003
  37. Aging (Albany NY). 2019 Jul 13.
    Neuzil J, Berridge MV.
      
    Keywords:  cancer; de novo pyrimidine synthesis; mitochondrial DNA; mitochondrial transfer; respiration
    DOI:  https://doi.org/10.18632/aging.102103