bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2020‒10‒25
forty-three papers selected by
Christian Frezza
University of Cambridge, MRC Cancer Unit

  1. Trends Cell Biol. 2020 Oct 19. pii: S0962-8924(20)30190-2. [Epub ahead of print]
    Baksh SC, Finley LWS.
      Cell fate determination requires faithful execution of gene expression programs, which are increasingly recognized to respond to metabolic inputs. In particular, the family of α-ketoglutarate (αKG)-dependent dioxygenases, which include several chromatin-modifying enzymes, are emerging as key mediators of metabolic control of cell fate. αKG-dependent dioxygenases consume the metabolite αKG (also known as 2-oxoglutarate) as an obligate cosubstrate and are inhibited by succinate, fumarate, and 2-hydroxyglutarate. Here, we review the role of these metabolites in the control of dioxygenase activity and cell fate programs. We discuss the biochemical and transcriptional mechanisms enabling these metabolites to control cell fate and review evidence that nutrient availability shapes tissue-specific fate programs via αKG-dependent dioxygenases.
    Keywords:  2-hydroxyglutarate; alpha-ketoglutarate; cell fate; chromatin modifications; succinate; αKG-dependent dioxygenases
  2. Nat Cell Biol. 2020 Oct 19.
    Saliakoura M, Rossi Sebastiano M, Pozzato C, Heidel FH, Schnöder TM, Savic Prince S, Bubendorf L, Pinton P, A Schmid R, Baumgartner J, Freigang S, Berezowska SA, Rimessi A, Konstantinidou G.
      Mutant KRAS modulates the metabolic plasticity of cancer cells to confer a growth advantage during hypoxia, but the molecular underpinnings are largely unknown. Using a lipidomic screen, we found that PLCγ1 is suppressed during hypoxia in KRAS-mutant human lung adenocarcinoma cancer cell lines. Suppression of PLCγ1 in hypoxia promotes a less oxidative cancer cell metabolism state, reduces the formation of mitochondrial reactive oxygen species and switches tumour bioenergetics towards glycolysis by impairing Ca2+ entry into the mitochondria. This event prevents lipid peroxidation, antagonizes apoptosis and increases cancer cell proliferation. Accordingly, loss of function of Plcg1 in a mouse model of KrasG12D-driven lung adenocarcinoma increased the expression of glycolytic genes, boosted tumour growth and reduced survival. In patients with KRAS-mutant lung adenocarcinomas, low PLCγ1 expression correlates with increased expression of hypoxia markers and predicts poor patient survival. Thus, our work reveals a mechanism of cancer cell adaptation to hypoxia with potential therapeutic value.
  3. Nat Metab. 2020 Oct 19.
    Koch LM, Birkeland ES, Battaglioni S, Helle X, Meerang M, Hiltbrunner S, Ibáñez AJ, Peter M, Curioni-Fontecedro A, Opitz I, Dechant R.
      Enhanced growth and proliferation of cancer cells are accompanied by profound changes in cellular metabolism. These metabolic changes are also common under physiological conditions, and include increased glucose fermentation accompanied by elevated cytosolic pH (pHc)1,2. However, how these changes contribute to enhanced cell growth and proliferation is unclear. Here, we show that elevated pHc specifically orchestrates an E2F-dependent transcriptional programme to drive cell proliferation by promoting cyclin D1 expression. pHc-dependent transcription of cyclin D1 requires the transcription factors CREB1, ATF1 and ETS1, and the histone acetyltransferases p300 and CBP. Biochemical characterization revealed that the CREB1-p300/CBP interaction acts as a pH sensor and coincidence detector, integrating different mitotic signals to regulate cyclin D1 transcription. We also show that elevated pHc contributes to increased cyclin D1 expression in malignant pleural mesotheliomas (MPMs), and renders these cells hypersensitive to pharmacological reduction of pHc. Taken together, these data demonstrate that elevated pHc is a critical cellular signal regulating G1 progression, and provide a mechanism linking elevated pHc to oncogenic activation of cyclin D1 in MPMs, and possibly other cyclin D1~dependent tumours. Thus, an increase of pHc may represent a functionally important, early event in the aetiology of cancer that is amenable to therapeutic intervention.
  4. Nat Cancer. 2020 Oct;1(10): 976-989
    Smith AL, Whitehall JC, Bradshaw C, Gay D, Robertson F, Blain AP, Hudson G, Pyle A, Houghton D, Hunt M, Sampson JN, Stamp C, Mallett G, Amarnath S, Leslie J, Oakley F, Wilson L, Baker A, Russell OM, Johnson R, Richardson CA, Gupta B, McCallum I, McDonald SA, Kelly S, Mathers JC, Heer R, Taylor RW, Perkins ND, Turnbull DM, Sansom OJ, Greaves LC.
      Oxidative phosphorylation (OXPHOS) defects caused by somatic mitochondrial DNA (mtDNA) mutations increase with age in human colorectal epithelium and are prevalent in colorectal tumours, but whether they actively contribute to tumorigenesis remains unknown. Here we demonstrate that mtDNA mutations causing OXPHOS defects are enriched during the human adenoma/carcinoma sequence, suggesting they may confer a metabolic advantage. To test this we deleted the tumour suppressor Apc in OXPHOS deficient intestinal stem cells in mice. The resulting tumours were larger than in control mice due to accelerated cell proliferation and reduced apoptosis. We show that both normal crypts and tumours undergo metabolic remodelling in response to OXPHOS deficiency by upregulating the de novo serine synthesis pathway (SSP). Moreover, normal human colonic crypts upregulate the SSP in response to OXPHOS deficiency prior to tumorigenesis. Our data show that age-associated OXPHOS deficiency causes metabolic remodelling that can functionally contribute to accelerated intestinal cancer development.
  5. Commun Biol. 2020 Oct 21. 3(1): 596
    Lobo MJ, Reverte-Salisa L, Chao YC, Koschinski A, Gesellchen F, Subramaniam G, Jiang H, Pace S, Larcom N, Paolocci E, Pfeifer A, Zanivan S, Zaccolo M.
      Programmed degradation of mitochondria by mitophagy, an essential process to maintain mitochondrial homeostasis, is not completely understood. Here we uncover a regulatory process that controls mitophagy and involves the cAMP-degrading enzyme phosphodiesterase 2A2 (PDE2A2). We find that PDE2A2 is part of a mitochondrial signalosome at the mitochondrial inner membrane where it interacts with the mitochondrial contact site and organizing system (MICOS). As part of this compartmentalised signalling system PDE2A2 regulates PKA-mediated phosphorylation of the MICOS component MIC60, resulting in modulation of Parkin recruitment to the mitochondria and mitophagy. Inhibition of PDE2A2 is sufficient to regulate mitophagy in the absence of other triggers, highlighting the physiological relevance of PDE2A2 in this process. Pharmacological inhibition of PDE2 promotes a 'fat-burning' phenotype to retain thermogenic beige adipocytes, indicating that PDE2A2 may serve as a novel target with potential for developing therapies for metabolic disorders.
  6. Cell Calcium. 2020 Oct 16. pii: S0143-4160(20)30150-0. [Epub ahead of print]92 102308
    Genovese I, Vezzani B, Danese A, Modesti L, Vitto VAM, Corazzi V, Pelucchi S, Pinton P, Giorgi C.
      As pivotal players in cellular metabolism, mitochondria have a double-faceted role in the final decision of cell fate. This is true for all cell types, but it is even more important and intriguing in the cancer setting. Mitochondria regulate cell fate in many diverse ways: through metabolism, by producing ATP and other metabolites deemed vital or detrimental for cancer cells; through the regulation of Ca2+ homeostasis, especially by the joint participation of the endoplasmic reticulum in a membranous tethering system for Ca2+ signaling called mitochondria-ER associated membranes (MAMs); and by regulating signaling pathways involved in the survival of cancer cells such as mitophagy. Recent studies have shown that mitochondria can also play a role in the regulation of inflammatory pathways in cancer cells, for example, through the release of mitochondrial DNA (mtDNA) involved in the activation of the cGAS-cGAMP-STING pathway. In this review, we aim to explore the role of mitochondria as decision makers in fostering cancer cell death or survival depending on the tumor cell stage and describe novel anticancer therapeutic strategies targeting mitochondria.
    Keywords:  Ca(2+) signaling; Mitochondria; bioenergetics; cGAS-cGAMP-STING pathway; cancer; mitophagy
  7. Sci Adv. 2020 Oct;pii: eabe5310. [Epub ahead of print]6(43):
    Kory N, Uit de Bos J, van der Rijt S, Jankovic N, Güra M, Arp N, Pena IA, Prakash G, Chan SH, Kunchok T, Lewis CA, Sabatini DM.
      The nicotinamide adenine dinucleotide (NAD+/NADH) pair is a cofactor in redox reactions and is particularly critical in mitochondria as it connects substrate oxidation by the tricarboxylic acid (TCA) cycle to adenosine triphosphate generation by the electron transport chain (ETC) and oxidative phosphorylation. While a mitochondrial NAD+ transporter has been identified in yeast, how NAD enters mitochondria in metazoans is unknown. Here, we mine gene essentiality data from human cell lines to identify MCART1 (SLC25A51) as coessential with ETC components. MCART1-null cells have large decreases in TCA cycle flux, mitochondrial respiration, ETC complex I activity, and mitochondrial levels of NAD+ and NADH. Isolated mitochondria from cells lacking or overexpressing MCART1 have greatly decreased or increased NAD uptake in vitro, respectively. Moreover, MCART1 and NDT1, a yeast mitochondrial NAD+ transporter, can functionally complement for each other. Thus, we propose that MCART1 is the long sought mitochondrial transporter for NAD in human cells.
  8. Cell Death Discov. 2020 ;6 104
    Burke L, Guterman I, Palacios Gallego R, Britton RG, Burschowsky D, Tufarelli C, Rufini A.
      The metabolism of the non-essential amino acid L-proline is emerging as a key pathway in the metabolic rewiring that sustains cancer cells proliferation, survival and metastatic spread. Pyrroline-5-carboxylate reductase (PYCR) and proline dehydrogenase (PRODH) enzymes, which catalyze the last step in proline biosynthesis and the first step of its catabolism, respectively, have been extensively associated with the progression of several malignancies, and have been exposed as potential targets for anticancer drug development. As investigations into the links between proline metabolism and cancer accumulate, the complexity, and sometimes contradictory nature of this interaction emerge. It is clear that the role of proline metabolism enzymes in cancer depends on tumor type, with different cancers and cancer-related phenotypes displaying different dependencies on these enzymes. Unexpectedly, the outcome of rewiring proline metabolism also differs between conditions of nutrient and oxygen limitation. Here, we provide a comprehensive review of proline metabolism in cancer; we collate the experimental evidence that links proline metabolism with the different aspects of cancer progression and critically discuss the potential mechanisms involved.
    Keywords:  Cancer; Cancer metabolism
  9. Nat Rev Cancer. 2020 Oct 21.
    Losman JA, Koivunen P, Kaelin WG.
      2-Oxoglutarate-dependent dioxygenases (2OGDDs) are a superfamily of enzymes that play diverse roles in many biological processes, including regulation of hypoxia-inducible factor-mediated adaptation to hypoxia, extracellular matrix formation, epigenetic regulation of gene transcription and the reprogramming of cellular metabolism. 2OGDDs all require oxygen, reduced iron and 2-oxoglutarate (also known as α-ketoglutarate) to function, although their affinities for each of these co-substrates, and hence their sensitivity to depletion of specific co-substrates, varies widely. Numerous 2OGDDs are recurrently dysregulated in cancer. Moreover, cancer-specific metabolic changes, such as those that occur subsequent to mutations in the genes encoding succinate dehydrogenase, fumarate hydratase or isocitrate dehydrogenase, can dysregulate specific 2OGDDs. This latter observation suggests that the role of 2OGDDs in cancer extends beyond cancers that harbour mutations in the genes encoding members of the 2OGDD superfamily. Herein, we review the regulation of 2OGDDs in normal cells and how that regulation is corrupted in cancer.
  10. Neuropathol Appl Neurobiol. 2020 Oct 20.
    Braun Y, Filipski K, Bernatz S, Baumgarten P, Roller B, Zinke J, Zeiner PS, Ilina E, Senft C, Ronellenfitsch MW, Plate KH, Bähr O, Hattingen E, Steinbach JP, Mittelbronn M, Harter PN.
      AIMS: Changes in metabolism are known to contribute to tumour phenotypes. If and how metabolic alterations in brain tumours contribute to patient outcome is still poorly understood. Epigenetics impact metabolism and mitochondrial function. The aim of this study is a characterization of metabolic features in molecular subgroups of isocitrate dehydrogenase mutant (IDHmut) and isocitrate dehydrogenase wildtype (IDHwt) gliomas.METHODS: We employed DNA methylation pattern analyses with a special focus on metabolic genes, large-scale metabolism panel immunohistochemistry (IHC), qPCR-based determination of mitochondrial DNA copy number, and immune cell content using IHC and deconvolution of DNA methylation data. We analysed molecularly characterised gliomas (n=57) for in depth DNA methylation, a cohort of primary and recurrent gliomas (n=22) for mitochondrial copy number and validated these results in a large glioma cohort (n=293). Finally, we investigated the potential of metabolic markers in Bevacizumab (Bev)-treated gliomas (n=29).
    RESULTS: DNA methylation patterns of metabolic genes successfully distinguished the molecular subtypes of IDHmut and IDHwt gliomas. Promoter methylation of lactate dehydrogenase A negatively correlated with protein expression and was associated with IDHmut gliomas. Mitochondrial DNA copy number was increased in IDHmut tumours and did not change in recurrent tumours.Hierarchical clustering based on metabolism panel IHC revealed distinct subclasses of IDHmut and IDHwt gliomas with an impact on patient outcome. Further quantification of these markers allowed for the prediction of survival under antiangiogenic therapy.
    CONCLUSION: A mitochondrial signature was associated with increased survival in all analyses, which could indicate tumour subgroups with specific metabolic vulnerabilities.
    Keywords:  DNA methylation; IDH mutation; glioma; metabolism; mitochondria
  11. Front Cell Dev Biol. 2020 ;8 583850
    Console L, Scalise M, Mazza T, Pochini L, Galluccio M, Giangregorio N, Tonazzi A, Indiveri C.
      Metabolic flexibility is a peculiar hallmark of cancer cells. A growing number of observations reveal that tumors can utilize a wide range of substrates to sustain cell survival and proliferation. The diversity of carbon sources is indicative of metabolic heterogeneity not only across different types of cancer but also within those sharing a common origin. Apart from the well-assessed alteration in glucose and amino acid metabolisms, there are pieces of evidence that cancer cells display alterations of lipid metabolism as well; indeed, some tumors use fatty acid oxidation (FAO) as the main source of energy and express high levels of FAO enzymes. In this metabolic pathway, the cofactor carnitine is crucial since it serves as a "shuttle-molecule" to allow fatty acid acyl moieties entering the mitochondrial matrix where these molecules are oxidized via the β-oxidation pathway. This role, together with others played by carnitine in cell metabolism, underlies the fine regulation of carnitine traffic among different tissues and, within a cell, among different subcellular compartments. Specific membrane transporters mediate carnitine and carnitine derivatives flux across the cell membranes. Among the SLCs, the plasma membrane transporters OCTN2 (Organic cation transport novel 2 or SLC22A5), CT2 (Carnitine transporter 2 or SLC22A16), MCT9 (Monocarboxylate transporter 9 or SLC16A9) and ATB0, + [Sodium- and chloride-dependent neutral and basic amino acid transporter B(0+) or SLC6A14] together with the mitochondrial membrane transporter CAC (Mitochondrial carnitine/acylcarnitine carrier or SLC25A20) are the most acknowledged to mediate the flux of carnitine. The concerted action of these proteins creates a carnitine network that becomes relevant in the context of cancer metabolic rewiring. Therefore, molecular mechanisms underlying modulation of function and expression of carnitine transporters are dealt with furnishing some perspective for cancer treatment.
    Keywords:  SLC; cancer; carnitine; drugs; mitochondria; transporters; β-oxidation
  12. J Clin Invest. 2020 Oct 20. pii: 139929. [Epub ahead of print]
    Huang F, Huffman K, Wang Z, Wang X, Li K, Cai F, Yang C, Cai L, Shih TS, Zacharias LG, Chung AS, Yang Q, Chalishazar MD, Ireland AS, Stewart CA, Cargill KR, Girard L, Liu Y, Ni M, Xu J, Wu X, Zhu H, Drapkin BJ, Byers LA, Oliver TG, Gazdar A, Minna J, DeBerardinis R.
      MYC stimulates both metabolism and protein synthesis, but it is unknown how cells coordinate these complementary programs. Previous work reported that in a subset of small cell lung cancer (SCLC) cell lines, MYC activates guanosine triphosphate (GTP) synthesis and results in sensitivity to inhibitors of the GTP synthesis enzyme inosine monophosphate dehydrogenase (IMPDH). Here we demonstrated that primary MYCHigh human SCLC tumors also contain abundant guanosine nucleotides. We also found that elevated MYC in SCLCs with acquired chemoresistance rendered these otherwise recalcitrant tumors dependent on IMPDH. Unexpectedly, our data indicated that IMPDH links the metabolic and protein synthesis outputs of oncogenic MYC. Co-expression analysis placed IMPDH within the MYC-driven ribosome program, and GTP depletion prevented RNA Polymerase I (Pol I) from localizing to ribosomal DNA. Furthermore, the GTPases GPN1 and GPN3 were upregulated by MYC and directed Pol I to ribosomal DNA. Constitutively GTP-bound GPN1/3 mutants mitigated the effect of GTP depletion on Pol I, protecting chemoresistant SCLC cells from IMPDH inhibition. GTP therefore functions as a metabolic gate tethering MYC-dependent ribosome biogenesis to nucleotide sufficiency through GPN1 and GPN3. IMPDH dependence is a targetable vulnerability in chemoresistant, MYCHigh SCLC.
    Keywords:  Intermediary metabolism; Lung cancer; Metabolism; Oncogenes; Oncology
  13. Oncol Lett. 2020 Dec;20(6): 313
    Rai NK, Mathur S, Singh SK, Tiwari M, Singh VK, Haque R, Tiwari S, Kumar Sharma L.
      Mitochondria serve a vital role in cellular homeostasis as they regulate cell proliferation and death pathways, which are attributed to mitochondrial bioenergetics, free radicals and metabolism. Alterations in mitochondrial functions have been reported in various diseases, including cancer. Colorectal cancer (CRC) is one of the most common metastatic cancer types with high mortality rates. Although mitochondrial oxidative stress has been associated with CRC, its specific mechanism and contribution to metastatic progression remain poorly understood. Therefore, the aims of the present study were to investigate the role of mitochondria in CRC cells with low and high metastatic potential and to evaluate the contribution of mitochondrial respiratory chain (RC) complexes in oncogenic signaling pathways. The present results demonstrated that cell lines with low metastatic potential were resistant to mitochondrial complex I (C-I)-mediated oxidative stress, and had C-I inhibition with impaired mitochondrial functions. These adaptations enabled cells to cope with higher oxidative stress. Conversely, cells with high metastatic potential demonstrated functional C-I with improved mitochondrial function due to coordinated upregulation of mitochondrial biogenesis and metabolic reprogramming. Pharmacological inhibition of C-I in high metastatic cells resulted in increased sensitivity to cell death and decreased metastatic signaling. The present findings identified the differential regulation of mitochondrial functions in CRC cells, based on CRC metastatic potential. Specifically, it was suggested that a functional C-I is required for high metastatic features of cancer cells, and the role of C-I could be further examined as a potential target in the development of novel therapies for diagnosing high metastatic cancer types.
    Keywords:  apoptosis; colorectal cancer; metastasis; mitochondria; mitochondrial complex I; oxidative stress
  14. Cell Mol Life Sci. 2020 Oct 19.
    Romanello V, Sandri M.
      The dynamic coordination of processes controlling the quality of the mitochondrial network is crucial to maintain the function of mitochondria in skeletal muscle. Changes of mitochondrial proteolytic system, dynamics (fusion/fission), and mitophagy induce pathways that affect muscle mass and performance. When muscle mass is lost, the risk of disease onset and premature death is dramatically increased. For instance, poor quality of muscles correlates with the onset progression of several age-related disorders such as diabetes, obesity, cancer, and aging sarcopenia. To date, there are no drug therapies to reverse muscle loss, and exercise remains the best approach to improve mitochondrial health and to slow atrophy in several diseases. This review will describe the principal mechanisms that control mitochondrial quality and the pathways that link mitochondrial dysfunction to muscle mass regulation.
    Keywords:  Atrophy; Autophagy; FGF21; Fission; Fusion; Mitochondria; Mitochondrial proteostasis; Mitophagy; Myokines; Skeletal muscle
  15. Trends Cell Biol. 2020 Oct 19. pii: S0962-8924(20)30188-4. [Epub ahead of print]
    Gao S, Hu J.
      Mitochondria are highly dynamic organelles that constantly undergo fission and fusion. Disruption of mitochondrial dynamics undermines their function and causes several human diseases. The fusion of the outer (OMM) and inner mitochondrial membranes (IMM) is mediated by two classes of dynamin-like protein (DLP): mitofusin (MFN)/fuzzy onions 1 (Fzo1) and optic atrophy 1/mitochondria genome maintenance 1 (OPA1/Mgm1). Given the lack of structural information on these fusogens, the molecular mechanisms underlying mitochondrial fusion remain unclear, even after 20 years. Here, we review recent advances in structural studies of the mitochondrial fusion machinery, discuss their implication for DLPs, and summarize the pathogenic mechanisms of disease-causing mutations in mitochondrial fusion DLPs.
    Keywords:  Dynamin superfamily; Mitofusin/Fzo1; OPA1/Mgm1; cristae formation; mitochondrial fusion; structure
  16. Cell Death Differ. 2020 Oct 20.
    Krassikova L, Zhang B, Nagarajan D, Queiroz AL, Kacal M, Samakidis E, Vakifahmetoglu-Norberg H, Norberg E.
      Cancer cells undergo complex metabolic alterations. The mechanisms underlying the tuning of cancer metabolism are under active investigation. Here, we identify the uncharacterized deubiquitinase JOSD2 as a positive regulator of cancer cell proliferation by displaying comprehensive effects on glucose catabolism. We found that JOSD2 directly controls a metabolic enzyme complex that includes Aldolase A, Phosphofructokinase-1 and Phosphoglycerate dehydrogenase, in vitro and in vivo. Further, JOSD2 expression, but not a catalytically inactive mutant, deubiquitinates and stabilizes the enzyme complex, thereby enhancing their activities and the glycolytic rate. This represents a selective JOSD2 feature that is not shared among other Machado-Joseph disease DUBs or observed in nontransformed cells. JOSD2 deficiency displays cytostatic effects and reduces glycolysis in a broad spectrum of tumor cells of distinct origin and its expression correlates with poor prognosis in non-small cell lung cancer. Overall, our study provides evidence for a previously unknown biological mechanism in which JOSD2 integrates glucose and serine metabolism with potential therapeutic implications.
  17. Trends Genet. 2020 Oct 19. pii: S0168-9525(20)30270-5. [Epub ahead of print]
    Carthew RW.
      It is recognized that cell metabolism is tightly connected to other cellular processes such as regulation of gene expression. Metabolic pathways not only provide the precursor molecules necessary for gene expression, but they also provide ATP, the primary fuel driving gene expression. However, metabolic conditions are highly variable since nutrient uptake is not a uniform process. Thus, cells must continually calibrate gene expression to their changing metabolite and energy budgets. This review discusses recent advances in understanding the molecular and biophysical mechanisms that connect metabolism and gene regulation as cells navigate their growth, proliferation, and differentiation. Particular focus is given to these mechanisms in the context of organismal development.
    Keywords:  ATP; gene regulation; glucose metabolism
  18. Free Radic Biol Med. 2020 Oct 16. pii: S0891-5849(20)31285-5. [Epub ahead of print]161 163-174
    Jarmuszkiewicz W, Dominiak K, Galganski L, Galganska H, Kicinska A, Majerczak J, Zoladz JA.
      We elucidated the impact of eight weeks of endurance training on the oxidative metabolism of rat lungs. Adult 3.5-month-old male rats were randomly allocated to a treadmill training group or a sedentary group as control. In the lungs, endurance training raised the expression level of the oxygen sensors hypoxia inducible factor 1α (HIF1α) and lysine-specific demethylase 6A (KDM6A) as well as stimulated mitochondrial oxidative capacity and mitochondrial biogenesis, while lactate dehydrogenase activity was reduced. Endurance training enhanced antioxidant systems (the coenzyme Q content and superoxide dismutase) in lung tissue but decreased them (and uncoupling protein 2) in lung mitochondria. In the lung mitochondria of trained rats, the decreased Q content and Complex I (CI) activity and the enhanced cytochrome pathway activity (CIII + CIV) may account for the diminished Q reduction level, resulting in a general decrease in H2O2 formation by mitochondria. Endurance training enhanced oxidation of glutamate and fatty acids and caused opposite effects in functional mitochondrial properties during malate and succinate oxidation, which were related to reduced activity of CI and increased activity of CII, respectively. In addition, endurance training downregulated CI in supercomplexes and upregulated CIII in the CIII2+CIV supercomplex in the oxidative phosphorylation system. We concluded that the adaptive lung responses observed could be due to hypoxia and oxidative stress induced by strenuous endurance training.
    Keywords:  Endurance training and mitochondrial biogenesis; Hypoxia; Lung mitochondria function; Oxidative metabolism; Oxidative stress
  19. Int J Mol Sci. 2020 Oct 21. pii: E7780. [Epub ahead of print]21(20):
    Lettieri-Barbato D, Minopoli G, Caggiano R, Izzo R, Santillo M, Aquilano K, Faraonio R.
      A common metabolic condition for living organisms is starvation/fasting, a state that could play systemic-beneficial roles. Complex adaptive responses are activated during fasting to help the organism to maintain energy homeostasis and avoid nutrient stress. Metabolic rearrangements during fasting cause mild oxidative stress in skeletal muscle. The nuclear factor erythroid 2-related factor 2 (Nrf2) controls adaptive responses and remains the major regulator of quenching mechanisms underlying different types of stress. Here, we demonstrate a positive role of fasting as a protective mechanism against oxidative stress in skeletal muscle. In particular, by using in vivo and in vitro models of fasting, we found that typical Nrf2-dependent genes, including those controlling iron (e.g., Ho-1) and glutathione (GSH) metabolism (e.g., Gcl, Gsr) are induced along with increased levels of the glutathione peroxidase 4 (Gpx4), a GSH-dependent antioxidant enzyme. These events are associated with a significant reduction in malondialdehyde, a well-known by-product of lipid peroxidation. Our results suggest that fasting could be a valuable approach to boost the adaptive anti-oxidant responses in skeletal muscle.
    Keywords:  Nrf2; lipid peroxides; metabolism; nutrient restriction; oxidative stress
  20. Mol Oncol. 2020 Oct 17.
    Shi L, Liu J, Peng Y, Zhang J, Dai X, Zhang S, Wang Y, Liu J, Long J.
      Dynamin-related protein 1 (Drp1) is a cytosolic protein responsible for mitochondrial fission and is essential in the initiation and development of several human diseases, including cancer. However, the regulation of Drp1, especially of its ubiquitination, remains unclear. In this study, we report that the ovarian tumor-associated protease deubiquitinase 6A (OTUD6A) deubiquitylates and stabilizes Drp1, thereby facilitating regulation of mitochondrial morphology and tumorigenesis. OTUD6A is upregulated in human patients with colorectal cancer. Depletion of OTUD6A leads to lower Drp1 levels and suppressed mitochondrial fission and the affected cells are consequently less prone to tumorigenesis. Conversely, overexpression of OTUD6A increases Drp1 levels and its protein half-life and enhances cancer cell growth. Therefore, our results reveal a novel upstream protein of Drp1, and its role in tumorigenesis that is played, in part, through the activation of mitochondrial fission mediated by Drp1.
    Keywords:  Drp1; OTUD6A; cancer cell growth; deubiquitination; mitochondrial fission
  21. Cell Rep. 2020 Oct 20. pii: S2211-1247(20)31282-1. [Epub ahead of print]33(3): 108293
    Maitituoheti M, Keung EZ, Tang M, Yan L, Alam H, Han G, Singh AK, Raman AT, Terranova C, Sarkar S, Orouji E, Amin SB, Sharma S, Williams M, Samant NS, Dhamdhere M, Zheng N, Shah T, Shah A, Axelrad JB, Anvar NE, Lin YH, Jiang S, Chang EQ, Ingram DR, Wang WL, Lazar A, Lee MG, Muller F, Wang L, Ying H, Rai K.
      Histone methyltransferase KMT2D harbors frequent loss-of-function somatic point mutations in several tumor types, including melanoma. Here, we identify KMT2D as a potent tumor suppressor in melanoma through an in vivo epigenome-focused pooled RNAi screen and confirm the finding by using a genetically engineered mouse model (GEMM) based on conditional and melanocyte-specific deletion of KMT2D. KMT2D-deficient tumors show substantial reprogramming of key metabolic pathways, including glycolysis. KMT2D deficiency aberrantly upregulates glycolysis enzymes, intermediate metabolites, and glucose consumption rates. Mechanistically, KMT2D loss causes genome-wide reduction of H3K4me1-marked active enhancer chromatin states. Enhancer loss and subsequent repression of IGFBP5 activates IGF1R-AKT to increase glycolysis in KMT2D-deficient cells. Pharmacological inhibition of glycolysis and insulin growth factor (IGF) signaling reduce proliferation and tumorigenesis preferentially in KMT2D-deficient cells. We conclude that KMT2D loss promotes tumorigenesis by facilitating an increased use of the glycolysis pathway for enhanced biomass needs via enhancer reprogramming, thus presenting an opportunity for therapeutic intervention through glycolysis or IGF pathway inhibitors.
    Keywords:  2-DG; IGFBP5; KMT2D; Linsitinib; RNAi screen; chromatin; epigenetics; glycolysis; melanoma; mouse model
  22. Sci Adv. 2020 Oct;pii: eaaz4452. [Epub ahead of print]6(43):
    Sural S, Liang CY, Wang FY, Ching TT, Hsu AL.
      Heat shock factor-1 (HSF-1) is a master regulator of stress responses across taxa. Overexpression of HSF-1 or genetic ablation of its conserved negative regulator, heat shock factor binding protein 1 (HSB-1), results in robust life-span extension in Caenorhabditis elegans Here, we found that increased HSF-1 activity elevates histone H4 levels in somatic tissues during development, while knockdown of H4 completely suppresses HSF-1-mediated longevity. Moreover, overexpression of H4 is sufficient to extend life span. Ablation of HSB-1 induces an H4-dependent increase in micrococcal nuclease protection of both nuclear chromatin and mitochondrial DNA (mtDNA), which consequently results in reduced transcription of mtDNA-encoded complex IV genes, decreased respiratory capacity, and a mitochondrial unfolded protein response-dependent life-span extension. Collectively, our findings reveal a previously unknown role of HSB-1/HSF-1 signaling in modulation of mitochondrial function via mediating histone H4-dependent regulation of mtDNA gene expression and concomitantly acting as a determinant of organismal longevity.
  23. J Biol Chem. 2020 Oct 21. pii: jbc.RA120.013716. [Epub ahead of print]
    Corum DG, Jenkins DP, Heslop JA, Tallent LM, Beeson GC, Barth JL, Schnellmann RG, Muise-Helmericks RC.
      Akt3 regulates mitochondrial content in endothelial cells through the inhibition of PGC-1α nuclear localization and is also required for angiogenesis. However, whether there is a direct link between mitochondrial function and angiogenesis is unknown. Here we show that Akt3 depletion in primary endothelial cells (EC) results in decreased uncoupled oxygen consumption, increased fission, decreased membrane potential and increased expression of the mitochondria-specific protein chaperones, HSP60 and HSP10, suggesting that Akt3 is required for mitochondrial homeostasis. Direct inhibition of mitochondrial homeostasis by the model oxidant paraquat results in decreased angiogenesis showing a direct link between angiogenesis and mitochondrial function. Next, in exploring functional links to PGC-1α, the master regulator of mitochondrial biogenesis, we searched for compounds that induce this process. We found that sildenafil, a phosphodiesterase 5 (PDE5) inhibitor induced mitochondrial biogenesis as measured by increased uncoupled oxygen consumption, mitochondrial DNA content and voltage-dependent anion channel protein expression.  Sildenafil rescued the effects on mitochondria by Akt3 depletion or pharmacological inhibition and promoted angiogenesis, further supporting that mitochondrial homeostasis is required for angiogenesis. Sildenafil also induces the expression of PGC-1 family member, PRC and can compensate for PGC-1α activity during mitochondrial stress by an Akt3-independent mechanism. The induction of PRC by sildenafil is dependent upon cAMP and the transcription factor CREB. Thus, PRC can functionally substitute during Akt3 depletion for absent PGC-1α activity to restore mitochondrial homeostasis and promote angiogenesis. These findings show that mitochondrial homeostasis as controlled by the PGC family of transcriptional activators is required for angiogenic responses.
    Keywords:  Akt PKB; Akt3; PRC; angiogenesis; mitochondria; peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1a)(PPARGC1A); phosphodiesterases
  24. Cell Mol Life Sci. 2020 Oct 21.
    Purohit PK, Saini N.
      Mitochondria are not only important for cellular bioenergetics but also lie at the heart of critical metabolic pathways. They can rapidly adjust themselves in response to changing conditions and the metabolic needs of the cell. Mitochondrial involvement as well as its dysfunction has been found to be associated with variety of pathological processes and diseases. mitomiRs are class of miRNA(s) that regulate mitochondrial gene expression and function. This review sheds light on the role of mitomiRs in regulating different biological processes-mitochondrial dynamics, oxidative stress, cell metabolism, chemoresistance, apoptosis,and their relevance in metabolic diseases, neurodegenerative disorders, and cancer. Insilico analysis of predicted targets of mitomiRs targeting energy metabolism identified several significantly altered pathways (needs in vivo validations) that may provide a new therapeutic approach for the treatment of human diseases. Last part of the review discusses about the clinical aspects of miRNA(s) and mitomiRs in Medicine.
    Keywords:  Cancer; Cardiovascular disease; Clinical medicine; Diabetes; Metabolic disorders; Neurodegenerative disorders; microRNA; mitomiR
  25. Mol Cancer Ther. 2020 Oct 21. pii: molcanther.0271.2020. [Epub ahead of print]
    Rashmi R, Jayachandran K, Zhang J, Menon V, Muhammad N, Zahner M, Ruiz F, Zhang S, Cho K, Wang Y, Huang X, Huang Y, McCormick ML, Rogers BE, Spitz DR, Patti GJ, Schwarz JK.
      The purpose of the study was to determine if radiation resistant cervical cancers are dependent upon glutamine metabolism driven by activation of the PI3K pathway and test whether PI3K pathway mutation predicts radio-sensitization by inhibition of glutamine metabolism. Cervical cancer cell lines with and without PI3K pathway mutations, including SiHa and SiHa PTEN-/- cells engineered by CRISPR/Cas9, were used for mechanistic studies performed in vitro in the presence and absence of glutamine starvation and the glutaminase inhibitor, telaglenastat (CB-839). These studies included cell survival, proliferation, quantification of oxidative stress parameters, metabolic tracing with stable isotope labeled substrates, metabolic rescue and combination studies with L-buthionine sulfoximine (BSO), auranofin (AUR), and radiation (RT). In vivo studies of telaglenastat ± RT were performed using CaSki and SiHa xenografts grown in immune compromised mice. PI3K activated cervical cancer cells were selectively sensitive to glutamine deprivation through a mechanism that included thiol-mediated oxidative stress. Telaglenastat treatment decreased total glutathione pools, increased the percent glutathione disulfide, and caused clonogenic cell killing that was reversed by treatment with the thiol antioxidant, N-acetylcysteine. Telaglenastat also sensitized cells to killing by glutathione depletion with BSO, thioredoxin reductase inhibition with AUR, and RT. Glutamine dependent PI3K activated cervical cancer xenografts were sensitive to telaglenastat monotherapy, and telaglenastat selectively radio-sensitized cervical cancer cells in vitro and in vivo. These novel preclinical data support the utility of telaglenastat for glutamine dependent radio-resistant cervical cancers and demonstrate that PI3K pathway mutations may be used as a predictive biomarker for telaglenastat sensitivity.
  26. Front Cell Dev Biol. 2020 ;8 572182
    Joaquim M, Escobar-Henriques M.
      Mitochondria entail an incredible dynamism in their morphology, impacting death signaling and selective elimination of the damaged organelles. In turn, by recycling the superfluous or malfunctioning mitochondria, mostly prevalent during aging, mitophagy contributes to maintain a healthy mitochondrial network. Mitofusins locate at the outer mitochondrial membrane and control the plastic behavior of mitochondria, by mediating fusion events. Besides deciding on mitochondrial interconnectivity, mitofusin 2 regulates physical contacts between mitochondria and the endoplasmic reticulum, but also serves as a decisive docking platform for mitophagy and apoptosis effectors. Thus, mitofusins integrate multiple bidirectional inputs from and into mitochondria and ensure proper energetic and metabolic cellular performance. Here, we review the role of mitofusins and mitophagy at the cross-road between life and apoptotic death decisions. Furthermore, we highlight the impact of this interplay on disease, focusing on how mitofusin 2 and mitophagy affect non-alcoholic fatty liver disease.
    Keywords:  MFN2; NAFLD; apoptosis; mitochondria; mitofusins; mitophagy
  27. Autophagy. 2020 Oct 19.
    Kumar S, Jain A, Choi SW, Peixoto Duarte da Silva G, Allers L, Mudd MH, Peters RS, Anonsen JH, Rusten TE, Lazarou M, Deretic V.
      Macroautophagy/autophagy delivers cytoplasmic cargo to lysosomes for degradation. In yeast, the single Atg8 protein plays a role in the formation of autophagosomes whereas in mammalian cells there are five to seven paralogs, referred to as mammalian Atg8s (mAtg8s: GABARAP, GABARAPL1, GABARAPL2, LC3A, LC3B, LC3B2 and LC3C) with incompletely defined functions. Here we show that a subset of mAtg8s directly control lysosomal biogenesis. This occurs at the level of TFEB, the principal regulator of the lysosomal transcriptional program. mAtg8s promote TFEB's nuclear translocation in response to stimuli such as starvation. GABARAP interacts directly with TFEB, whereas RNA-Seq analyses reveal that knockout of six genes encoding mAtg8s, or a triple knockout of the genes encoding all GABARAPs, diminishes the TFEB transcriptional program. We furthermore show that GABARAPs in cooperation with other proteins, IRGM, a factor implicated in tuberculosis and Crohn disease, and STX17, are required during starvation for optimal inhibition of MTOR, an upstream kinase of TFEB, and activation of the PPP3/calcineurin phosphatase that dephosphorylates TFEB, thus promoting its nuclear translocation. In conclusion, mAtg8s, IRGM and STX17 control lysosomal biogenesis by their combined or individual effects on MTOR, TFEB, and PPP3/calcineurin, independently of their roles in the formation of autophagosomal membranes.
    Keywords:  Crohn’s disease; GABARAP; HIV; LC3; MTOR; Mycobacterium tuberculosis; TFEB; autophagy; lysosome; metabolism
  28. Cancers (Basel). 2020 Oct 17. pii: E3023. [Epub ahead of print]12(10):
    DeBlasi JM, DeNicola GM.
      The transcription factor NRF2 (nuclear factor-erythroid 2 p45-related factor 2 or NFE2L2) plays a critical role in response to cellular stress. Following an oxidative insult, NRF2 orchestrates an antioxidant program, leading to increased glutathione levels and decreased reactive oxygen species (ROS). Mounting evidence now implicates the ability of NRF2 to modulate metabolic processes, particularly those at the interface between antioxidant processes and cellular proliferation. Notably, NRF2 regulates the pentose phosphate pathway, NADPH production, glutaminolysis, lipid and amino acid metabolism, many of which are hijacked by cancer cells to promote proliferation and survival. Moreover, deregulation of metabolic processes in both normal and cancer-based physiology can stabilize NRF2. We will discuss how perturbation of metabolic pathways, including the tricarboxylic acid (TCA) cycle, glycolysis, and autophagy can lead to NRF2 stabilization, and how NRF2-regulated metabolism helps cells deal with these metabolic stresses. Finally, we will discuss how the negative regulator of NRF2, Kelch-like ECH-associated protein 1 (KEAP1), may play a role in metabolism through NRF2 transcription-independent mechanisms. Collectively, this review will address the interplay between the NRF2/KEAP1 complex and metabolic processes.
    Keywords:  KEAP1; NADPH; NRF2; amino acids; cancer metabolism; lipids; oxidative stress
  29. Cell Death Differ. 2020 Oct 23.
    Wang K, Zhang Z, Tsai HI, Liu Y, Gao J, Wang M, Song L, Cao X, Xu Z, Chen H, Gong A, Wang D, Cheng F, Zhu H.
      Ferroptosis, a form of iron-dependent cell death driven by cellular metabolism and iron-dependent lipid peroxidation, has been implicated as a tumor-suppressor function for cancer therapy. Recent advance revealed that the sensitivity to ferroptosis is tightly linked to numerous biological processes, including metabolism of amino acid and the biosynthesis of glutathione. Here, by using a high-throughput CRISPR/Cas9-based genetic screen in HepG2 hepatocellular carcinoma cells to search for metabolic proteins inhibiting ferroptosis, we identified a branched-chain amino acid aminotransferase 2 (BCAT2) as a novel suppressor of ferroptosis. Mechanistically, ferroptosis inducers (erastin, sorafenib, and sulfasalazine) activated AMPK/SREBP1 signaling pathway through iron-dependent ferritinophagy, which in turn inhibited BCAT2 transcription. We further confirmed that BCAT2 as the key enzyme mediating the metabolism of sulfur amino acid, regulated intracellular glutamate level, whose activation by ectopic expression specifically antagonize system Xc- inhibition and protected liver and pancreatic cancer cells from ferroptosis in vitro and in vivo. On the contrary, direct inhibition of BCAT2 by RNA interference, or indirect inhibition by blocking system Xc- activity, triggers ferroptosis. Finally, our results demonstrate the synergistic effect of sorafenib and sulfasalazine in downregulating BCAT2 expression and dictating ferroptotic death, where BCAT2 can also be used to predict the responsiveness of cancer cells to ferroptosis-inducing therapies. Collectively, these findings identify a novel role of BCAT2 in ferroptosis, suggesting a potential therapeutic strategy for overcoming sorafenib resistance.
  30. J Cell Biol. 2020 Dec 07. pii: e202002144. [Epub ahead of print]219(12):
    English AM, Schuler MH, Xiao T, Kornmann B, Shaw JM, Hughes AL.
      Mitochondria are dynamic organelles with essential roles in signaling and metabolism. We recently identified a cellular structure called the mitochondrial-derived compartment (MDC) that is generated from mitochondria in response to amino acid overabundance stress. How cells form MDCs is unclear. Here, we show that MDCs are dynamic structures that form and stably persist at sites of contact between the ER and mitochondria. MDC biogenesis requires the ER-mitochondria encounter structure (ERMES) and the conserved GTPase Gem1, factors previously implicated in lipid exchange and membrane tethering at ER-mitochondria contacts. Interestingly, common genetic suppressors of abnormalities displayed by ERMES mutants exhibit distinct abilities to rescue MDC formation in ERMES-depleted strains and are incapable of rescuing MDC formation in cells lacking Gem1. Thus, the function of ERMES and Gem1 in MDC biogenesis may extend beyond their conventional role in maintaining mitochondrial phospholipid homeostasis. Overall, this study identifies an important function for ER-mitochondria contacts in the biogenesis of MDCs.
  31. Nat Biotechnol. 2020 Oct 19.
    Cui L, Gouw AM, LaGory EL, Guo S, Attarwala N, Tang Y, Qi J, Chen YS, Gao Z, Casey KM, Bazhin AA, Chen M, Hu L, Xie J, Fang M, Zhang C, Zhu Q, Wang Z, Giaccia AJ, Gambhir SS, Zhu W, Felsher DW, Pegram MD, Goun EA, Le A, Rao J.
      Depletion of mitochondrial copper, which shifts metabolism from respiration to glycolysis and reduces energy production, is known to be effective against cancer types that depend on oxidative phosphorylation. However, existing copper chelators are too toxic or ineffective for cancer treatment. Here we develop a safe, mitochondria-targeted, copper-depleting nanoparticle (CDN) and test it against triple-negative breast cancer (TNBC). We show that CDNs decrease oxygen consumption and oxidative phosphorylation, cause a metabolic switch to glycolysis and reduce ATP production in TNBC cells. This energy deficiency, together with compromised mitochondrial membrane potential and elevated oxidative stress, results in apoptosis. CDNs should be less toxic than existing copper chelators because they favorably deprive copper in the mitochondria in cancer cells instead of systemic depletion. Indeed, we demonstrate low toxicity of CDNs in healthy mice. In three mouse models of TNBC, CDN administration inhibits tumor growth and substantially improves survival. The efficacy and safety of CDNs suggest the potential clinical relevance of this approach.
  32. Elife. 2020 Oct 23. pii: e59996. [Epub ahead of print]9
    Rundqvist H, Veliça P, Barbieri L, Gameiro PA, Bargiela D, Gojkovic M, Mijwel S, Reitzner SM, Wulliman D, Ahlstedt E, Ule J, Östman A, Johnson RS.
      Exercise has a wide range of systemic effects. In animal models, repeated exertion reduces malignant tumor progression, and clinically, exercise can improve outcome for cancer patients. The etiology of the effects of exercise on tumor progression are unclear, as are the cellular actors involved. We show here that in mice, exercise-induced reduction in tumor growth is dependent on CD8+ T cells, and that metabolites produced in skeletal muscle and excreted into plasma at high levels during exertion in both mice and humans enhance the effector profile of CD8+ T-cells. We found that activated murine CD8+ T cells alter their central carbon metabolism in response to exertion in vivo, and that immune cells from trained mice are more potent antitumor effector cells when transferred into tumor-bearing untrained animals. These data demonstrate that CD8+ T cells are metabolically altered by exercise in a manner that acts to improve their antitumoral efficacy.
    Keywords:  cancer biology; exercise; human; immunology; immunotherapy; inflammation; metabolism; mouse
  33. FEBS J. 2020 Oct 22.
    Markaki M, Tavernarakis N.
      Autophagy is the main catabolic process by which cells recycle cytoplasmic components and superfluous or damaged organelles to preserve metabolic homeostasis under normal conditions and promote survival under stress. As a tightly regulated and dynamic process, autophagy has critical roles in development and cell differentiation, immune function, organismal health and lifespan. Accumulating findings suggest that defective or dysregulated autophagy accelerates ageing and increases susceptibility to diseases, such as neurodegenerative disorders and cancer, among others. This virtual issue of the FEBS Journal on Autophagy includes a collection of articles that present recent advances on the regulation of autophagy and provide a view of its complex roles in physiological and pathological contexts.
  34. Rev Physiol Biochem Pharmacol. 2020 Oct 17.
    Petan T.
      Lipid droplets have a unique structure among organelles consisting of a dense hydrophobic core of neutral lipids surrounded by a single layer of phospholipids decorated with various proteins. Often labeled merely as passive fat storage repositories, they in fact have a remarkably dynamic life cycle. Being formed within the endoplasmic reticulum membrane, lipid droplets rapidly grow, shrink, traverse the cytosol, and engage in contacts with other organelles to exchange proteins and lipids. Their lipid and protein composition changes dynamically in response to cellular states and nutrient availability. Remarkably, their biogenesis is induced when cells experience various forms of nutrient, energy, and redox imbalances, including lipid excess and complete nutrient deprivation. Cancer cells are continuously exposed to nutrient and oxygen fluctuations and have the capacity to switch between alternative nutrient acquisition and metabolic pathways in order to strive even during severe stress. Their supply of lipids is ensured by a series of nutrient uptake and scavenging mechanisms, upregulation of de novo lipid synthesis, repurposing of their structural lipids via enzymatic remodeling, or lipid recycling through autophagy. Importantly, most of these pathways of lipid acquisition converge at lipid droplets, which combine different lipid fluxes and control their usage based on specific cellular needs. It is thus not surprising that lipid droplet breakdown is an elaborately regulated process that occurs via a complex interplay of neutral lipases and autophagic degradation. Cancer cells employ lipid droplets to ensure energy production and redox balance, modulate autophagy, drive membrane synthesis, and control its composition, thereby minimizing stress and fostering tumor progression. As regulators of (poly)unsaturated fatty acid trafficking, lipid droplets are also emerging as modulators of lipid peroxidation and sensitivity to ferroptosis. Clearly, dysregulated lipid droplet turnover may also be detrimental to cancer cells, which should provide potential therapeutic opportunities in the future. In this review, we explore how lipid droplets consolidate lipid acquisition and trafficking pathways in order to match lipid supply with the requirements for cancer cell survival, growth, and metastasis.
    Keywords:  Autophagy; Cancer; Fatty acid; Ferroptosis; Lipid droplets; Metabolism; Stress
  35. Cell Rep. 2020 Oct 20. pii: S2211-1247(20)31285-7. [Epub ahead of print]33(3): 108296
    Tlemsani C, Pongor L, Elloumi F, Girard L, Huffman KE, Roper N, Varma S, Luna A, Rajapakse VN, Sebastian R, Kohn KW, Krushkal J, Aladjem MI, Teicher BA, Meltzer PS, Reinhold WC, Minna JD, Thomas A, Pommier Y.
      CellMiner-SCLC ( integrates drug sensitivity and genomic data, including high-resolution methylome and transcriptome from 118 patient-derived small cell lung cancer (SCLC) cell lines, providing a resource for research into this "recalcitrant cancer." We demonstrate the reproducibility and stability of data from multiple sources and validate the SCLC consensus nomenclature on the basis of expression of master transcription factors NEUROD1, ASCL1, POU2F3, and YAP1. Our analyses reveal transcription networks linking SCLC subtypes with MYC and its paralogs and the NOTCH and HIPPO pathways. SCLC subsets express specific surface markers, providing potential opportunities for antibody-based targeted therapies. YAP1-driven SCLCs are notable for differential expression of the NOTCH pathway, epithelial-mesenchymal transition (EMT), and antigen-presenting machinery (APM) genes and sensitivity to mTOR and AKT inhibitors. These analyses provide insights into SCLC biology and a framework for future investigations into subtype-specific SCLC vulnerabilities.
    Keywords:  PARP; SLFN11; STING; Schlafen; genomics; immune checkpoints; mutations; native immune response; neuroendocrine tumors; replication
  36. Proc Natl Acad Sci U S A. 2020 Oct 19. pii: 201920377. [Epub ahead of print]
    Bartish M, Tong D, Pan Y, Wallerius M, Liu H, Ristau J, de Souza Ferreira S, Wallmann T, van Hoef V, Masvidal L, Kerzel T, Joly AL, Goncalves C, Preston SEJ, Ebrahimian T, Seitz C, Bergh J, Pietras K, Lehoux S, Naldini L, Andersson J, Squadrito ML, Del Rincón SV, Larsson O, Rolny C.
      Tumor-associated macrophages (TAMs) continuously fine tune their immune modulatory properties, but how gene expression programs coordinate this immune cell plasticity is largely unknown. Selective mRNA translation, controlled by MNK1/MNK2 and mTOR pathways impinging on eIF4E, facilitates reshaping of proteomes without changes in abundance of corresponding mRNAs. Using polysome profiling developed for small samples we show that, during tumor growth, gene expression in TAMs is predominately modulated via mRNA-selective changes in translational efficiencies. These alterations in gene expression paralleled accumulation of antiinflammatory macrophages with augmented phosphorylation of eIF4E, a target of the MNK1 and MNK2 kinases, known to selectively modulate mRNA translation. Furthermore, suppression of the MNK2, but not the mTOR signaling pathway, reprogrammed antiinflammatory macrophages toward a proinflammatory phenotype with the ability to activate CD8+ T cells. Thus, selective changes of mRNA translation depending on MNK2 signaling represents a key node regulating macrophage antiinflammatory functions.
    Keywords:  MNK2; T cell activation; eIF4E; mRNA translation; tumor-associated macrophages
  37. Nat Rev Mol Cell Biol. 2020 Oct 22.
    Song J, Herrmann JM, Becker T.
      Mitochondria contain about 1,000-1,500 proteins that fulfil multiple functions. Mitochondrial proteins originate from two genomes: mitochondrial and nuclear. Hence, proper mitochondrial function requires synchronization of gene expression in the nucleus and in mitochondria and necessitates efficient import of mitochondrial proteins into the organelle from the cytosol. Furthermore, the mitochondrial proteome displays high plasticity to allow the adaptation of mitochondrial function to cellular requirements. Maintenance of this complex and adaptable mitochondrial proteome is challenging, but is of crucial importance to cell function. Defects in mitochondrial proteostasis lead to proteotoxic insults and eventually cell death. Different quality control systems monitor the mitochondrial proteome. The cytosolic ubiquitin-proteasome system controls protein transport across the mitochondrial outer membrane and removes damaged or mislocalized proteins. Concomitantly, a number of mitochondrial chaperones and proteases govern protein folding and degrade damaged proteins inside mitochondria. The quality control factors also regulate processing and turnover of native proteins to control protein import, mitochondrial metabolism, signalling cascades, mitochondrial dynamics and lipid biogenesis, further ensuring proper function of mitochondria. Thus, mitochondrial protein quality control mechanisms are of pivotal importance to integrate mitochondria into the cellular environment.
  38. Biochim Biophys Acta Mol Cell Res. 2020 Oct 19. pii: S0167-4889(20)30251-2. [Epub ahead of print] 118893
    Shanbhag VC, Gudekar N, Jasmer K, Papageorgiou C, Singh K, Petris MJ.
      The last 25 years have witnessed tremendous progress in identifying and characterizing proteins that regulate the uptake, intracellular trafficking and export of copper. Although dietary copper is required in trace amounts, sufficient quantities of this metal are needed to sustain growth and development in humans and other mammals. However, copper is also a rate-limiting nutrient for the growth and proliferation of cancer cells. Oral copper chelators taken with food have been shown to confer anti-neoplastic and anti-metastatic benefits in animals and humans. Recent studies have begun to identify specific roles for copper in pathways of oncogenic signaling and resistance to anti-neoplastic drugs. Here, we review the general mechanisms of cellular copper homeostasis and discuss roles of copper in cancer progression, highlighting metabolic vulnerabilities that may be targetable in the development of anticancer therapies.
    Keywords:  Copper homeostasis; cancer; cisplatin chemotherapy; copper chelation; metallochaperone; nutrition
  39. Nat Cell Biol. 2020 Oct 19.
    Ros M, Nguyen AT, Chia J, Le Tran S, Le Guezennec X, McDowall R, Vakhrushev S, Clausen H, Humphries MJ, Saltel F, Bard FA.
      Tumour growth and invasiveness require extracellular matrix (ECM) degradation and are stimulated by the GALA pathway, which induces protein O-glycosylation in the endoplasmic reticulum (ER). ECM degradation requires metalloproteases, but whether other enzymes are required is unclear. Here, we show that GALA induces the glycosylation of the ER-resident calnexin (Cnx) in breast and liver cancer. Glycosylated Cnx and its partner ERp57 are trafficked to invadosomes, which are sites of ECM degradation. We find that disulfide bridges are abundant in connective and liver ECM. Cell surface Cnx-ERp57 complexes reduce these extracellular disulfide bonds and are essential for ECM degradation. In vivo, liver cancer cells but not hepatocytes display cell surface Cnx. Liver tumour growth and lung metastasis of breast and liver cancer cells are inhibited by anti-Cnx antibodies. These findings uncover a moonlighting function of Cnx-ERp57 at the cell surface that is essential for ECM breakdown and tumour development.
  40. Dis Model Mech. 2020 Oct 22. pii: dmm.046706. [Epub ahead of print]
    Thorsen AS, Khamis D, Kemp R, Colombé M, Lourenço FC, Morrissey E, Winton D.
      Somatic models of tissue pathology commonly utilise induction of gene specific mutations in mice mediated by spatiotemporal regulation of Cre recombinase. Subsequent investigation of the onset and development of disease can be limited by the inability to track changing cellular behaviours over time. Here a lineage tracing approach based on ligand dependent activation of Dre recombinase that can be employed independently of Cre is described. The clonal biology of intestinal epithelium following Cre-mediated stabilisation of ß-catenin reveals that within tumours many new clones rapidly become extinct. Surviving clones show accelerated population of tumour glands compared to normal intestinal crypts but in a non-uniform manner indicating that intra-tumour glands follow heterogeneous dynamics. In tumour adjacent epithelium clone sizes are smaller than in the background epithelium as a whole. This suggests a zone of around 5 crypt diameters within which clone expansion is inhibited by tumours and that may facilitate their growth.
    Keywords:  Cancer; Epithelial; Intestine; Lineage tracing
  41. Metabolites. 2020 Oct 19. pii: E418. [Epub ahead of print]10(10):
    Weiss HJ, Angiari S.
      In the past decade, the rise of immunometabolism has fundamentally reshaped the face of immunology. As the functions and properties of many (immuno)metabolites have now been well described, their exchange among cells and their environment have only recently sparked the interest of immunologists. While many metabolites bind specific receptors to induce signaling cascades, some are actively exchanged between cells to communicate, or induce metabolic reprograming. In this review, we give an overview about how active metabolite transport impacts immune cell function and shapes immunological responses. We present some examples of how specific transporters feed into metabolic pathways and initiate intracellular signaling events in immune cells. In particular, we focus on the role of metabolite transporters in the activation and effector functions of T cells and macrophages, as prototype adaptive and innate immune cell populations.
    Keywords:  T cells; cell metabolism; immunity; macrophages; metabolite transporter; solute carrier
  42. Mol Syst Biol. 2020 Oct;16(10): e9518
    Gillies TE, Pargett M, Silva JM, Teragawa CK, McCormick F, Albeck JG.
      Activating mutations in RAS are present in ~ 30% of human tumors, and the resulting aberrations in ERK/MAPK signaling play a central role in oncogenesis. However, the form of these signaling changes is uncertain, with activating RAS mutants linked to both increased and decreased ERK activation in vivo. Rationally targeting the kinase activity of this pathway requires clarification of the quantitative effects of RAS mutations. Here, we use live-cell imaging in cells expressing only one RAS isoform to quantify ERK activity with a new level of accuracy. We find that despite large differences in their biochemical activity, mutant KRAS isoforms within cells have similar ranges of ERK output. We identify roles for pathway-level effects, including variation in feedback strength and feedforward modulation of phosphatase activity, that act to rescale pathway sensitivity, ultimately resisting changes in the dynamic range of ERK activity while preserving responsiveness to growth factor stimuli. Our results reconcile seemingly inconsistent reports within the literature and imply that the signaling changes induced by RAS mutations early in oncogenesis are subtle.
    Keywords:  FRET biosensor; RAS disease; computational modeling; epidermal growth factor; single-cell kinetics
  43. Br J Cancer. 2020 Oct 19.
    Cha PH, Hwang JH, Kwak DK, Koh E, Kim KS, Choi KY.
      BACKGROUND: Most cancer cells employ the Warburg effect to support anabolic growth and tumorigenesis. Here, we discovered a key link between Warburg effect and aberrantly activated Wnt/β-catenin signalling, especially by pathologically significant APC loss, in CRC.METHODS: Proteomic analyses were performed to evaluate the global effects of KYA1797K, Wnt/β-catenin signalling inhibitor, on cellular proteins in CRC. The effects of APC-loss or Wnt ligand on the identified enzymes, PKM2 and LDHA, as well as Warburg effects were investigated. A linkage between activation of Wnt/β-catenin signalling and cancer metabolism was analysed in tumour of Apcmin/+ mice and CRC patients. The roles of PKM2 in cancer metabolism, which depends on Wnt/β-catenin signalling, were assessed in xenograft-tumours.
    RESULTS: By proteomic analysis, PKM2 and LDHA were identified as key molecules regulated by Wnt/β-catenin signalling. APC-loss caused the increased expression of metabolic genes including PKM2 and LDHA, and increased glucose consumption and lactate secretion. Pathological significance of this linkage was indicated by increased expression of glycolytic genes with Wnt target genes in tumour of Apcmin/+ mice and CRC patients. Warburg effect and growth of xenografted tumours-induced by APC-mutated-CRC cells were suppressed by PKM2-depletion.
    CONCLUSIONS: The β-catenin-PKM2 regulatory axis induced by APC loss activates the Warburg effect in CRC.