bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2019‒11‒10
28 papers selected by
Christian Frezza
University of Cambridge, MRC Cancer Unit


  1. Nature. 2019 Nov 06.
    MacVicar T, Ohba Y, Nolte H, Mayer FC, Tatsuta T, Sprenger HG, Lindner B, Zhao Y, Li J, Bruns C, Krüger M, Habich M, Riemer J, Schwarzer R, Pasparakis M, Henschke S, Brüning JC, Zamboni N, Langer T.
      Reprogramming of mitochondria provides cells with the metabolic flexibility required to adapt to various developmental transitions such as stem cell activation or immune cell reprogramming, and to respond to environmental challenges such as those encountered under hypoxic conditions or during tumorigenesis1-3. Here we show that the i-AAA protease YME1L rewires the proteome of pre-existing mitochondria in response to hypoxia or nutrient starvation. Inhibition of mTORC1 induces a lipid signalling cascade via the phosphatidic acid phosphatase LIPIN1, which decreases phosphatidylethanolamine levels in mitochondrial membranes and promotes proteolysis. YME1L degrades mitochondrial protein translocases, lipid transfer proteins and metabolic enzymes to acutely limit mitochondrial biogenesis and support cell growth. YME1L-mediated mitochondrial reshaping supports the growth of pancreatic ductal adenocarcinoma (PDAC) cells as spheroids or xenografts. Similar changes to the mitochondrial proteome occur in the tumour tissues of patients with PDAC, suggesting that YME1L is relevant to the pathophysiology of these tumours. Our results identify the mTORC1-LIPIN1-YME1L axis as a post-translational regulator of mitochondrial proteostasis at the interface between metabolism and mitochondrial dynamics.
    DOI:  https://doi.org/10.1038/s41586-019-1738-6
  2. Cell Rep. 2019 Nov 05. pii: S2211-1247(19)31269-0. [Epub ahead of print]29(6): 1399-1409.e5
    Aspernig H, Heimbucher T, Qi W, Gangurde D, Curic S, Yan Y, Donner von Gromoff E, Baumeister R, Thien A.
      Autophagy is stimulated by stress conditions and needs to be precisely tuned to ensure cellular homeostasis and organismal development and health. The kinase mechanistic target of rapamycin (mTOR) forms the enzymatic core of the highly conserved mTOR complexes mTORC1 and mTORC2. mTORC1 is a key inhibitor of autophagy, yet the function of mTORC2 in autophagy is controversial. We here show that inactivation of mTORC2 and its direct target serum- and glucocorticoid-inducible kinase 1 (SGK-1) potently induces autophagy and the autophagic degradation of mitochondria in C. elegans. Enhanced autophagy in mTORC2- or SGK-1-deficient animals contributes to their developmental and reproductive defects and is independent of the canonical SGK-1 effector DAF-16/FOXO. Importantly, we find that inactivation of mTORC2-SGK-1 signaling impairs mitochondrial homeostasis and triggers an increased release of mitochondria-derived reactive oxygen species (mtROS) to induce autophagy. Thus, mitochondrial stress couples reduced mTORC2 activity to enhanced autophagic turnover.
    Keywords:  ROS; SGK-1; autophagy; mTOR; mTORC2; mammalian target of rapamycin; mitochondria; mitophagy; reactive oxygen species; serum glucocorticoid-regulated kinase 1
    DOI:  https://doi.org/10.1016/j.celrep.2019.09.072
  3. Mol Cell Biol. 2019 Nov 04. pii: MCB.00212-19. [Epub ahead of print]
    Shaw E, Talwadekar M, Rashida Z, Mohan N, Acharya A, Khatri S, Laxman S, Kolthur-Seetharam U.
      Anabolic and catabolic signalling mediated via mTOR and AMPK have to be intrinsically coupled to mitochondrial functions for maintaining homeostasis and mitigate cellular/organismal stress. Although, glutamine is known to activate mTOR, if/how differential mitochondrial utilization of glutamine impinges on mTOR signalling is less explored. Mitochondrial SIRT4, which unlike other sirtuins is induced in a fed state, is known to inhibit catabolic signalling/pathways through AMPK-PGC1α/SIRT1-PPARα axis and negatively regulate glutamine metabolism via TCA cycle. However, physiological significance of SIRT4 functions during a fed state is still unknown. Here, we establish SIRT4 as key anabolic factor that activates TORC1 signalling and regulates lipogenesis, autophagy and cell proliferation. Mechanistically, we demonstrate that the ability of SIRT4 to inhibit anaplerotic conversion of glutamine to α-ketoglutarate potentiates TORC1. Interestingly, we also show that mitochondrial glutamine sparing or utilization is critical for differentially regulating TORC1 under fed and fasted conditions. Moreover, we conclusively show that differential expression of SIRT4 during fed and fasted states is vital for coupling mitochondrial energetics and glutamine utilization with anabolic pathways. These significant findings also illustrate that SIRT4 integrates nutrient inputs with mitochondrial retrograde signals to maintain a balance between anabolic and catabolic pathways.
    DOI:  https://doi.org/10.1128/MCB.00212-19
  4. Nat Rev Cancer. 2019 Nov 04.
    Hoxhaj G, Manning BD.
      The altered metabolic programme of cancer cells facilitates their cell-autonomous proliferation and survival. In normal cells, signal transduction pathways control core cellular functions, including metabolism, to couple the signals from exogenous growth factors, cytokines or hormones to adaptive changes in cell physiology. The ubiquitous, growth factor-regulated phosphoinositide 3-kinase (PI3K)-AKT signalling network has diverse downstream effects on cellular metabolism, through either direct regulation of nutrient transporters and metabolic enzymes or the control of transcription factors that regulate the expression of key components of metabolic pathways. Aberrant activation of this signalling network is one of the most frequent events in human cancer and serves to disconnect the control of cell growth, survival and metabolism from exogenous growth stimuli. Here we discuss our current understanding of the molecular events controlling cellular metabolism downstream of PI3K and AKT and of how these events couple two major hallmarks of cancer: growth factor independence through oncogenic signalling and metabolic reprogramming to support cell survival and proliferation.
    DOI:  https://doi.org/10.1038/s41568-019-0216-7
  5. Cell Death Dis. 2019 Nov 07. 10(11): 851
    Kleih M, Böpple K, Dong M, Gaißler A, Heine S, Olayioye MA, Aulitzky WE, Essmann F.
      Patients with high-grade serous ovarian cancer (HGSC) frequently receive platinum-based chemotherapeutics, such as cisplatin. Cisplatin binds to DNA and induces DNA-damage culminating in mitochondria-mediated apoptosis. Interestingly, mitochondrial DNA is critically affected by cisplatin but its relevance in cell death induction is scarcely investigated. We find that cisplatin sensitive HGSC cell lines contain higher mitochondrial content and higher levels of mitochondrial ROS (mtROS) than cells resistant to cisplatin induced cell death. In clonal sub-lines from OVCAR-3 mitochondrial content and basal oxygen consumption rate correlate with sensitivity to cisplatin induced apoptosis. Mitochondria are in two ways pivotal for cisplatin sensitivity because not only knock-down of BAX and BAK but also the ROS scavenger glutathione diminish cisplatin induced apoptosis. Mitochondrial ROS correlates with mitochondrial content and reduction of mitochondrial biogenesis by knock-down of transcription factors PGC1α or TFAM attenuates both mtROS induction and cisplatin induced apoptosis. Increasing mitochondrial ROS by inhibition or knock-down of the ROS-protective uncoupling protein UCP2 enhances cisplatin induced apoptosis. Similarly, enhancing ROS by high-dose ascorbic acid or H2O2 augments cisplatin induced apoptosis. In summary, mitochondrial content and the resulting mitochondrial capacity to produce ROS critically determine HGSC cell sensitivity to cisplatin induced apoptosis. In line with this observation, data from the human protein atlas (www.proteinatlas.org) indicates that high expression of mitochondrial marker proteins (TFAM and TIMM23) is a favorable prognostic factor in ovarian cancer patients. Thus, we propose mitochondrial content as a biomarker for the response to platinum-based therapies. Functionally, this might be exploited by increasing mitochondrial content or mitochondrial ROS production to enhance sensitivity to cisplatin based anti-cancer therapies.
    DOI:  https://doi.org/10.1038/s41419-019-2081-4
  6. J Mol Biol. 2019 Nov 02. pii: S0022-2836(19)30611-4. [Epub ahead of print]
    Fritsch LE, Moore ME, Sarraf SA, Pickrell AM.
      Selective autophagy of mitochondria, or mitophagy, refers to the specific removal and degradation of damaged or surplus mitochondria via targeting to the lysosome for destruction. Disruptions in this homeostatic process may contribute to disease. The identification of diverse mitophagic pathways and how selectivity for each of these pathways is conferred is just beginning to be understood. The removal of both damaged and healthy mitochondria under disease and physiological conditions is controlled by either ubiquitin-dependent or receptor-dependent mechanisms. In this review, we will discuss the known types of mitophagy observed in mammals, recent findings related to PINK1/Parkin-mediated mitophagy (which is the most well-studied form of mitophagy), discuss the implications of defective mitophagy to neurodegenerative processes, and unanswered questions inspiring future research that would enhance our understanding of mitochondrial quality control.
    Keywords:  ATG8; BNIP3L/Nix; PINK1/Parkin; autophagosome; mitochondria; ubiquitin
    DOI:  https://doi.org/10.1016/j.jmb.2019.10.015
  7. Mol Metab. 2019 Oct 18. pii: S2212-8778(19)30921-4. [Epub ahead of print]
    Lacroix M, Riscal R, Arena G, Linares LK, Le Cam L.
      BACKGROUND: The TP53 gene is one of the most commonly inactivated tumor suppressors in human cancers. p53 functions during cancer progression have been linked to a variety of transcriptional and non-transcriptional activities that lead to the tight control of cell proliferation, senescence, DNA repair, and cell death. However, converging evidence indicates that p53 also plays a major role in metabolism in both normal and cancer cells.SCOPE OF REVIEW: We provide an overview of the current knowledge on the metabolic activities of wild type (WT) p53 and highlight some of the mechanisms by which p53 contributes to whole body energy homeostasis. We will also pinpoint some evidences suggesting that deregulation of p53-associated metabolic activities leads to human pathologies beyond cancer, including obesity, diabetes, liver, and cardiovascular diseases.
    MAJOR CONCLUSIONS: p53 is activated when cells are metabolically challenged but the origin, duration, and intensity of these stresses will dictate the outcome of the p53 response. p53 plays pivotal roles both upstream and downstream of several key metabolic regulators and is involved in multiple feedback-loops that ensure proper cellular homeostasis. The physiological roles of p53 in metabolism involve complex mechanisms of regulation implicating both cell autonomous effects as well as autocrine loops. However, the mechanisms by which p53 coordinates metabolism at the organismal level remain poorly understood. Perturbations of p53-regulated metabolic activities contribute to various metabolic disorders and are pivotal during cancer progression.
    Keywords:  Cancer; Metabolism; Normal tissue homeostasis; p53
    DOI:  https://doi.org/10.1016/j.molmet.2019.10.002
  8. Front Oncol. 2019 ;9 1053
    Romero-Garcia S, Prado-Garcia H, Valencia-Camargo AD, Alvarez-Pulido A.
      Lactic acidosis, glucose deprivation and hypoxia are conditions frequently found in solid tumors because, among other reasons, tumors switch to Warburg effect and secrete high levels of lactate, which decreases the pH (<6. 9) in the microenvironment. We hypothesized that lung cancer cells consume lactate and induce mitochondrial biogenesis to support survival and proliferation in lactic acidosis with glucose deprivation even under hypoxia. We examined lung adenocarcinoma cell lines (A-427 and A-549), a breast cancer cell line (MCF-7) and non-transformed fibroblasts (MRC-5). Cells were cultured using RPMI-1640 medium with 28 mM lactate varying pH (6.2 or 7.2) under normoxia (atmospheric O2) or hypoxia (2% O2). Cellular growth was followed during 96 h, as well as lactate, glutamine and glutamate levels, which were measured using a biochemical analyzer. The expression levels of monocarboxylate transporters (MCT1 and MCT4) were evaluated by flow cytometry. To evaluate mitochondrial biogenesis, mitochondrial mass was analyzed by flow cytometry and epifluorescence microscopy. Also, mitochondrial DNA (mtDNA) was measured by qPCR. Transcript levels of Nuclear Respiratory Factors (NRF-1 and NRF-2) and Transcription Factor A Mitochondrial (TFAM) were determined using RT-qPCR. The specific growth rate of A-549 and A-427 cells increased in lactic acidosis compared with neutral lactosis, either under normoxia or hypoxia, a phenomenon that was not observed in MRC-5 fibroblasts. Under hypoxia, A-427 and MCF-7 cells did not survive in neutral lactosis but survived in lactic acidosis. Under lactic acidosis, A-427 and MCF-7 cells increased MCT1 levels, reduced MCT4 levels and consumed higher lactate amounts, while A-549 cells consumed glutamine and decreased MCT1 and MCT4 levels with respect to neutral lactosis condition. Lactic acidosis, either under normoxia or hypoxia, increased mitochondrial mass and mtDNA levels compared with neutral lactosis in all tumor cells but not in fibroblasts. A-549 and MCF-7 cells increased levels of NRF-1, NRF-2, and TFAM with respect to MRC-5 cells, whereas A-427 cells upregulated these transcripts under lactic acidosis compared with neutral lactosis. Thus, lung adenocarcinoma cells induce mitochondrial biogenesis to support survival and proliferation in lactic acidosis with glucose deprivation.
    Keywords:  glucose deprivation; glutamine; mitochondrial DNA (mtDNA); mitochondrial mass; monocarboxylate transporter (MCT); nuclear respiratory factor (NRF); tumor growth rate
    DOI:  https://doi.org/10.3389/fonc.2019.01053
  9. Nat Commun. 2019 Nov 07. 10(1): 5072
    Nilsson A, Björnson E, Flockhart M, Larsen FJ, Nielsen J.
      Human muscles are tailored towards ATP synthesis. When exercising at high work rates muscles convert glucose to lactate, which is less nutrient efficient than respiration. There is hence a trade-off between endurance and power. Metabolic models have been developed to study how limited catalytic capacity of enzymes affects ATP synthesis. Here we integrate an enzyme-constrained metabolic model with proteomics data from muscle fibers. We find that ATP synthesis is constrained by several enzymes. A metabolic bypass of mitochondrial complex I is found to increase the ATP synthesis rate per gram of protein compared to full respiration. To test if this metabolic mode occurs in vivo, we conduct a high resolved incremental exercise tests for five subjects. Their gas exchange at different work rates is accurately reproduced by a whole-body metabolic model incorporating complex I bypass. The study therefore shows how proteome allocation influences metabolism during high intensity exercise.
    DOI:  https://doi.org/10.1038/s41467-019-12934-8
  10. J Cell Biol. 2019 Nov 05. pii: jcb.201907022. [Epub ahead of print]
    Reina-Campos M, Diaz-Meco MT, Moscat J.
      The serine glycine and one-carbon pathway (SGOCP) is a crucially important metabolic network for tumorigenesis, of unanticipated complexity, and with implications in the clinic. Solving how this network is regulated is key to understanding the underlying mechanisms of tumor heterogeneity and therapy resistance. Here, we review its role in cancer by focusing on key enzymes with tumor-promoting functions and important products of the SGOCP that are of physiological relevance for tumorigenesis. We discuss the regulatory mechanisms that coordinate the metabolic flux through the SGOCP and their deregulation, as well as how the actions of this metabolic network affect other cells in the tumor microenvironment, including endothelial and immune cells.
    DOI:  https://doi.org/10.1083/jcb.201907022
  11. Front Immunol. 2019 ;10 2386
    Basit F, de Vries IJM.
      Dendritic cell (DCs) activation by Toll-like receptor (TLR) agonist induces robust metabolic rewiring toward glycolysis. Recent findings in the field identified mechanistic details governing these metabolic adaptations. However, it is unknown whether a switch to glycolysis from oxidative phosphorylation (OXPHOS) is a general characteristic of DCs upon pathogen encounter. Here we show that engagement of different TLR triggers differential metabolic adaptations in DCs. We demonstrate that LPS-mediated TLR4 stimulation induces glycolysis in DCs. Conversely, activation of TLR7/8 with protamine-RNA complex, pRNA, leads to an increase in OXPHOS. Mechanistically, we found that pRNA stimulation phosphorylates BCKDE1α in a PINK1-dependent manner. pRNA stimulation increased branched-chain amino acid levels and increased fatty acid oxidation. Increased FAO and OXPHOS are required for DC activation. PINK1 deficient DCs switch to glycolysis to maintain ATP levels and viability. Moreover, pharmacological induction of PINK1 kinase activity primed immunosuppressive DC for immunostimulatory function. Our findings provide novel insight into differential metabolic adaptations and reveal the important role of branched-chain amino acid in regulating immune response in DC.
    Keywords:  PINK1; branched chain amino acid (BCAA); dendritic cell metabolism; fatty acid oxidation (FAO); toll like 7/8 receptors
    DOI:  https://doi.org/10.3389/fimmu.2019.02386
  12. RNA Biol. 2019 Nov 07.
    Ayyub SA, Varshney U.
      ATP is generated in mitochondria of eukaryotic cells by oxidative phosphorylation (OXPHOS). The OXPHOS complex, which is crucial for cellular metabolism, comprises of both nuclear and mitochondrially encoded subunits. Also, the occurrence of several pathologies because of mutations in the mitochondrial translation apparatus indicates the importance of mitochondrial translation and its regulation. The mitochondrial translation apparatus is similar to its prokaryotic counterpart due to a common origin of evolution. However, mitochondrial translation has diverged from prokaryotic translation in many ways by reductive evolution. In this review, we focus on mammalian mitochondrial translation initiation, a highly regulated step of translation, and present a comparison with prokaryotic translation.
    Keywords:  mammalian mitochondria; mitochondrial disease; mitoribosome; protein synthesis; ribosome; translation initiation
    DOI:  https://doi.org/10.1080/15476286.2019.1690099
  13. Cell Rep. 2019 Nov 05. pii: S2211-1247(19)31284-7. [Epub ahead of print]29(6): 1728-1738.e9
    Busch JD, Cipullo M, Atanassov I, Bratic A, Silva Ramos E, Schöndorf T, Li X, Pearce SF, Milenkovic D, Rorbach J, Larsson NG.
      Mitochondria harbor specialized ribosomes (mitoribosomes) necessary for the synthesis of key membrane proteins of the oxidative phosphorylation (OXPHOS) machinery located in the mitochondrial inner membrane. To date, no animal model exists to study mitoribosome composition and mitochondrial translation coordination in mammals in vivo. Here, we create MitoRibo-Tag mice as a tool enabling affinity purification and proteomics analyses of mitoribosomes and their interactome in different tissues. We also define the composition of an assembly intermediate formed in the absence of MTERF4, necessary for a late step in mitoribosomal biogenesis. We identify the orphan protein PUSL1, which interacts with a large subunit assembly intermediate, and demonstrate that it is an inner-membrane-associated mitochondrial matrix protein required for efficient mitochondrial translation. This work establishes MitoRibo-Tag mice as a powerful tool to study mitoribosomes in vivo, enabling future studies on the mitoribosome interactome under different physiological states, as well as in disease and aging.
    Keywords:  MitoRibo-Tag mice; OXPHOS; in vivo mouse model; mitochondria; mitochondrial DNA; mitochondrial biogenesis; mitochondrial gene expression; mitochondrial ribosome; ribosome; translation
    DOI:  https://doi.org/10.1016/j.celrep.2019.09.080
  14. Autophagy. 2019 Nov 07. 1-3
    Puri R, Cheng XT, Lin MY, Huang N, Sheng ZH.
      Chronic mitochondrial stress is associated with major neurodegenerative diseases; and thus, the recovery of those mitochondria constitutes a critical step of energy maintenance in early stages of neurodegeneration. Our recent study provides the first lines of evidence showing that the MUL1-MFN2 pathway acts as an early checkpoint to maintain mitochondrial integrity by regulating mitochondrial morphology and interplay with the endoplasmic reticulum (ER). This mechanism ensures that degradation through mitophagy is restrained in neurons under early stress conditions. MUL1 deficiency increases MFN2 activity, triggering the first phase of mitochondrial hyperfusion and acting as an antagonist of ER-mitochondria (ER-Mito) tethering. Reduced ER-Mito interplay enhances the cytoplasmic Ca2+ load that induces the DNM1L/Drp1-dependent second phase of mitochondrial fragmentation and mitophagy. Our study provides new mechanistic insights into neuronal mitochondrial maintenance under stress conditions. Identifying this pathway is particularly relevant because chronic mitochondrial dysfunction and altered ER-Mito contacts have been reported in major neurodegenerative diseases.
    Keywords:  DNM1L; ER-Mitochondrial contact; MUL1; Mfn2; PRKN; endoplasmic reticulum; mitochondrial ubiquitin ligase; mitophagy; neuronal mitochondria
    DOI:  https://doi.org/10.1080/15548627.2019.1687216
  15. Autophagy. 2019 Nov 05.
    Zhang Z, Yan J, Bowman AB, Bryan MR, Singh R, Aschner M.
      Epidemiological and clinical studies have long shown that exposure to high levels of heavy metals are associated with increased risks of neurodegenerative diseases. It is widely accepted that autophagic dysfunction is involved in pathogenesis of various neurodegenerative disorders; however, the role of heavy metals in regulation of macroautophagy/autophagy is unclear. Here, we show that manganese (Mn) induces a decline in nuclear localization of TFEB (transcription factor EB), a master regulator of the autophagy-lysosome pathway, leading to autophagic dysfunction in astrocytes of mouse striatum. We further show that Mn exposure suppresses autophagic-lysosomal degradation of mitochondria and induces accumulation of unhealthy mitochondria. Activation of autophagy by rapamycin or TFEB overexpression ameliorates Mn-induced mitochondrial respiratory dysfunction and reactive oxygen species (ROS) generation in astrocytes, suggesting a causal relation between autophagic failure and mitochondrial dysfunction in Mn toxicity. Taken together, our data demonstrate that Mn inhibits TFEB activity, leading to impaired autophagy that is causally related to mitochondrial dysfunction in astrocytes. These findings reveal a previously unappreciated role for Mn in dysregulation of autophagy and identify TFEB as a potential therapeutic target to mitigate Mn toxicity.
    Keywords:  TFEB; astrocytes; autophagy; manganese toxicity; mitochondrial dysfunction; rapamycin
    DOI:  https://doi.org/10.1080/15548627.2019.1688488
  16. Cell Metab. 2019 Nov 05. pii: S1550-4131(19)30565-0. [Epub ahead of print]30(5): 845-846
    Weber R, Birsoy K.
      Cells can take up cysteine or synthesize it de novo from methionine, but synthesis alone does not meet the high demands of cancer cells to proliferate. In this issue, Zhu et al. (2019) identify the SAH:SAM ratio, indicative of the cellular methylation state, as limiting for effective cysteine synthesis and the growth of some tumors.
    DOI:  https://doi.org/10.1016/j.cmet.2019.10.009
  17. Semin Cancer Biol. 2019 Nov 02. pii: S1044-579X(19)30271-8. [Epub ahead of print]
    Ooi A.
      Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC) is an autosomal dominant hereditary cancer syndrome with incomplete penetrance. It is caused by a germline amorphic allele of the FH gene, which encodes the TCA cycle enzyme, fumarate hydratase (FH). HLRCC patients are genetically predisposed to develop skin leiomyomas, uterine fibroids, and the aggressive kidney cancer of type 2 papillary morphology. Loss-of-heterozygocity at the FH locus that cause a complete loss of FH enzymatic function is always detected in these tumor tissues. Molecular pathway elucidation, genomic studies, and systematic genetics screens reported over the last two decades have identified several FH-inactivation driven pathways alterations, as well as rationally conceived treatment strategies that specifically target FH-/- tumor cells. These treatment strategies include ferroptosis induction, oxidative stress promotion, and metabolic alteration. As the fundamental biology of HLRCC continues to be uncovered, these treatment strategies continue to be refined and may one day lead to a strategy to prevent disease onset among HLRCC patients. With a more complete picture of HLRCC biology, the safe translation of experimental treatment strategies into clinical practice is achievable in the foreseeable future.
    DOI:  https://doi.org/10.1016/j.semcancer.2019.10.016
  18. Trends Endocrinol Metab. 2019 Nov 04. pii: S1043-2760(19)30208-5. [Epub ahead of print]
    Arias E, Cuervo AM.
      Autophagy contributes to cellular quality control and energetics through lysosomal breakdown and recycling of essential cellular components. Chaperone-mediated autophagy (CMA) adds to these autophagic functions the ability to timely and selectively degrade single tagged proteins to terminate their cellular function and, in this way, participate in the regulation of multiple cellular processes. Many cancer cells upregulate CMA for protumorigenic and prosurvival purposes. However, growing evidence supports a physiological role for CMA in limiting malignant transformation. Understanding the mechanisms behind this functional switch of CMA from antioncogenic to pro-oncogenic is fundamental for targeting CMA in cancer treatment. We summarize current understanding of CMA functions in cancer biology and discuss the basis for its context-dependent dual role in oncogenesis.
    Keywords:  chaperones; lysosomes; metabolism; oncogenes; protein degradation; tumorigenesis
    DOI:  https://doi.org/10.1016/j.tem.2019.09.007
  19. Autophagy. 2019 Nov 06. 1-2
    Zhang H, Simon AK.
      Organismal aging is associated with compromised cellular function, which can be partially attributed to accumulation of cellular damage. Being the major, if not only, cellular bulk-degradation mechanism, macroautophagy (hereafter autophagy) declines with age in multiple tissues and organisms. Spermidine is an endogenous polyamine metabolite that also declines with age. It prolongs lifespan and improves tissue functions of model organisms in an autophagy-dependent manner. We report that autophagic flux is significantly reduced in B cells from old mice. Spermidine induces autophagy and improves the function of both old mouse and old human B cells. Mechanistically, spermidine post-translationally modifies (hypusinates) the translation factor EIF5A. Hypusinated EIF5A specifically regulates the synthesis of the master autophagy and lysosome transcription factor, TFEB (transcription factor EB). This pathway declines with age in both mice and humans, which may eventually lead to declining autophagy and impaired tissue functions in old individuals.
    Keywords:  Aging; B cells; EIF5A; TFEB; autophagy; hypusine; spermidine; translation
    DOI:  https://doi.org/10.1080/15548627.2019.1687967
  20. Front Oncol. 2019 ;9 965
    Gimple RC, Wang X.
      Cancer is a devastating disease process that touches the lives of millions worldwide. Despite advances in our understanding of the genomic architecture of cancers and the mechanisms that underlie cancer development, a great therapeutic challenge remains. Here, we revisit the birthplace of cancer biology and review how one of the first discovered oncogenes, RAS, drives cancers in new and unexpected ways. As our understanding of oncogenic signaling has evolved, it is clear that RAS signaling is not homogenous, but activates distinct downstream effectors in different cancer types and grades. RAS signaling is tightly controlled through a series of post-transcriptional mechanisms, which are frequently distorted in the context of cancer, and establish key metabolic and immunologic states that support cancer growth, migration, survival, metastasis, and plasticity. While targeting RAS has been fiercely pursued for decades, new strategies have recently emerged with the potential for therapeutic efficacy. Thus, understanding the complexities of RAS biology may translate into improved therapies for patients with RAS-driven cancers.
    Keywords:  RAS; cancer; cancer therapy; immunology; metabolism; mitogen activated kinase
    DOI:  https://doi.org/10.3389/fonc.2019.00965
  21. Biochim Biophys Acta Gene Regul Mech. 2019 Nov 01. pii: S1874-9399(19)30213-5. [Epub ahead of print] 194436
    Choi S, Pfleger J, Jeon YH, Yang Z, He M, Shin H, Sayed D, Astrof S, Abdellatif M.
      Histone H2A.Z plays an essential role in regulating transcriptional rates and memory. Interestingly, H2A.Z-bound nucleosomes are located in both transcriptionally active and inactive promotors, with no clear understanding of the mechanisms via which it differentially regulates transcription. We hypothesized that its functions are mediated through recruitment of regulatory proteins to promoters. Using rapid chromatin immunoprecipitation-mass spectrometry, we uncovered the association of H2A.Z-bound chromatin with the metabolic enzymes, oxoglutarate dehydrogenase (OGDH) and acetyl-CoA acyltransferase 2 (ACAA2). Recombinant green florescence fusion proteins, combined with mutations of predicted nuclear localization signals, confirmed their nuclear localization and chromatin binding. Conclusively, chromatin immunoprecipitation-deep sequencing, confirmed the predominant association of OGDH and ACAA2 with H2A.Z-occupied transcription start sites and enhancers, the former of which we confirmed is conserved in both mouse and human tissue. Furthermore, H2A.Z-deficient human HAP1 cells exhibited reduced chromatin-bound metabolic enzymes, accompanied with reduced posttranslational histone modifications, including acetylation and succinylation. Specifically, knockdown of OGDH diminished H4 succinylation. Thus, the data reveal that select metabolic enzymes are assembled at active, H2A.Z-occupied, promoters, for potential site-directed production of metabolic intermediates that are required for histone modifications.
    Keywords:  ACAA2; Chromatin immunoprecipitation; H2A.Z; Histone acetylation; Histone succinylation; Mitochondria; OGDH
    DOI:  https://doi.org/10.1016/j.bbagrm.2019.194436
  22. Nat Med. 2019 Nov 07.
    Gómez-Banoy N, Guseh JS, Li G, Rubio-Navarro A, Chen T, Poirier B, Putzel G, Rosselot C, Pabón MA, Camporez JP, Bhambhani V, Hwang SJ, Yao C, Perry RJ, Mukherjee S, Larson MG, Levy D, Dow LE, Shulman GI, Dephoure N, Garcia-Ocana A, Hao M, Spiegelman BM, Ho JE, Lo JC.
      Type 2 diabetes is characterized by insulin resistance and a gradual loss of pancreatic beta cell mass and function1,2. Currently, there are no therapies proven to prevent beta cell loss and some, namely insulin secretagogues, have been linked to accelerated beta cell failure, thereby limiting their use in type 2 diabetes3,4. The adipokine adipsin/complement factor D controls the alternative complement pathway and generation of complement component C3a, which acts to augment beta cell insulin secretion5. In contrast to other insulin secretagogues, we show that chronic replenishment of adipsin in diabetic db/db mice ameliorates hyperglycemia and increases insulin levels while preserving beta cells by blocking dedifferentiation and death. Mechanistically, we find that adipsin/C3a decreases the phosphatase Dusp26; forced expression of Dusp26 in beta cells decreases expression of core beta cell identity genes and sensitizes to cell death. In contrast, pharmacological inhibition of DUSP26 improves hyperglycemia in diabetic mice and protects human islet cells from cell death. Pertaining to human health, we show that higher concentrations of circulating adipsin are associated with a significantly lower risk of developing future diabetes among middle-aged adults after adjusting for body mass index (BMI). Collectively, these data suggest that adipsin/C3a and DUSP26-directed therapies may represent a novel approach to achieve beta cell health to treat and prevent type 2 diabetes.
    DOI:  https://doi.org/10.1038/s41591-019-0610-4
  23. Cell Rep. 2019 Nov 05. pii: S2211-1247(19)31267-7. [Epub ahead of print]29(6): 1511-1523.e5
    Wang Y, An H, Liu T, Qin C, Sesaki H, Guo S, Radovick S, Hussain M, Maheshwari A, Wondisford FE, O'Rourke B, He L.
      Impaired mitochondrial respiratory activity contributes to the development of insulin resistance in type 2 diabetes. Metformin, a first-line antidiabetic drug, functions mainly by improving patients' hyperglycemia and insulin resistance. However, its mechanism of action is still not well understood. We show here that pharmacological metformin concentration increases mitochondrial respiration, membrane potential, and ATP levels in hepatocytes and a clinically relevant metformin dose increases liver mitochondrial density and complex 1 activity along with improved hyperglycemia in high-fat- diet (HFD)-fed mice. Metformin, functioning through 5' AMP-activated protein kinase (AMPK), promotes mitochondrial fission to improve mitochondrial respiration and restore the mitochondrial life cycle. Furthermore, HFD-fed-mice with liver-specific knockout of AMPKα1/2 subunits exhibit higher blood glucose levels when treated with metformin. Our results demonstrate that activation of AMPK by metformin improves mitochondrial respiration and hyperglycemia in obesity. We also found that supra-pharmacological metformin concentrations reduce adenine nucleotides, resulting in the halt of mitochondrial respiration. These findings suggest a mechanism for metformin's anti-tumor effects.
    Keywords:  AMPK; Drp1; adenine nucleotides; diabetes; insulin resistance; membrane potential; metformin; mitochondrial respiration/fission
    DOI:  https://doi.org/10.1016/j.celrep.2019.09.070
  24. Cancer Res. 2019 Nov 06. pii: canres.1389.2019. [Epub ahead of print]
    Zhang Y, Nguyen TTT, Shang E, Mela A, Humala N, Mahajan A, Zhao J, Shu C, Torrini C, Sanchez-Quintero MJ, Kleiner G, Bianchetti E, Westhoff MA, Quinzii CM, Karpel-Massler G, Bruce JN, Canoll P, Siegelin MD.
      The receptor kinase c-MET has emerged as a target for glioblastoma therapy. However, treatment resistance emerges inevitably. Here, we performed global metabolite screening with metabolite set enrichment coupled with transcriptome and gene set enrichment analysis and proteomic screening, and identified substantial reprogramming of tumor metabolism involving oxidative phosphorylation and fatty acid oxidation (FAO) with substantial accumulation of acyl-carnitines accompanied by an increase of PGC1α in response to genetic (shRNA and CRISPR/Cas9) and pharmacological (crizotinib) inhibition of c-MET. Extracellular flux and carbon tracing analyses (U-13C-Glucose, U-13C-Glutamine and U-13C-palmitic acid) demonstrated enhanced oxidative metabolism, which was driven by FAO and supported by increased anaplerosis of glucose carbons. These findings were observed in concert with increased number and fusion of mitochondria and production of reactive oxygen species (ROS). Genetic interference with PGC1α rescued this oxidative phenotype driven by c-MET inhibition. Silencing and chromatin immunoprecipitation experiments demonstrated that CREB regulates the expression of PGC1α in the context of c-MET inhibition. Interference with both oxidative phosphorylation (metformin, oligomycin) and beta-oxidation of fatty acids (etomoxir) enhanced the anti-tumor efficacy of c-MET inhibition. Synergistic cell death was observed with c-MET inhibition and gamitrinib treatment. In patient-derived xenograft models, combination treatments of crizotinib and etomoxir, and crizotinib and gamitrinib were significantly more efficacious than single treatments and did not induce toxicity. Collectively, we have unraveled the mechanistic underpinnings of c-MET inhibition and identified novel combination therapies that may enhance its therapeutic efficacy.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-19-1389
  25. Nat Struct Mol Biol. 2019 Nov 06.
    Gorelik A, Bartual SG, Borodkin VS, Varghese J, Ferenbach AT, van Aalten DMF.
      Modification of specific Ser and Thr residues of nucleocytoplasmic proteins with O-GlcNAc, catalyzed by O-GlcNAc transferase (OGT), is an abundant posttranslational event essential for proper animal development and is dysregulated in various diseases. Due to the rapid concurrent removal by the single O-GlcNAcase (OGA), precise functional dissection of site-specific O-GlcNAc modification in vivo is currently not possible without affecting the entire O-GlcNAc proteome. Exploiting the fortuitous promiscuity of OGT, we show that S-GlcNAc is a hydrolytically stable and accurate structural mimic of O-GlcNAc that can be encoded in mammalian systems with CRISPR-Cas9 in an otherwise unperturbed O-GlcNAcome. Using this approach, we target an elusive Ser 405 O-GlcNAc site on OGA, showing that this site-specific modification affects OGA stability.
    DOI:  https://doi.org/10.1038/s41594-019-0325-8
  26. Science. 2019 Nov 07. pii: eaav2588. [Epub ahead of print]
    Leone RD, Zhao L, Englert JM, Sun IM, Oh MH, Sun IH, Arwood ML, Bettencourt IA, Patel CH, Wen J, Tam A, Blosser RL, Prchalova E, Alt J, Rais R, Slusher BS, Powell JD.
      The metabolic characteristics of tumors present significant hurdles to immune cell function and cancer immunotherapy. Using a novel glutamine antagonist, we metabolically dismantled the immunosuppressive microenvironment of tumors. We demonstrate that glutamine blockade in tumor-bearing mice suppresses oxidative and glycolytic metabolism of cancer cells, leading to decreased hypoxia, acidosis, and nutrient depletion. In contrast, effector T cells responded to glutamine antagonism by markedly upregulating oxidative metabolism and adopting a long-lived, highly-activated phenotype. These divergent changes in cellular metabolism and programming form the basis for potent anti-tumor responses. Glutamine antagonism therefore exposes a previously undefined difference in metabolic plasticity between cancer cells and effector T cells that can be exploited as a "metabolic checkpoint" for tumor immunotherapy.
    DOI:  https://doi.org/10.1126/science.aav2588
  27. Cell. 2019 Nov 05. pii: S0092-8674(19)31213-9. [Epub ahead of print]
    Shen K, Rogala KB, Chou HT, Huang RK, Yu Z, Sabatini DM.
      mTORC1 controls anabolic and catabolic processes in response to nutrients through the Rag GTPase heterodimer, which is regulated by multiple upstream protein complexes. One such regulator, FLCN-FNIP2, is a GTPase activating protein (GAP) for RagC/D, but despite its important role, how it activates the Rag GTPase heterodimer remains unknown. We used cryo-EM to determine the structure of FLCN-FNIP2 in a complex with the Rag GTPases and Ragulator. FLCN-FNIP2 adopts an extended conformation with two pairs of heterodimerized domains. The Longin domains heterodimerize and contact both nucleotide binding domains of the Rag heterodimer, while the DENN domains interact at the distal end of the structure. Biochemical analyses reveal a conserved arginine on FLCN as the catalytic arginine finger and lead us to interpret our structure as an on-pathway intermediate. These data reveal features of a GAP-GTPase interaction and the structure of a critical component of the nutrient-sensing mTORC1 pathway.
    DOI:  https://doi.org/10.1016/j.cell.2019.10.036
  28. J Inherit Metab Dis. 2019 Nov 05.
    Veiga-da-Cunha M, Van Schaftingen E, Bommer GT.
      It is traditionally assumed that enzymes of intermediary metabolism are extremely specific and that this is sufficient to prevent the production of useless and/or toxic side-products. Recent work indicates that this statement is not entirely correct. In reality, enzymes are not strictly specific, they often display weak side activities on intracellular metabolites (substrate promiscuity) that resemble their physiological substrate or slowly catalyze abnormal reactions on their physiological substrate (catalytic promiscuity). They thereby produce non-classical metabolites that are not efficiently metabolized by conventional enzymes. In an increasing number of cases, metabolite repair enzymes are being discovered that serve to eliminate these non-classical metabolites and prevent their accumulation. Metabolite repair enzymes also eliminate non-classical metabolites that are formed through spontaneous (i.e., not enzyme-catalyzed) reactions. Importantly, genetic deficiencies in several metabolite repair enzymes lead to 'inborn errors of metabolite repair', such as L-2-hydroxyglutaric aciduria, D-2-hydroxyglutaric aciduria, 'ubiquitous glucose-6-phosphatase' (G6PC3) deficiency, the neutropenia present in Glycogen Storage Disease type Ib or defects in the enzymes that repair the hydrated forms of NADH or NADPH. Metabolite repair defects may be difficult to identify as such, because the mutated enzymes are non-classical enzymes that act on non-classical metabolites, which in some cases accumulate only inside the cells, and at rather low, yet toxic, concentrations. It is therefore likely that many additional metabolite repair enzymes remain to be discovered and that many diseases of metabolite repair still await elucidation. This article is protected by copyright. All rights reserved.
    DOI:  https://doi.org/10.1002/jimd.12187