bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2020‒04‒12
thirty-nine papers selected by
Christian Frezza
University of Cambridge, MRC Cancer Unit

  1. Cell Metab. 2020 Apr 07. pii: S1550-4131(20)30123-6. [Epub ahead of print]31(4): 852-861.e6
    Williams RT, Guarecuco R, Gates LA, Barrows D, Passarelli MC, Carey B, Baudrier L, Jeewajee S, La K, Prizer B, Malik S, Garcia-Bermudez J, Zhu XG, Cantor J, Molina H, Carroll T, Roeder RG, Abdel-Wahab O, Allis CD, Birsoy K.
      Activating transcription factor 4 (ATF4) is a master transcriptional regulator of the integrated stress response (ISR) that enables cell survival under nutrient stress. The mechanisms by which ATF4 couples metabolic stresses to specific transcriptional outputs remain unknown. Using functional genomics, we identified transcription factors that regulate the responses to distinct amino acid deprivation conditions. While ATF4 is universally required under amino acid starvation, our screens yielded a transcription factor, Zinc Finger and BTB domain-containing protein 1 (ZBTB1), as uniquely essential under asparagine deprivation. ZBTB1 knockout cells are unable to synthesize asparagine due to reduced expression of asparagine synthetase (ASNS), the enzyme responsible for asparagine synthesis. Mechanistically, ZBTB1 binds to the ASNS promoter and promotes ASNS transcription. Finally, loss of ZBTB1 sensitizes therapy-resistant T cell leukemia cells to L-asparaginase, a chemotherapeutic that depletes serum asparagine. Our work reveals a critical regulator of the nutrient stress response that may be of therapeutic value.
    Keywords:  ATF4; CRISPR; asparaginase; cancer metabolism; genetic screen; leukemia; transcription
  2. Autophagy. 2020 Apr 05.
    Hu Y, Chen H, Zhang L, Lin X, Li X, Zhuang H, Fan H, Meng T, He Z, Huang H, Gong Q, Zhu D, Xu Y, He P, Li L, Feng D.
      Energy deprivation activates the cellular energy sensor AMP-activated protein kinase (AMPK), which in turn induces macroautophagy/autophagy. The mitochondrial-associated ER membrane (MAM) plays a key role in mitochondrial division and autophagy, and the mitochondrial fusion protein MFN2 (mitofusin 2) tethers the MAM, but the mechanism by which AMPK and MFN2 regulate autophagy in response to energy stress remains unclear. Here, we found that energy stress not only triggers mitochondrial fission and autophagy, but more importantly increases the number of MAMs, a process that requires AMPK. Interestingly, under energy stress, considerable amounts of AMPK translocate from cytosol to the MAM and the mitochondrion as mitochondrial fission occurs. Unexpectedly, AMPK interacts directly with MFN2. The autophagic ability of mouse embryonic fibroblasts (MEFs) lacking MFN2 (mfn2-/-) is significantly attenuated in response to energy stress as compared to wild-type MEFs (WT MEFs), while re-expression of MFN2 in mfn2-/- cells rescues the autophagy defects of these cells. The abundance of MAMs is also greatly reduced in MFN2-deficient cells. Functional experiments show that the oxygen consumption rate and the glycolytic function of cells lacking MFN2 but not MFN1 are obviously attenuated, and MFN2 is important for cell survival under energy stress. In conclusion, our study establishes the molecular link between the energy sensor AMPK and the MAM tether MFN2, and reveals the important role of AMPK and MFN2 in energy stress-induced autophagy and MAM dynamics.
    Keywords:  AMPK; MAM; MFN2; autophagy; fusion; metformin; mitochondrial energy stress; mitochondrial fission; rotenone
  3. J Cell Biol. 2020 Jun 01. pii: e201907067. [Epub ahead of print]219(6):
    Liu YJ, McIntyre RL, Janssens GE, Williams EG, Lan J, van Weeghel M, Schomakers B, van der Veen H, van der Wel NN, Yao P, Mair WB, Aebersold R, MacInnes AW, Houtkooper RH.
      Mitochondrial form and function are closely interlinked in homeostasis and aging. Inhibiting mitochondrial translation is known to increase lifespan in C. elegans, and is accompanied by a fragmented mitochondrial network. However, whether this link between mitochondrial translation and morphology is causal in longevity remains uncharacterized. Here, we show in C. elegans that disrupting mitochondrial network homeostasis by blocking fission or fusion synergizes with reduced mitochondrial translation to prolong lifespan and stimulate stress response such as the mitochondrial unfolded protein response, UPRMT. Conversely, immobilizing the mitochondrial network through a simultaneous disruption of fission and fusion abrogates the lifespan increase induced by mitochondrial translation inhibition. Furthermore, we find that the synergistic effect of inhibiting both mitochondrial translation and dynamics on lifespan, despite stimulating UPRMT, does not require it. Instead, this lifespan-extending synergy is exclusively dependent on the lysosome biogenesis and autophagy transcription factor HLH-30/TFEB. Altogether, our study reveals the mechanistic crosstalk between mitochondrial translation, mitochondrial dynamics, and lysosomal signaling in regulating longevity.
  4. J Cell Sci. 2020 Apr 07. pii: jcs.237917. [Epub ahead of print]
    Martinez-Guzman O, Willoughby MM, Saini A, Dietz JV, Bohovych I, Medlock AE, Khalimonchuk O, Reddi AR.
      Heme is a cofactor and signaling molecule that is essential for much of aerobic life. All heme-dependent processes in eukaryotes require that heme is trafficked from its site of synthesis in the mitochondria to hemoproteins located throughout the cell. However, the mechanisms governing the mobilization of heme out of the mitochondria, and the spatio-temporal dynamics of these processes, are poorly understood. Herein, using genetically encoded fluorescent heme sensors, we developed a live cell assay to monitor heme distribution dynamics between the mitochondrial inner-membrane, where heme is synthesized, and the mitochondrial matrix, cytosol, and nucleus. Surprisingly, heme trafficking to the nucleus is ∼25% faster than to the cytosol or mitochondrial matrix, which are nearly identical, potentially supporting a role for heme as a mitochondrial-nuclear retrograde signal. Moreover, we discovered that the heme synthetic enzyme, 5-aminolevulinic acid synthase (ALAS), and GTPases in control of the mitochondrial dynamics machinery, Mgm1 and Dnm1, and ER contact sites, Gem1, regulate the flow of heme between the mitochondria and nucleus. Overall, our results indicate that there are parallel pathways for the distribution of bioavailable heme.
    Keywords:  Heme; Heme transport; Mitochondrial dynamics; Yeast
  5. Genes Dev. 2020 Apr 09.
    Qiao S, Koh SB, Vivekanandan V, Salunke D, Patra KC, Zaganjor E, Ross K, Mizukami Y, Jeanfavre S, Chen A, Mino-Kenudson M, Ramaswamy S, Clish C, Haigis M, Bardeesy N, Ellisen LW.
      Human cancers with activating RAS mutations are typically highly aggressive and treatment-refractory, yet RAS mutation itself is insufficient for tumorigenesis, due in part to profound metabolic stress induced by RAS activation. Here we show that loss of REDD1, a stress-induced metabolic regulator, is sufficient to reprogram lipid metabolism and drive progression of RAS mutant cancers. Redd1 deletion in genetically engineered mouse models (GEMMs) of KRAS-dependent pancreatic and lung adenocarcinomas converts preneoplastic lesions into invasive and metastatic carcinomas. Metabolic profiling reveals that REDD1-deficient/RAS mutant cells exhibit enhanced uptake of lysophospholipids and lipid storage, coupled to augmented fatty acid oxidation that sustains both ATP levels and ROS-detoxifying NADPH. Mechanistically, REDD1 loss triggers HIF-dependent activation of a lipid storage pathway involving PPARγ and the prometastatic factor CD36. Correspondingly, decreased REDD1 expression and a signature of REDD1 loss predict poor outcomes selectively in RAS mutant but not RAS wild-type human lung and pancreas carcinomas. Collectively, our findings reveal the REDD1-mediated stress response as a novel tumor suppressor whose loss defines a RAS mutant tumor subset characterized by reprogramming of lipid metabolism, invasive and metastatic progression, and poor prognosis. This work thus provides new mechanistic and clinically relevant insights into the phenotypic heterogeneity and metabolic rewiring that underlies these common cancers.
    Keywords:  RAS; REDD1; energy stress; fatty acid oxidation; glycolysis; lipid metabolism; lysophospholipids; metastasis; oxidative stress
  6. Int Rev Cell Mol Biol. 2020 ;pii: S1937-6448(20)30008-3. [Epub ahead of print]351 101-148
    Rosa N, Sneyers F, Parys JB, Bultynck G.
      Inositol 1,4,5-trisphosphate (IP3) receptors (IP3Rs), intracellular calcium (Ca2+) release channels, fulfill key functions in cell death and survival processes, whose dysregulation contributes to oncogenesis. This is essentially due to the presence of IP3Rs in microdomains of the endoplasmic reticulum (ER) in close proximity to the mitochondria. As such, IP3Rs enable efficient Ca2+ transfers from the ER to the mitochondria, thus regulating metabolism and cell fate. This review focuses on one of the three IP3R isoforms, the type 3 IP3R (IP3R3), which is linked to proapoptotic ER-mitochondrial Ca2+ transfers. Alterations in IP3R3 expression have been highlighted in numerous cancer types, leading to dysregulations of Ca2+ signaling and cellular functions. However, the outcome of IP3R3-mediated Ca2+ transfers for mitochondrial function is complex with opposing effects on oncogenesis. IP3R3 can either suppress cancer by promoting cell death and cellular senescence or support cancer by driving metabolism, anabolic processes, cell cycle progression, proliferation and invasion. The aim of this review is to provide an overview of IP3R3 dysregulations in cancer and describe how such dysregulations alter critical cellular processes such as proliferation or cell death and survival. Here, we pose that the IP3R3 isoform is not only linked to proapoptotic ER-mitochondrial Ca2+ transfers but might also be involved in prosurvival signaling.
    Keywords:  Apoptosis; Calcium signaling; Cancer; Cell death; Cell survival; Expression; ITPR3; Inositol 1,4,5-trisphosphate receptors; Modulation; Oncogenesis; Tumor suppressor
  7. Cell Chem Biol. 2020 Apr 06. pii: S2451-9456(20)30109-4. [Epub ahead of print]
    Conrad M, Proneth B.
      The trace elements iron and selenium play decisive roles in a distinct form of necrotic cell death, known as ferroptosis. While iron promotes ferroptosis by contributing to Fenton-type reactions and uncontrolled lipid autoxidation, the hallmark of ferroptosis, selenium in the form of glutathione peroxidase 4 (GPX4), subdues phospholipid peroxidation and associated cell death. Beyond the canonical cystine/glutamate antiporter system xc-/glutathione/GPX4 nexus, recent studies unveiled the second mainstay in ferroptosis entailing extra-mitochondrial ubiquinone, ferroptosis suppressor protein 1, and NAD(P)H as electron donor. Unlike GPX4, this selenium- and thiol-independent system acts on the level of peroxyl radicals in membranes, thereby restraining lipid peroxidation. Therefore, ferroptosis is a multifaceted cell-death paradigm characterized by several metabolic networks, whereby metabolic dyshomeostasis may cause ferroptotic cell death and organ failure. Here, we discuss the basic features of ferroptosis with a focus on selenium, offering exciting opportunities to control diseases linked to ferroptosis, including transient ischemia/reperfusion and neurodegeneration.
    Keywords:  PUFA; ferroptosis; ferroptosis suppressor protein 1; glutathione peroxidase 4; selenium
  8. Cell Metab. 2020 Apr 07. pii: S1550-4131(20)30116-9. [Epub ahead of print]31(4): 666-668
    Lundø K, Trauelsen M, Pedersen SF, Schwartz TW.
      Lactate accumulation in tumors-a hallmark of the Warburg effect-has recently been shown to regulate cancer cell metabolism and survival through autocrine activation of GPR81. Now, Brown et al. (2020) demonstrate that lactate surprisingly also controls immune evasion through paracrine activation of GPR81 on stromal dendritic cells.
  9. Cell Metab. 2020 Apr 07. pii: S1550-4131(20)30127-3. [Epub ahead of print]31(4): 660-662
    Maynard AG, Kanarek N.
      In this issue of Cell Metabolism, Yang et al., 2020 report that serine is a source of mitochondrial NADH derived from one-carbon metabolism. Serine becomes a major source of NADH when cellular respiration is inhibited, and the un-utilized, accumulated NADH inhibits the TCA cycle and slows proliferation.
  10. JCI Insight. 2020 Apr 09. pii: 135071. [Epub ahead of print]5(7):
    Valvezan AJ, McNamara MC, Miller SK, Torrence ME, Asara JM, Henske EP, Manning BD.
      Recent studies in distinct preclinical tumor models have established the nucleotide synthesis enzyme inosine-5'-monophosphate dehydrogenase (IMPDH) as a viable target for antitumor therapy. IMPDH inhibitors have been used clinically for decades as safe and effective immunosuppressants. However, the potential to repurpose these pharmacological agents for antitumor therapy requires further investigation, including direct comparisons of available compounds. Therefore, we tested structurally distinct IMPDH inhibitors in multiple cell and mouse tumor models of the genetic tumor syndrome tuberous sclerosis complex (TSC). TSC-associated tumors are driven by uncontrolled activation of the growth-promoting protein kinase complex mechanistic target of rapamycin (mTOR) complex 1 (mTORC1), which is also aberrantly activated in the majority of sporadic cancers. Despite eliciting similar immunosuppressive effects, the IMPDH inhibitor mizoribine, used clinically throughout Asia, demonstrated far superior antitumor activity compared with the FDA-approved IMPDH inhibitor mycophenolate mofetil (or CellCept, a prodrug of mycophenolic acid). When compared directly to the mTOR inhibitor rapamycin, mizoribine treatment provided a more durable antitumor response associated with tumor cell death. These results provide preclinical support for repurposing mizoribine, over other IMPDH inhibitors, as an alternative to mTOR inhibitors for the treatment of TSC-associated tumors and possibly other tumors featuring uncontrolled mTORC1 activity.
    Keywords:  Cancer; Genetic diseases; Metabolism; Therapeutics; Tumor suppressors
  11. Curr Opin Physiol. 2018 Jun;3 101-109
    Walker MA, Tian R.
      Mitochondria are intracellular organelles that oxidize nutrients, make ATP, and fuel eukaryotic life. Their energy providing function is directly dependent on enzymes and coenzymes contained within the organelle. Perhaps, the most important coenzymes for energy yielding reactions are the pyridine nucleotides NAD(H) and NADP(H). Both aerobic and anaerobic metabolism rely on the electron carrying properties of pyridine nucleotides to regulate energy production. The intracellular NAD+/NADH ratio controls the rate of ATP synthesis by regulating flux through NAD(H)-linked dehydrogenases and by activating NAD+ dependent enzymes that post-translationally modify proteins. Thus, mitochondrial energy transduction pathways can be substantially mediated by NAD+; as an electron carrier exerting control over dehydrogenase enzymes or by activating enzymes that affect protein modification. The importance of this is highlighted in the explosion of recent studies linking impaired NAD+ metabolism to human health and disease. Most notably, studies linking changes in NAD+ availability or altered NAD+/NADH ratio to derangements in metabolic and cellular energy transduction processes. In this review, we focus on the most recent investigative efforts to identify the role NAD+ plays in modulating mitochondrial function and also summarize the current knowledge describing the therapeutic application of elevating NAD+ levels via pharmacologic and genetic approaches to treat human disease.
  12. Nat Metab. 2019 Jul;1(7): 731-742
    Seim GL, Britt EC, John SV, Yeo FJ, Johnson AR, Eisenstein RS, Pagliarini DJ, Fan J.
      In response to signals associated with infection or tissue damage, macrophages undergo a series of dynamic phenotypic changes. Here we show that during the response to LPS and interferon-γ stimulation, metabolic reprogramming in macrophages is also highly dynamic. Specifically, the TCA cycle undergoes a two-stage remodeling: the early stage is characterized by a transient accumulation of intermediates including succinate and itaconate, while the late stage is marked by the subsidence of these metabolites. The metabolic transition into the late stage is largely driven by the inhibition of pyruvate dehydrogenase complex (PDHC) and oxoglutarate dehydrogenase complex (OGDC), which is controlled by the dynamic changes in lipoylation state of both PDHC and OGDC E2 subunits and phosphorylation of PDHC E1 subunit. This dynamic metabolic reprogramming results in a transient metabolic state that strongly favors HIF-1α stabilization during the early stage, which subsides by the late stage; consistently, HIF-1α levels follow this trend. This study elucidates a dynamic and mechanistic picture of metabolic reprogramming in LPS and interferon-γ stimulated macrophages, and provides insights into how changing metabolism can regulate the functional transitions in macrophages over a course of immune response.
  13. J Am Heart Assoc. 2020 Apr 07. 9(7): e014366
    Ponce JM, Coen G, Spitler KM, Dragisic N, Martins I, Hinton A, Mungai M, Tadinada SM, Zhang H, Oudit GY, Song LS, Li N, Sicinski P, Strack S, Abel ED, Mitchell C, Hall DD, Grueter CE.
      Background Nuclear-to-mitochondrial communication regulating gene expression and mitochondrial function is a critical process following cardiac ischemic injury. In this study, we determined that cyclin C, a component of the Mediator complex, regulates cardiac and mitochondrial function in part by modifying mitochondrial fission. We tested the hypothesis that cyclin C functions as a transcriptional cofactor in the nucleus and a signaling molecule stimulating mitochondrial fission in response to stimuli such as cardiac ischemia. Methods and Results We utilized gain- and loss-of-function mouse models in which the CCNC (cyclin C) gene was constitutively expressed (transgenic, CycC cTg) or deleted (knockout, CycC cKO) in cardiomyocytes. The knockout and transgenic mice exhibited decreased cardiac function and altered mitochondria morphology. The hearts of knockout mice had enlarged mitochondria with increased length and area, whereas mitochondria from the hearts of transgenic mice were significantly smaller, demonstrating a role for cyclin C in regulating mitochondrial dynamics in vivo. Hearts from knockout mice displayed altered gene transcription and metabolic function, suggesting that cyclin C is essential for maintaining normal cardiac function. In vitro and in vivo studies revealed that cyclin C translocates to the cytoplasm, enhancing mitochondria fission following stress. We demonstrated that cyclin C interacts with Cdk1 (cyclin-dependent kinase 1) in vivo following ischemia/reperfusion injury and that, consequently, pretreatment with a Cdk1 inhibitor results in reduced mitochondrial fission. This finding suggests a potential therapeutic target to regulate mitochondrial dynamics in response to stress. Conclusions Our study revealed that cyclin C acts as a nuclear-to-mitochondrial signaling factor that regulates both cardiac hypertrophic gene expression and mitochondrial fission. This finding provides new insights into the regulation of cardiac energy metabolism following acute ischemic injury.
    Keywords:  ischemia; mitochondria; signal transduction; transcriptional coactivator; transgenic mice
  14. Int Rev Cell Mol Biol. 2020 ;pii: S1937-6448(20)30035-6. [Epub ahead of print]351 xi-xv
    Spetz J, Galluzzi L.
    Keywords:  Apoptosis; Autophagy; Immunogenic cell death; Mitochondrial outer membrane permeabilization; Mitochondrial permeability transition; Necroptosis; Parthanatos; Pyroptosis
  15. Nat Commun. 2020 Apr 08. 11(1): 1740
    Wei W, Pagnamenta AT, Gleadall N, Sanchis-Juan A, Stephens J, Broxholme J, Tuna S, Odhams CA, , , Fratter C, Turro E, Caulfield MJ, Taylor JC, Rahman S, Chinnery PF.
      Several strands of evidence question the dogma that human mitochondrial DNA (mtDNA) is inherited exclusively down the maternal line, most recently in three families where several individuals harbored a 'heteroplasmic haplotype' consistent with biparental transmission. Here we report a similar genetic signature in 7 of 11,035 trios, with allelic fractions of 5-25%, implying biparental inheritance of mtDNA in 0.06% of offspring. However, analysing the nuclear whole genome sequence, we observe likely large rare or unique nuclear-mitochondrial DNA segments (mega-NUMTs) transmitted from the father in all 7 families. Independently detecting mega-NUMTs in 0.13% of fathers, we see autosomal transmission of the haplotype. Finally, we show the haplotype allele fraction can be explained by complex concatenated mtDNA-derived sequences rearranged within the nuclear genome. We conclude that rare cryptic mega-NUMTs can resemble paternally mtDNA heteroplasmy, but find no evidence of paternal transmission of mtDNA in humans.
  16. Front Oncol. 2020 ;10 231
    Baltazar F, Afonso J, Costa M, Granja S.
      To sustain their high proliferation rates, most cancer cells rely on glycolytic metabolism, with production of lactic acid. For many years, lactate was seen as a metabolic waste of glycolytic metabolism; however, recent evidence has revealed new roles of lactate in the tumor microenvironment, either as metabolic fuel or as a signaling molecule. Lactate plays a key role in the different models of metabolic crosstalk proposed in malignant tumors: among cancer cells displaying complementary metabolic phenotypes and between cancer cells and other tumor microenvironment associated cells, including endothelial cells, fibroblasts, and diverse immune cells. This cell metabolic symbiosis/slavery supports several cancer aggressiveness features, including increased angiogenesis, immunological escape, invasion, metastasis, and resistance to therapy. Lactate transport is mediated by the monocarboxylate transporter (MCT) family, while another large family of G protein-coupled receptors (GPCRs), not yet fully characterized in the cancer context, is involved in lactate/acidosis signaling. In this mini-review, we will focus on the role of lactate in the tumor microenvironment, from metabolic affairs to signaling, including the function of lactate in the cancer-cancer and cancer-stromal shuttles, as well as a signaling oncometabolite. We will also review the prognostic value of lactate metabolism and therapeutic approaches designed to target lactate production and transport.
    Keywords:  GPR81; lactate; lactate shuttles; metabolic fuel; monocarboxylate transporters; signaling molecule; warburg effect
  17. Cancer Res. 2020 Apr 09. pii: canres.3580.2019. [Epub ahead of print]
    Zhang Y, Shi J, Liu X, Xiao Z, Lei G, Lee H, Koppula P, Cheng W, Mao C, Zhuang L, Ma L, Li W, Gan B.
      Epigenetic regulation of gene transcription has been shown to coordinate with nutrient availability, yet the mechanisms underlying this coordination remain incompletely understood. Here we show that glucose starvation suppresses histone 2A K119 monoubiquitination (H2Aub), a histone modification that correlates with gene repression. Glucose starvation suppressed H2Aub levels independently of energy stress-mediated AMPK activation and possibly through NADPH depletion and subsequent inhibition of BMI1, an integral component of polycomb repressive complex 1 (PRC1) that catalyzes H2Aub on chromatin. Integrated transcriptomic and epigenomic analyses linked glucose starvation-mediated H2Aub repression to the activation of genes involved in the endoplasmic reticulum (ER) stress response. We further showed that this epigenetic mechanism has a role in glucose starvation-induced cell death and that pharmacologic inhibition of glucose transporter 1 (GLUT1) and PRC1 synergistically promoted ER stress and suppressed tumor growth in vivo. Together, these results reveal a hitherto unrecognized epigenetic mechanism coupling glucose availability to the ER stress response.
  18. Nat Commun. 2020 Apr 09. 11(1): 1755
    Deng L, Yao P, Li L, Ji F, Zhao S, Xu C, Lan X, Jiang P.
      Asparagine synthetase (ASNS) catalyses the ATP-dependent conversion of aspartate to asparagine. However, both the regulation and biological functions of asparagine in tumour cells remain largely unknown. Here, we report that p53 suppresses asparagine synthesis through the transcriptional downregulation of ASNS expression and disrupts asparagine-aspartate homeostasis, leading to lymphoma and colon tumour growth inhibition in vivo and in vitro. Moreover, the removal of asparagine from culture medium or the inhibition of ASNS impairs cell proliferation and induces p53/p21-dependent senescence and cell cycle arrest. Mechanistically, asparagine and aspartate regulate AMPK-mediated p53 activation by physically binding to LKB1 and oppositely modulating LKB1 activity. Thus, we found that p53 regulates asparagine metabolism and dictates cell survival by generating an auto-amplification loop via asparagine-aspartate-mediated LKB1-AMPK signalling. Our findings highlight a role for LKB1 in sensing asparagine and aspartate and connect asparagine metabolism to the cellular signalling transduction network that modulates cell survival.
  19. Dev Cell. 2020 Apr 07. pii: S1534-5807(20)30192-1. [Epub ahead of print]
    De Henau S, Pagès-Gallego M, Pannekoek WJ, Dansen TB.
      Symmetry breaking is an essential step in cell differentiation and early embryonic development. However, the molecular cues that trigger symmetry breaking remain largely unknown. Here, we show that mitochondrial H2O2 acts as a symmetry-breaking cue in the C. elegans zygote. We find that symmetry breaking is marked by a local H2O2 increase and coincides with a relocation of mitochondria to the cell cortex. Lowering endogenous H2O2 levels delays the onset of symmetry breaking, while artificially targeting mitochondria to the cellular cortex using a light-induced heterodimerization technique is sufficient to initiate symmetry breaking in a H2O2-dependent manner. In wild-type development, both sperm and maternal mitochondria contribute to symmetry breaking. Our findings reveal that mitochondrial H2O2-signaling promotes the onset of polarization, a fundamental process in development and cell differentiation, and this is achieved by both mitochondrial redistribution and differential H2O2-production.
    Keywords:  C. elegans; H(2)O(2); cell polarity; embryonic development; mitochondria; redox signaling; symmetry breaking
  20. Cell. 2020 Apr 03. pii: S0092-8674(20)30321-4. [Epub ahead of print]
    Jain IH, Calvo SE, Markhard AL, Skinner OS, To TL, Ast T, Mootha VK.
      Human cells are able to sense and adapt to variations in oxygen levels. Historically, much research in this field has focused on hypoxia-inducible factor (HIF) signaling and reactive oxygen species (ROS). Here, we perform genome-wide CRISPR growth screens at 21%, 5%, and 1% oxygen to systematically identify gene knockouts with relative fitness defects in high oxygen (213 genes) or low oxygen (109 genes), most without known connection to HIF or ROS. Knockouts of many mitochondrial pathways thought to be essential, including complex I and enzymes in Fe-S biosynthesis, grow relatively well at low oxygen and thus are buffered by hypoxia. In contrast, in certain cell types, knockout of lipid biosynthetic and peroxisomal genes causes fitness defects only in low oxygen. Our resource nominates genetic diseases whose severity may be modulated by oxygen and links hundreds of genes to oxygen homeostasis.
    Keywords:  CoQ biosynthesis; FASII; MPC; TMEM189; hypoxia; iron-sulfur clusters; membrane fluidity; plasmalogens; pyruvate dehydrogenase; type II fatty acid synthesis
  21. Biochim Biophys Acta Mol Basis Dis. 2020 Apr 03. pii: S0925-4439(20)30137-X. [Epub ahead of print] 165792
    Liu Y, Fu Y, Liu Z, Shu S, Wang Y, Cai J, Ang CT, Dong Z.
      Renal ischemia-reperfusion is a major cause of acute kidney injury, a disease currently without effective treatments. Irisin was initially identified as an important factor produced by muscles to mediate the health benefits of exercise, and recent work has further suggested its protective effect against lung and liver injury. However, the role of Irisin in kidney diseases, including renal ischemia-reperfusion injury (IRI), remains unknown. In the present study, we found that the Irisin precursor, fibronectin type III domain-containing protein 5 (Fndc5), was induced in renal tubules in a mouse model of renal IRI and in cultured mouse renal proximal tubular cells subjected ATP depletion injury. Functionally, silencing Fndc5 in cultured proximal tubular cells increased the sensitivity to ATP depletion-induced apoptosis, whereas both Fndc5 overexpression and supplementation of recombinant Irisin alleviated ATP depletion-induced apoptosis. In vivo, administration of recombinant Irisin dramatically attenuated kidney dysfunction, tissue damage, tubular cell apoptosis, and inflammation during renal IRI in mice. Mechanistically, Irisin suppressed the activation of p53 in renal IRI, a critical factor in tubular cell death. Together, these results indicate that Irisin is induced in renal IRI as a protective mechanism for renal tubular cells, suggesting the therapeutic potential of recombinant Irisin in renal IRI and related kidney diseases.
    Keywords:  Acute kidney injury; Apoptosis; Irisin; Renal ischemia-reperfusion; p53
  22. Carcinogenesis. 2020 Apr 07. pii: bgaa032. [Epub ahead of print]
    Haumann S, Boix J, Knuever J, Bieling A, Vila Sanjurjo A, Elson JL, Blakely EL, Taylor RW, Riet N, Abken H, Kashkar H, Hornig-Do HT, Wiesner RJ.
      Functioning mitochondria are crucial for cancer metabolism, but aerobic glycolysis is still considered to be an important pathway for energy production in many tumor cells. Here we show that two well established, classic Hodgkin lymphoma cell lines (cHL) harbor deleterious variants within mitochondrial DNA (mtDNA) and thus exhibit reduced steady state levels of respiratory chain complexes. However, instead of resulting in the expected bioenergetic defect, these mtDNA variants evoke a retrograde signaling response that induces mitochondrial biogenesis and ultimately results in increased mitochondrial mass as well as function and enhances proliferation in vitro as well as tumor growth in mice in vivo. When complex I assembly was impaired by knock-down of one of its subunits, this led to further increased mitochondrial mass and function and, consequently, further accelerated tumor growth in vivo. In contrast, inhibition of mitochondrial respiration in vivo by the mitochondrial complex I inhibitor metformin efficiently slowed down growth. We conclude that, as a new mechanism, mildly deleterious mtDNA variants in cHL cancer cells cause an increase of mitochondrial mass and enhanced function as a compensatory effect using a retrograde signaling pathway, which provides an obvious advantage for tumor growth.
  23. Front Cell Dev Biol. 2020 ;8 200
    Chen G, Kroemer G, Kepp O.
      Mitochondrial dysfunction constitutes one of the hallmarks of aging and is characterized by irregular mitochondrial morphology, insufficient ATP production, accumulation of mitochondrial DNA (mtDNA) mutations, increased production of mitochondrial reactive oxygen species (ROS) and the consequent oxidative damage to nucleic acids, proteins and lipids. Mitophagy, a mitochondrial quality control mechanism enabling the degradation of damaged and superfluous mitochondria, prevents such detrimental effects and reinstates cellular homeostasis in response to stress. To date, there is increasing evidence that mitophagy is significantly impaired in several human pathologies including aging and age-related diseases such as neurodegenerative disorders, cardiovascular pathologies and cancer. Therapeutic interventions aiming at the induction of mitophagy may have the potency to ameliorate these dysfunctions. In this review, we summarize recent findings on mechanisms controlling mitophagy and its role in aging and the development of human pathologies.
    Keywords:  ROS; aging; caloric restriction; mitochondria; mitophagy
  24. Cell Metab. 2020 Apr 07. pii: S1550-4131(20)30124-8. [Epub ahead of print]31(4): 862-877.e14
    Rohlenova K, Goveia J, García-Caballero M, Subramanian A, Kalucka J, Treps L, Falkenberg KD, de Rooij LPMH, Zheng Y, Lin L, Sokol L, Teuwen LA, Geldhof V, Taverna F, Pircher A, Conradi LC, Khan S, Stegen S, Panovska D, De Smet F, Staal FJT, Mclaughlin RJ, Vinckier S, Van Bergen T, Ectors N, De Haes P, Wang J, Bolund L, Schoonjans L, Karakach TK, Yang H, Carmeliet G, Liu Y, Thienpont B, Dewerchin M, Eelen G, Li X, Luo Y, Carmeliet P.
      Endothelial cell (EC) metabolism is an emerging target for anti-angiogenic therapy in tumor angiogenesis and choroidal neovascularization (CNV), but little is known about individual EC metabolic transcriptomes. By single-cell RNA sequencing 28,337 murine choroidal ECs (CECs) and sprouting CNV-ECs, we constructed a taxonomy to characterize their heterogeneity. Comparison with murine lung tumor ECs (TECs) revealed congruent marker gene expression by distinct EC phenotypes across tissues and diseases, suggesting similar angiogenic mechanisms. Trajectory inference predicted that differentiation of venous to angiogenic ECs was accompanied by metabolic transcriptome plasticity. ECs displayed metabolic transcriptome heterogeneity during cell-cycle progression and in quiescence. Hypothesizing that conserved genes are important, we used an integrated analysis, based on congruent transcriptome analysis, CEC-tailored genome-scale metabolic modeling, and gene expression meta-analysis in cross-species datasets, followed by in vitro and in vivo validation, to identify SQLE and ALDH18A1 as previously unknown metabolic angiogenic targets.
    Keywords:  angiogenesis; choroidal neovascularization; endothelial cells; metabolism; scRNA-seq; tumor angiogenesis
  25. Front Immunol. 2020 ;11 521
    Salminen TS, Vale PF.
      Understanding why the response to infection varies between individuals remains one of the major challenges in immunology and infection biology. A substantial proportion of this heterogeneity can be explained by individual genetic differences which result in variable immune responses, and there are many examples of polymorphisms in nuclear-encoded genes that alter immunocompetence. However, how immunity is affected by genetic polymorphism in an additional genome, inherited maternally inside mitochondria (mtDNA), has been relatively understudied. Mitochondria are increasingly recognized as important mediators of innate immune responses, not only because they are the main source of energy required for costly immune responses, but also because by-products of mitochondrial metabolism, such as reactive oxygen species (ROS), may have direct microbicidal action. Yet, it is currently unclear how naturally occurring variation in mtDNA contributes to heterogeneity in infection outcomes. In this review article, we describe potential sources of variation in mitochondrial function that may arise due to mutations in vital nuclear and mitochondrial components of energy production or due to a disruption in mito-nuclear crosstalk. We then highlight how these changes in mitochondrial function can impact immune responses, focusing on their effects on ATP- and ROS-generating pathways, as well as immune signaling. Finally, we outline how being a powerful and genetically tractable model of infection, immunity and mitochondrial genetics makes the fruit fly Drosophila melanogaster ideally suited to dissect mitochondrial effects on innate immune responses to infection.
    Keywords:  Drosophila melanogaster; cybrid; infection; innate immunity; mitochondria; mtDNA; oxidative phosphorylation; reactive oxygen species
  26. Cell Metab. 2020 Apr 07. pii: S1550-4131(20)30126-1. [Epub ahead of print]31(4): 669-678
    Sung AY, Floyd BJ, Pagliarini DJ.
      Defining functions for the full complement of proteins is a grand challenge in the post-genomic era and is essential for our understanding of basic biology and disease pathogenesis. In recent times, this endeavor has benefitted from a combination of modern large-scale and classical reductionist approaches-a process we refer to as "systems biochemistry"-that helps surmount traditional barriers to the characterization of poorly understood proteins. This strategy is proving to be particularly effective for mitochondria, whose well-defined proteome has enabled comprehensive analyses of the full mitochondrial system that can position understudied proteins for fruitful mechanistic investigations. Recent systems biochemistry approaches have accelerated the identification of new disease-related mitochondrial proteins and of long-sought "missing" proteins that fulfill key functions. Collectively, these studies are moving us toward a more complete understanding of mitochondrial activities and providing a molecular framework for the investigation of mitochondrial pathogenesis.
    Keywords:  mitochondria; multi-omics; orphan proteins; rare disease; systems biochemistry
  27. Cell Death Dis. 2020 Apr 08. 11(4): 226
    Zhang L, Zhang Y, Chang X, Zhang X.
      An imbalance in mitochondrial dynamics induced by oxidative stress may lead to hepatocyte epithelial mesenchymal transition (EMT) and liver fibrosis. However, the underlying molecular mechanisms have not been fully elucidated. This study investigated the role of mitochondrial dynamics in hepatocyte EMT and liver fibrosis using an in vitro human (L-02 cells, hepatic cell line) and an in vivo mouse model of liver fibrosis. Findings showed that oxidative stress-induced mitochondrial DNA damage was associated with abnormal mitochondrial fission and hepatocyte EMT. The reactive oxygen species (ROS) scavengers apocynin and mito-tempo effectively attenuated carbon tetrachloride (CCl4)-induced abnormal mitochondrial fission and liver fibrosis. Restoring mitochondrial biogenesis attenuated hepatocyte EMT. Oxidative stress-induced abnormal hepatocyte mitochondrial fission events by a mechanism that involved the down regulation of PGC-1α. PGC-1α knockout mice challenged with CCl4 had increased abnormal mitochondrial fission and more severe liver fibrosis than wild type mice. These results indicate that PGC-1α has a protective role in oxidative stress-induced-hepatocyte EMT and liver fibrosis.
  28. Cell Chem Biol. 2020 Apr 07. pii: S2451-9456(20)30111-2. [Epub ahead of print]
    Bayır H, Anthonymuthu TS, Tyurina YY, Patel SJ, Amoscato AA, Lamade AM, Yang Q, Vladimirov GK, Philpott CC, Kagan VE.
      Redox balance is essential for normal brain, hence dis-coordinated oxidative reactions leading to neuronal death, including programs of regulated death, are commonly viewed as an inevitable pathogenic penalty for acute neuro-injury and neurodegenerative diseases. Ferroptosis is one of these programs triggered by dyshomeostasis of three metabolic pillars: iron, thiols, and polyunsaturated phospholipids. This review focuses on: (1) lipid peroxidation (LPO) as the major instrument of cell demise, (2) iron as its catalytic mechanism, and (3) thiols as regulators of pro-ferroptotic signals, hydroperoxy lipids. Given the central role of LPO, we discuss the engagement of selective and specific enzymatic pathways versus random free radical chemical reactions in the context of the phospholipid substrates, their biosynthesis, intracellular location, and related oxygenating machinery as participants in ferroptotic cascades. These concepts are discussed in the light of emerging neuro-therapeutic approaches controlling intracellular production of pro-ferroptotic phospholipid signals and their non-cell-autonomous spreading, leading to ferroptosis-associated necroinflammation.
    Keywords:  cerebral hemorrhage; cerebral ischemia; glutathione peroxidase 4; lipoxygenase; neurodegeneration; phospholipid; redox lipidomics; regulated cell death; traumatic brain injury
  29. Proc Natl Acad Sci U S A. 2020 Apr 06. pii: 202001936. [Epub ahead of print]
    Hughes JW, Cho JH, Conway HE, DiGruccio MR, Ng XW, Roseman HF, Abreu D, Urano F, Piston DW.
      Pancreatic islets regulate glucose homeostasis through coordinated actions of hormone-secreting cells. What underlies the function of the islet as a unit is the close approximation and communication among heterogeneous cell populations, but the structural mediators of islet cellular cross talk remain incompletely characterized. We generated mice specifically lacking β-cell primary cilia, a cellular organelle that has been implicated in regulating insulin secretion, and found that the β-cell cilia are required for glucose sensing, calcium influx, insulin secretion, and cross regulation of α- and δ-cells. Protein expression profiling in islets confirms perturbation in these cellular processes and reveals additional targets of cilia-dependent signaling. At the organism level, the deletion of β-cell cilia disrupts circulating hormone levels, impairs glucose homeostasis and fuel usage, and leads to the development of diabetes. Together, these findings demonstrate that primary cilia not only orchestrate β-cell-intrinsic activity but also mediate cross talk both within the islet and from islets to other metabolic tissues, thus providing a unique role of cilia in nutrient metabolism and insight into the pathophysiology of diabetes.
  30. Metabolism. 2020 Apr 07. pii: S0026-0495(20)30089-5. [Epub ahead of print] 154225
    Mooli RGR, Mukhi D, Watt M, Edmunds L, Xie B, Capooci J, Reslink M, Eze C, Mills A, Stolz DB, Jurczak M, Ramakrishnan SK.
      BACKGROUND: Caloric restriction (CR) delays the onset of metabolic and age-related disorders. Recent studies have demonstrated that formation of beige adipocytes induced by CR is strongly associated with extracellular remodeling in adipose tissue, decrease in adipose tissue inflammation, and improved systemic metabolic homeostasis. However, beige adipocytes rapidly transition to white upon CR withdrawal through unclear mechanisms.MATERIALS AND METHODS: Six-week old C57BL6 mice were fed with 40% CR chow diet for 6 weeks. Subsequently, one group of mice was switched back to ad libitum chow diet, which was continued for additional 2 weeks. Adipose tissues were assessed histologically and biochemically for beige adipocytes.
    RESULTS: Beige adipocytes induced by CR rapidly transition to white adipocytes when CR is withdrawn independent of parkin-mediated mitophagy. We demonstrate that the involution of mitochondria during CR withdrawal is strongly linked with a decrease in mitochondrial biogenesis. We further demonstrate that beige-to-white fat transition upon β3-AR agonist-withdrawal could be attenuated by CR, partly via maintenance of mitochondrial biogenesis.
    CONCLUSION: In the model of CR, our study highlights the dominant role of mitochondrial biogenesis in the maintenance of beige adipocytes. We propose that loss of beige adipocytes upon β3-AR agonist withdrawal could be attenuated by CR.
    Keywords:  Beige adipocytes; Caloric restriction; Fission; Fusion; Mitochondrial biogenesis; Mitochondrial dynamics; Mitophagy
  31. J Biol Chem. 2020 Apr 07. pii: jbc.RA119.012213. [Epub ahead of print]
    Yamaguchi I, Yoshimura SH, Katoh H.
      The the cystine/glutamate transporter system xc- consists of the light-chain subunit xCT (SLC7A11) and the heavy-chain subunit CD98 (4F2hc or SLC3A2) and exchanges extracellular cystine for intracellular glutamate at the plasma membrane. The imported cystine is reduced to cysteine and used for synthesis of glutathione, which is one of the most important antioxidants in cancer cells. Because cancer cells have increased levels of reactive oxygen species (ROS), xCT, being responsible for cystine-glutamate exchange, is overexpressed in many cancers, including glioblastoma. However, under glucose-limited conditions, xCT overexpression induces ROS accumulation and cell death. Here, we report that cell survival under glucose deprivation depends on cell density. We found that a high cell density (HD) down-regulates xCT levels and increases cell viability under glucose deprivation. We also found that growth of glioblastoma cells at HD inactivates mTOR, and that treatment with the mTOR inhibitor Torin 1 of cells grown at low density (LD) down-regulates xCT and inhibits glucose deprivation-induced cell death. The lysosome inhibitor bafilomycin A1 (BafA1) suppressed xCT down-regulation in HD-cultured glioblastoma cells and in Torin 1-treated cells grown at LD. Additionally, BafA1 exposure or ectopic xCT expression restored glucose deprivation-induced cell death at HD. These results suggest that HD inactivates mTOR and promotes lysosomal degradation of xCT, leading to improved glioblastoma cell viability under glucose-limited conditions. Our findings provide evidence that the control of xCT protein expression via lysosomal degradation is an important mechanism for metabolic adaptation in glioblastoma cells.
    Keywords:  amino acid transport; cancer biology; cell biology; cell death; lysosome
  32. Cell Rep. 2020 Apr 07. pii: S2211-1247(20)30370-3. [Epub ahead of print]31(1): 107492
    Balka KR, Louis C, Saunders TL, Smith AM, Calleja DJ, D'Silva DB, Moghaddas F, Tailler M, Lawlor KE, Zhan Y, Burns CJ, Wicks IP, Miner JJ, Kile BT, Masters SL, De Nardo D.
      Stimulator of Interferon Genes (STING) is a critical component of host innate immune defense but can contribute to chronic autoimmune or autoinflammatory disease. Once activated, the cyclic guanosine monophosphate (GMP)-adenosine monophosphate (AMP) (cGAMP) synthase (cGAS)-STING pathway induces both type I interferon (IFN) expression and nuclear factor-κB (NF-κB)-mediated cytokine production. Currently, these two signaling arms are thought to be mediated by a single upstream kinase, TANK-binding kinase 1 (TBK1). Here, using genetic and pharmacological approaches, we show that TBK1 alone is dispensable for STING-induced NF-κB responses in human and mouse immune cells, as well as in vivo. We further demonstrate that TBK1 acts redundantly with IκB kinase ε (IKKε) to drive NF-κB upon STING activation. Interestingly, we show that activation of IFN regulatory factor 3 (IRF3) is highly dependent on TBK1 kinase activity, whereas NF-κB is significantly less sensitive to TBK1/IKKε kinase inhibition. Our work redefines signaling events downstream of cGAS-STING. Our findings further suggest that cGAS-STING will need to be targeted directly to effectively ameliorate the inflammation underpinning disorders associated with STING hyperactivity.
    Keywords:  IKKε; NF-κB; STING; TBK1; cGAS; cytokines; innate immunity; protein kinases; signal transduction; type I interferons
  33. Biomolecules. 2020 Apr 08. pii: E568. [Epub ahead of print]10(4):
    Kaiser P.
      Tumorigenesis is accompanied by the reprogramming of cellular metabolism. The shift from oxidative phosphorylation to predominantly glycolytic pathways to support rapid growth is well known and is often referred to as the Warburg effect. However, other metabolic changes and acquired needs that distinguish cancer cells from normal cells have also been discovered. The dependence of cancer cells on exogenous methionine is one of them and is known as methionine dependence or the Hoffman effect. This phenomenon describes the inability of cancer cells to proliferate when methionine is replaced with its metabolic precursor, homocysteine, while proliferation of non-tumor cells is unaffected by these conditions. Surprisingly, cancer cells can readily synthesize methionine from homocysteine, so their dependency on exogenous methionine reflects a general need for altered metabolic flux through pathways linked to methionine. In this review, an overview of the field will be provided and recent discoveries will be discussed.
    Keywords:  S-adenosylmethionine; SAM-checkpoint; cancer; cell cycle; methionine
  34. Cell Rep. 2020 Apr 07. pii: S2211-1247(20)30342-9. [Epub ahead of print]31(1): 107464
    Hirayama M, Wei FY, Chujo T, Oki S, Yakita M, Kobayashi D, Araki N, Takahashi N, Yoshida R, Nakayama H, Tomizawa K.
      N6-Methyladenosine (m6A) modification is the major chemical modification in mRNA that controls fundamental biological processes, including cell proliferation. Herein, we demonstrate that fat mass and obesity-associated (FTO) demethylates m6A modification of cyclin D1, the key regulator for G1 phase progression and controls cell proliferation in vitro and in vivo. FTO depletion upregulates cyclin D1 m6A modification, which in turn accelerates the degradation of cyclin D1 mRNA, leading to the impairment of G1 progression. m6A modification of cyclin D1 oscillates in a cell-cycle-dependent manner; m6A levels are suppressed during the G1 phase and enhanced during other phases. Low m6A levels during G1 are associated with the nuclear translocation of FTO from the cytosol. Furthermore, nucleocytoplasmic shuttling of FTO is regulated by casein kinase II-mediated phosphorylation of FTO. Our results highlight the role of m6A in regulating cyclin D1 mRNA stability and add another layer of complexity to cell-cycle regulation.
    Keywords:  FTO; N(6)-methyladenosine; RNA; casein kinase; cell cycle; cyclin D1; modification; phosphorylation
  35. Cancer Discov. 2020 Apr 10.
      Cysteine depletion caused ferroptosis in human pancreatic cancer cells and improved survival in mice.
  36. Elife. 2020 Apr 07. pii: e56418. [Epub ahead of print]9
    Plana-Bonamaisó A, López-Begines S, Fernández-Justel D, Junza A, Soler-Tapia A, Andilla J, Loza-Alvarez P, Rosa JL, Miralles E, Casals I, Yanes O, de la Villa P, Buey RM, Méndez A.
      We report the in vivo regulation of Inosine-5´-monophosphate dehydrogenase 1 (IMPDH1) in the retina. IMPDH1 catalyzes the rate-limiting step in the de novo synthesis of guanine nucleotides, impacting the cellular pools of GMP, GDP and GTP. Guanine nucleotide homeostasis is central to photoreceptor cells, where cGMP is the signal transducing molecule in the light response. Mutations in IMPDH1 lead to inherited blindness. We unveil a light-dependent phosphorylation of retinal IMPDH1 at Thr159/Ser160 in the Bateman domain that desensitizes the enzyme to allosteric inhibition by GDP/GTP. When exposed to bright light, living mice increase the rate of GTP and ATP synthesis in their retinas; concomitant with IMPDH1 aggregate formation at the outer segment layer. Inhibiting IMPDH activity in living mice delays rod mass recovery. We unveil a novel mechanism of regulation of IMPDH1 in vivo, important for understanding GTP homeostasis in the retina and the pathogenesis of adRP10 IMPDH1 mutations.
    Keywords:  biochemistry; chemical biology; mouse; neuroscience
  37. Cancer Discov. 2020 Apr 06. pii: CD-20-0057. [Epub ahead of print]
    Pine AR, Cirigliano SM, Nicholson JG, Hu Y, Linkous A, Miyaguchi K, Edwards L, Singhania R, Schwartz TH, Ramakrishna R, Pisapia DJ, Snuderl M, Elemento O, Fine HA.
      Glioblastoma, an incurable tumor, remains difficult to model and more importantly to treat due to its genetic/epigenetic heterogeneity and plasticity across cellular states. The ability of current tumor models to recapitulate the cellular states found in primary tumors remains unexplored. To address this issue, we compared single-cell RNA-sequencing of tumor cells from five patients across four patient-specific glioblastoma stem cell (GSC)-derived model types, including glioma spheres, tumor organoids, glioblastoma cerebral organoids (GLICO), and patient-derived xenografts. We find that GSCs within the GLICO model are enriched for a neural progenitor-like cell (NPC) subpopulation and recapitulate the cellular states and their plasticity found in the corresponding primary parental tumors. These data demonstrate how the contribution of a neuroanatomically accurate human microenvironment is critical and sufficient for recapitulating the cellular states found in human primary GBMs, a principle that may likely apply to other tumor models.
  38. Cell Chem Biol. 2020 Mar 27. pii: S2451-9456(20)30108-2. [Epub ahead of print]
    Anandhan A, Dodson M, Schmidlin CJ, Liu P, Zhang DD.
      Ferroptosis is a non-apoptotic mode of regulated cell death that is iron and lipid peroxidation dependent. As new mechanistic insight into ferroptotic effectors and how they are regulated in different disease contexts is uncovered, our understanding of the physiological and pathological relevance of this mode of cell death continues to grow. Along these lines, a host of pharmacological modulators of this pathway have been identified, targeting proteins involved in iron homeostasis; the generation and reduction of lipid peroxides; or cystine import and glutathione metabolism. Also, of note, many components of the ferroptosis cascade are target genes of the transcription factor nuclear factor erythroid 2-related factor 2 (NRF2), indicating its critical role in mediating the ferroptotic response. In this review, we discuss the in vitro, in vivo, and clinical evidence of ferroptosis in disease, including a brief discussion of targeting upstream mediators of this cascade, including NRF2, to treat ferroptosis-driven diseases.
    Keywords:  NRF2; cancer; cardiovascular disease; cell death; diabetes; ferritinophagy; ferroptosis; iron; lipid peroxidation; neurodegeneration
  39. Dev Cell. 2020 Apr 06. pii: S1534-5807(20)30221-5. [Epub ahead of print]53(1): 1-2
    Zhu M, Zernicka-Goetz M.
      It has long been known that glucose is required for the development of pre-implantation mouse embryos, but the mechanism accounting for such a requirement has remained unknown. In this issue of Developmental Cell, Chi et al. dissect the molecular pathways that respond to the state of glucose metabolism to drive the morula to blastocyst transition.