bims-mibica Biomed News
on Mitochondrial bioenergetics in cancer
Issue of 2020–10–25
57 papers selected by
Kelsey Fisher-Wellman, East Carolina University
  1. Age-associated mitochondrial DNA mutations cause metabolic remodelling that contributes to accelerated intestinal tumorigenesis.
  2. Mitochondrial copper depletion suppresses triple-negative breast cancer in mice.
  3. Carnitine Traffic in Cells. Link With Cancer.
  4. MCART1/SLC25A51 is required for mitochondrial NAD transport.
  5. Potent inhibition of tumour cell proliferation and immunoregulatory function by mitochondria-targeted atovaquone.
  6. Mitochondrial survivin reduces oxidative phosphorylation in cancer cells by inhibiting mitophagy.
  7. Mitochondrial respiratory capacity modulates LPS-induced inflammatory signatures in human blood.
  8. Differential regulation of mitochondrial complex I and oxidative stress based on metastatic potential of colorectal cancer cells.
  9. Novel approach to quantify mitochondrial content and intrinsic bioenergetic efficiency across organs.
  10. Mitochondria at Center of Exchanges between Cancer Cells and Cancer-Associated Fibroblasts during Tumor Progression.
  11. Uniparental isodisomy as a cause of mitochondrial complex I respiratory chain disorder due to a novel splicing NDUFS4 mutation.
  12. PLCγ1 suppression promotes the adaptation of KRAS-mutant lung adenocarcinomas to hypoxia.
  13. Branched-chain amino acid aminotransferase 2 regulates ferroptotic cell death in cancer cells.
  14. Bifidobacterium alters the gut microbiota and modulates the functional metabolism of T regulatory cells in the context of immune checkpoint blockade.
  15. Mitochondrial targeted doxorubicin derivatives delivered by ROS-responsive nanocarriers to breast tumor for overcoming of multidrug resistance.
  16. TIMELESS regulates sphingolipid metabolism and tumor cell growth through Sp1/ACER2/S1P axis in ER-positive breast cancer.
  17. Elevated plasma branched-chain amino acid levels correlate with type 2 diabetes-related metabolic disturbances.
  18. Targeting cancer-cell mitochondria and metabolism to improve radiotherapy response.
  19. Regulation of Cell Death by Mitochondrial Transport Systems of Calcium and Bcl-2 Proteins.
  20. PDE5 inhibition rescues mitochondrial dysfunction and angiogenic responses induced by Akt3 inhibition by promotion of PRC expression.
  21. Neutral Sphingomyelinase-2 (NSM 2) Controls T Cell Metabolic Homeostasis and Reprogramming During Activation.
  22. Effects of Novel Tacrine Derivatives on Mitochondrial Energy Metabolism and Monoamine Oxidase Activity-In Vitro Study.
  23. Stat2-Drp1 mediated mitochondrial mass increase is necessary for pro-inflammatory differentiation of macrophages.
  24. Mitochondria as the decision makers for cancer cell fate: from signaling pathways to therapeutic strategies.
  25. Cytosolic pH regulates proliferation and tumour growth by promoting expression of cyclin D1.
  26. Single-cell derived tumor organoids display diversity in HLA class I peptide presentation.
  27. Quality control of the mitochondrial proteome.
  28. Lung mitochondria adaptation to endurance training in rats.
  29. A Regulation Loop between YAP and NR4A1 Balances Cell Proliferation and Apoptosis.
  30. ER-resident oxidoreductases are glycosylated and trafficked to the cell surface to promote matrix degradation by tumour cells.
  31. Mitochondrial Potentiation Ameliorates Age-Related Heterogeneity in Hematopoietic Stem Cell Function.
  32. HSB-1/HSF-1 pathway modulates histone H4 in mitochondria to control mtDNA transcription and longevity.
  33. Inhibition of Lysosomal Function Mitigates Protective Mitophagy and Augments Ceramide Nanoliposome-Induced Cell Death in Head and Neck Squamous Cell Carcinoma.
  34. Systematic Proteome and Lysine Succinylome Analysis Reveals the Enhanced Cell Migration by Hyposuccinylation in Esophageal Squamous Cell Cancer.
  35. Autofluorescence imaging of 3D tumor-macrophage microscale cultures resolves spatial and temporal dynamics of macrophage metabolism.
  36. Deferasirox-Dependent Iron Chelation Enhances Mitochondrial Dysfunction and Restores p53 Signaling by Stabilization of p53 Family Members in Leukemic Cells.
  37. Deubiquitinase OTUD6A promotes proliferation of cancer cells via regulating Drp1 stability and mitochondrial fission.
  38. Combinatorial Approaches to Enhance DNA Damage Following Enzyme-mediated Depletion of L-Cyst(e)ine for Treatment of Pancreatic Cancer.
  39. Hydrogen Sulfide Oxidation by Sulfide Quinone Oxidoreductase.
  40. The connection between the dynamic remodeling of the mitochondrial network and the regulation of muscle mass.
  41. Dissecting the Crosstalk between NRF2 Signaling and Metabolic Processes in Cancer.
  42. Production of hydrogen sulfide by the intestinal microbiota and epithelial cells and consequences for the colonic and rectal mucosa.
  43. Guanosine triphosphate links MYC-dependent metabolic and ribosome programs in small cell lung cancer.
  44. Targeted CRISPR screening identifies PRMT5 as synthetic lethality combinatorial target with gemcitabine in pancreatic cancer cells.
  45. Midkine rewires the melanoma microenvironment toward a tolerogenic and immune-resistant state.
  46. Complex IV- the regulatory center of mitochondrial oxidative phosphorylation.
  47. Vestigial-like 1 is a shared targetable cancer-placenta antigen expressed by pancreatic and basal-like breast cancers.
  48. Glutaminase inhibitors induce thiol-mediated oxidative stress and radio-sensitization in treatment resistant cervical cancers.
  49. Phosphodiesterase 2A2 regulates mitochondria clearance through Parkin-dependent mitophagy.
  50. Type III ATP synthase is a symmetry-deviated dimer that induces membrane curvature through tetramerization.
  51. Altered bioenergetics and mitochondrial dysfunction of monocytes in patients with COVID-19 pneumonia.
  52. Mitochondrial microRNA (MitomiRs) in cancer and complex mitochondrial diseases: current status and future perspectives.
  53. PPARα Inhibition Overcomes Tumor-Derived Exosomal Lipid-Induced Dendritic Cell Dysfunction.
  54. MitoSegNet: Easy-to-use Deep Learning Segmentation for Analyzing Mitochondrial Morphology.
  55. Mammalian Atg8-family proteins are upstream regulators of the lysosomalsystem by controlling MTOR and TFEB.
  56. Deconstructing tumor heterogeneity: the stromal perspective.
  57. The Loss of Nuclear PTEN Increases Tumorigenesis in a Preclinical Mouse Model for Hepatocellular Carcinoma.
  1. Nat Cancer. 2020 Oct;1(10): 976-989
    Age-associated mitochondrial DNA mutations cause metabolic remodelling that contributes to accelerated intestinal tumorigenesis.
    Anna Lm Smith, Julia C Whitehall, Carla Bradshaw, David Gay, Fiona Robertson, Alasdair P Blain, Gavin Hudson, Angela Pyle, David Houghton, Matthew Hunt, James N Sampson, Craig Stamp, Grace Mallett, Shoba Amarnath, Jack Leslie, Fiona Oakley, Laura Wilson, Angela Baker, Oliver M Russell, Riem Johnson, Claire A Richardson, Bhavana Gupta, Iain McCallum, Stuart Ac McDonald, Seamus Kelly, John C Mathers, Rakesh Heer, Robert W Taylor, Neil D Perkins, Doug M Turnbull, Owen J Sansom, Laura C Greaves.
      Oxidative phosphorylation (OXPHOS) defects caused by somatic mitochondrial DNA (mtDNA) mutations increase with age in human colorectal epithelium and are prevalent in colorectal tumours, but whether they actively contribute to tumorigenesis remains unknown. Here we demonstrate that mtDNA mutations causing OXPHOS defects are enriched during the human adenoma/carcinoma sequence, suggesting they may confer a metabolic advantage. To test this we deleted the tumour suppressor Apc in OXPHOS deficient intestinal stem cells in mice. The resulting tumours were larger than in control mice due to accelerated cell proliferation and reduced apoptosis. We show that both normal crypts and tumours undergo metabolic remodelling in response to OXPHOS deficiency by upregulating the de novo serine synthesis pathway (SSP). Moreover, normal human colonic crypts upregulate the SSP in response to OXPHOS deficiency prior to tumorigenesis. Our data show that age-associated OXPHOS deficiency causes metabolic remodelling that can functionally contribute to accelerated intestinal cancer development.
    DOI:  https://doi.org/10.1038/s43018-020-00112-5
  2. Nat Biotechnol. 2020 Oct 19.
    Mitochondrial copper depletion suppresses triple-negative breast cancer in mice.
    Liyang Cui, Arvin M Gouw, Edward L LaGory, Shenghao Guo, Nabeel Attarwala, Yao Tang, Ji Qi, Yun-Sheng Chen, Zhou Gao, Kerriann M Casey, Arkadiy A Bazhin, Min Chen, Leeann Hu, Jinghang Xie, Mingxi Fang, Cissy Zhang, Qihua Zhu, Zhiyuan Wang, Amato J Giaccia, Sanjiv Sam Gambhir, Weiping Zhu, Dean W Felsher, Mark D Pegram, Elena A Goun, Anne Le, Jianghong Rao.
      Depletion of mitochondrial copper, which shifts metabolism from respiration to glycolysis and reduces energy production, is known to be effective against cancer types that depend on oxidative phosphorylation. However, existing copper chelators are too toxic or ineffective for cancer treatment. Here we develop a safe, mitochondria-targeted, copper-depleting nanoparticle (CDN) and test it against triple-negative breast cancer (TNBC). We show that CDNs decrease oxygen consumption and oxidative phosphorylation, cause a metabolic switch to glycolysis and reduce ATP production in TNBC cells. This energy deficiency, together with compromised mitochondrial membrane potential and elevated oxidative stress, results in apoptosis. CDNs should be less toxic than existing copper chelators because they favorably deprive copper in the mitochondria in cancer cells instead of systemic depletion. Indeed, we demonstrate low toxicity of CDNs in healthy mice. In three mouse models of TNBC, CDN administration inhibits tumor growth and substantially improves survival. The efficacy and safety of CDNs suggest the potential clinical relevance of this approach.
    DOI:  https://doi.org/10.1038/s41587-020-0707-9
  3. Front Cell Dev Biol. 2020 ;8 583850
    Carnitine Traffic in Cells. Link With Cancer.
    Lara Console, Mariafrancesca Scalise, Tiziano Mazza, Lorena Pochini, Michele Galluccio, Nicola Giangregorio, Annamaria Tonazzi, Cesare Indiveri.
      Metabolic flexibility is a peculiar hallmark of cancer cells. A growing number of observations reveal that tumors can utilize a wide range of substrates to sustain cell survival and proliferation. The diversity of carbon sources is indicative of metabolic heterogeneity not only across different types of cancer but also within those sharing a common origin. Apart from the well-assessed alteration in glucose and amino acid metabolisms, there are pieces of evidence that cancer cells display alterations of lipid metabolism as well; indeed, some tumors use fatty acid oxidation (FAO) as the main source of energy and express high levels of FAO enzymes. In this metabolic pathway, the cofactor carnitine is crucial since it serves as a "shuttle-molecule" to allow fatty acid acyl moieties entering the mitochondrial matrix where these molecules are oxidized via the β-oxidation pathway. This role, together with others played by carnitine in cell metabolism, underlies the fine regulation of carnitine traffic among different tissues and, within a cell, among different subcellular compartments. Specific membrane transporters mediate carnitine and carnitine derivatives flux across the cell membranes. Among the SLCs, the plasma membrane transporters OCTN2 (Organic cation transport novel 2 or SLC22A5), CT2 (Carnitine transporter 2 or SLC22A16), MCT9 (Monocarboxylate transporter 9 or SLC16A9) and ATB0, + [Sodium- and chloride-dependent neutral and basic amino acid transporter B(0+) or SLC6A14] together with the mitochondrial membrane transporter CAC (Mitochondrial carnitine/acylcarnitine carrier or SLC25A20) are the most acknowledged to mediate the flux of carnitine. The concerted action of these proteins creates a carnitine network that becomes relevant in the context of cancer metabolic rewiring. Therefore, molecular mechanisms underlying modulation of function and expression of carnitine transporters are dealt with furnishing some perspective for cancer treatment.
    Keywords:  SLC; cancer; carnitine; drugs; mitochondria; transporters; β-oxidation
    DOI:  https://doi.org/10.3389/fcell.2020.583850
  4. Sci Adv. 2020 Oct;pii: eabe5310. [Epub ahead of print]6(43):
    MCART1/SLC25A51 is required for mitochondrial NAD transport.
    Nora Kory, Jelmi Uit de Bos, Sanne van der Rijt, Nevena Jankovic, Miriam Güra, Nicholas Arp, Izabella A Pena, Gyan Prakash, Sze Ham Chan, Tenzin Kunchok, Caroline A Lewis, David M Sabatini.
      The nicotinamide adenine dinucleotide (NAD+/NADH) pair is a cofactor in redox reactions and is particularly critical in mitochondria as it connects substrate oxidation by the tricarboxylic acid (TCA) cycle to adenosine triphosphate generation by the electron transport chain (ETC) and oxidative phosphorylation. While a mitochondrial NAD+ transporter has been identified in yeast, how NAD enters mitochondria in metazoans is unknown. Here, we mine gene essentiality data from human cell lines to identify MCART1 (SLC25A51) as coessential with ETC components. MCART1-null cells have large decreases in TCA cycle flux, mitochondrial respiration, ETC complex I activity, and mitochondrial levels of NAD+ and NADH. Isolated mitochondria from cells lacking or overexpressing MCART1 have greatly decreased or increased NAD uptake in vitro, respectively. Moreover, MCART1 and NDT1, a yeast mitochondrial NAD+ transporter, can functionally complement for each other. Thus, we propose that MCART1 is the long sought mitochondrial transporter for NAD in human cells.
    DOI:  https://doi.org/10.1126/sciadv.abe5310
  5. Sci Rep. 2020 Oct 21. 10(1): 17872
    Potent inhibition of tumour cell proliferation and immunoregulatory function by mitochondria-targeted atovaquone.
    Gang Cheng, Micael Hardy, Paytsar Topchyan, Ryan Zander, Peter Volberding, Weiguo Cui, Balaraman Kalyanaraman.
      The FDA-approved prophylactic antimalarial drug atovaquone (ATO) recently was repurposed as an antitumor drug. Studies show that ATO exerts a profound antiproliferative effect in several cancer cells, including breast, ovarian, and glioma. Analogous to the mechanism of action proposed in parasites, ATO inhibits mitochondrial complex III and cell respiration. To enhance the chemotherapeutic efficacy and oxidative phosphorylation inhibition, we developed a mitochondria-targeted triphenylphosphonium-conjugated ATO with varying alkyl side chains (Mito4-ATO, Mito10-ATO, Mito12-ATO, and Mito16-ATO). Results show, for the first time, that triphenylphosphonium-conjugated ATO potently enhanced the antiproliferative effect of ATO in cancer cells and, depending upon the alkyl chain length, the molecular target of inhibition changes from mitochondrial complex III to complex I. Mito4-ATO and Mito10-ATO inhibit both pyruvate/malate-dependent complex I and duroquinol-dependent complex III-induced oxygen consumption whereas Mito12-ATO and Mito16-ATO inhibit only complex I-induced oxygen consumption. Mitochondrial target shifting may have immunoregulatory implications.
    DOI:  https://doi.org/10.1038/s41598-020-74808-0
  6. J Cell Sci. 2020 Oct 18. pii: jcs.247379. [Epub ahead of print]
    Mitochondrial survivin reduces oxidative phosphorylation in cancer cells by inhibiting mitophagy.
    Amelia R Townley, Sally P Wheatley.
      Survivin is a cancer-associated protein that is pivotal for cellular life and death: it is an essential mitotic protein and an inhibitor of apoptosis. In cancer cells, a small pool of survivin localises to the mitochondria, the function of which remains to be elucidated. Here, we report that mitochondrial survivin inhibits the selective form of autophagy, called "mitophagy", causing an accumulation of respiratory defective mitochondria. Mechanistically the data reveal that survivin prevents recruitment of the E3-ubiquitin ligase Parkin to mitochondria and their subsequent recognition by the autophagosome. The data also demonstrate that cells in which mitophagy has been blocked by survivin expression have an increased dependency on glycolysis. As these effects were found exclusively in cancer cells they suggest that the primary act of mitochondrial survivin is to steer cells towards the implementation of the Warburg transition by inhibiting mitochondrial turnover, which enables them to adapt and survive.
    Keywords:  Cancer; Mitochondria; Mitophagy; Respiration; Survivin
    DOI:  https://doi.org/10.1242/jcs.247379
  7. Brain Behav Immun Health. 2020 May;pii: 100080. [Epub ahead of print]5
    Mitochondrial respiratory capacity modulates LPS-induced inflammatory signatures in human blood.
    Kalpita Rashmi Karan, Caroline Trumpff, Marlon A McGill, Jacob E Thomas, Gabriel Sturm, Vincenzo Lauriola, Richard P Sloan, Nicolas Rohleder, Brett A Kaufman, Anna L Marsland, Martin Picard.
      Mitochondria modulate inflammatory processes in various model organisms, but it is unclear how much mitochondria regulate immune responses in human blood leukocytes. Here, we examine the effect of i) experimental perturbations of mitochondrial respiratory chain function, and ii) baseline inter-individual variation in leukocyte mitochondrial energy production capacity on stimulated cytokine release and glucocorticoid (GC) sensitivity. In a first cohort, whole blood from 20 healthy women and men was stimulated with increasing concentrations of the immune agonist lipopolysaccharide (LPS). Four inhibitors of mitochondrial respiratory chain Complexes I, III, IV, and V were used (LPS + Mito-Inhibitors) to acutely perturb mitochondrial function, GC sensitivity was quantified using the GC-mimetic dexamethasone (DEX) (LPS + DEX), and the resultant cytokine signatures mapped with a 20-cytokine array. Inhibiting mitochondrial respiration caused large inter-individual differences in LPS-stimulated IL-6 reactivity (Cohen's d = 0.72) and TNF-α (d = 1.55) but only minor alteration in EC50-based LPS sensitivity (d = 0.21). Specifically, inhibiting mitochondrial Complex IV potentiated LPS-induced IL-6 levels by 13%, but inhibited TNF-α induction by 72%, indicating mitochondrial regulation of the IL-6/TNF-α ratio. As expected, DEX treatment suppressed multiple LPS-induced pro-inflammatory cytokines (IFN-γ, IL-6, IL-8, IL-1β, .TNF-α) by >85% and increased the anti-inflammatory cytokine IL-10 by 80%. Inhibiting Complex I potentiated DEX suppression of IL-6 by a further 12% (d = 0.73), indicating partial mitochondrial modulation of glucocorticoid sensitivity. Finally, to examine if intrinsic mitochondrial respiratory capacity may explain a portion of immune reactivity differences across individuals, we measured biochemical respiratory chain enzyme activities and mitochondrial DNA copy number in isolated peripheral blood mononuclear cells (PBMCs) from a second cohort of 44 healthy individuals in parallel with LPS-stimulated IL-6 and TNF-α response. Respiratory chain .function, particularly Complex IV activity, was positively correlated with LPS-stimulated IL-6 levels (r = 0.45, p = 0.002). Overall, these data provide preliminary evidence that mitochondrial behavior modulates LPS-induced inflammatory cytokine signatures in human blood.
    Keywords:  Cytokines; Human blood; IL-6; Inflammation; LPS; Mitochondria; TNF-α
    DOI:  https://doi.org/10.1016/j.bbih.2020.100080
  8. Oncol Lett. 2020 Dec;20(6): 313
    Differential regulation of mitochondrial complex I and oxidative stress based on metastatic potential of colorectal cancer cells.
    Neeraj Kumar Rai, Shashank Mathur, Suraj Kumar Singh, Meenakshi Tiwari, Vijay Kumar Singh, Rizwanul Haque, Swasti Tiwari, Lokendra Kumar Sharma.
      Mitochondria serve a vital role in cellular homeostasis as they regulate cell proliferation and death pathways, which are attributed to mitochondrial bioenergetics, free radicals and metabolism. Alterations in mitochondrial functions have been reported in various diseases, including cancer. Colorectal cancer (CRC) is one of the most common metastatic cancer types with high mortality rates. Although mitochondrial oxidative stress has been associated with CRC, its specific mechanism and contribution to metastatic progression remain poorly understood. Therefore, the aims of the present study were to investigate the role of mitochondria in CRC cells with low and high metastatic potential and to evaluate the contribution of mitochondrial respiratory chain (RC) complexes in oncogenic signaling pathways. The present results demonstrated that cell lines with low metastatic potential were resistant to mitochondrial complex I (C-I)-mediated oxidative stress, and had C-I inhibition with impaired mitochondrial functions. These adaptations enabled cells to cope with higher oxidative stress. Conversely, cells with high metastatic potential demonstrated functional C-I with improved mitochondrial function due to coordinated upregulation of mitochondrial biogenesis and metabolic reprogramming. Pharmacological inhibition of C-I in high metastatic cells resulted in increased sensitivity to cell death and decreased metastatic signaling. The present findings identified the differential regulation of mitochondrial functions in CRC cells, based on CRC metastatic potential. Specifically, it was suggested that a functional C-I is required for high metastatic features of cancer cells, and the role of C-I could be further examined as a potential target in the development of novel therapies for diagnosing high metastatic cancer types.
    Keywords:  apoptosis; colorectal cancer; metastasis; mitochondria; mitochondrial complex I; oxidative stress
    DOI:  https://doi.org/10.3892/ol.2020.12176
  9. Sci Rep. 2020 Oct 19. 10(1): 17599
    Novel approach to quantify mitochondrial content and intrinsic bioenergetic efficiency across organs.
    Kelsey L McLaughlin, James T Hagen, Hannah S Coalson, Margaret A M Nelson, Kimberly A Kew, Ashley R Wooten, Kelsey H Fisher-Wellman.
      Human disease pathophysiology commonly involves metabolic disruption at both the cellular and subcellular levels. Isolated mitochondria are a powerful model for separating global cellular changes from intrinsic mitochondrial alterations. However, common laboratory practices for isolating mitochondria (e.g., differential centrifugation) routinely results in organelle preparations with variable mitochondrial purity. To overcome this issue, we developed a mass spectrometry-based method that quantitatively evaluates sample-specific percent mitochondrial enrichment. Sample-specific mitochondrial enrichment was then used to correct various biochemical readouts of mitochondrial function to a 'fixed' amount of mitochondrial protein, thus allowing for intrinsic mitochondrial bioenergetics, relative to the underlying proteome, to be assessed across multiple mouse tissues (e.g., heart, brown adipose, kidney, liver). Our results support the use of mitochondrial-targeted nLC-MS/MS as a method to quantitate mitochondrial enrichment on a per-sample basis, allowing for unbiased comparison of functional parameters between populations of mitochondria isolated from metabolically distinct tissues. This method can easily be applied across multiple experimental settings in which intrinsic shifts in the mitochondrial network are suspected of driving a given physiological or pathophysiological outcome.
    DOI:  https://doi.org/10.1038/s41598-020-74718-1
  10. Cancers (Basel). 2020 Oct 17. pii: E3017. [Epub ahead of print]12(10):
    Mitochondria at Center of Exchanges between Cancer Cells and Cancer-Associated Fibroblasts during Tumor Progression.
    Lisa Nocquet, Philippe P Juin, Frédérique Souazé.
      Resistance of solid cancer cells to chemotherapies and targeted therapies is not only due to the mutational status of cancer cells but also to the concurring of stromal cells of the tumor ecosystem, such as immune cells, vasculature and cancer-associated fibroblasts (CAFs). The reciprocal education of cancer cells and CAFs favors tumor growth, survival and invasion. Mitochondrial function control, including the regulation of mitochondrial metabolism, oxidative stress and apoptotic stress are crucial for these different tumor progression steps. In this review, we focus on how CAFs participate in cancer progression by modulating cancer cells metabolic functions and mitochondrial apoptosis. We emphasize that mitochondria from CAFs influence their activation status and pro-tumoral effects. We thus advocate that understanding mitochondria-mediated tumor-stroma interactions provides the possibility to consider cancer therapies that improve current treatments by targeting these interactions or mitochondria directly in tumor and/or stromal cells.
    Keywords:  BCL-2 family proteins; apoptosis; cancer; cancer-associated fibroblast; metabolism; mitochondria
    DOI:  https://doi.org/10.3390/cancers12103017
  11. Mol Genet Metab. 2020 Oct 16. pii: S1096-7192(20)30208-0. [Epub ahead of print]
    Uniparental isodisomy as a cause of mitochondrial complex I respiratory chain disorder due to a novel splicing NDUFS4 mutation.
    Adrián González-Quintana, María J Trujillo-Tiebas, Ana L Fernández-Perrone, Alberto Blázquez, Alejandro Lucia, María Morán, Cristina Ugalde, Joaquín Arenas, Carmen Ayuso, Miguel A Martín.
      Uniparental disomy (UPD) is an underestimated cause of autosomal recessive disorders. In this study, we aim to raise awareness about the possibility of UPD in mitochondrial disorders - where it is a hardly described event -, by functionally characterizing a novel variant in a structural subunit of complex I (CI) of the mitochondrial oxidative phosphorylation system. Using next-generation sequencing, we identified a new intronic homozygous c.350 + 5G > A variant in the NDUFS4 gene in a one-year-old girl (being alive at the age of 7) belonging to a non-consanguineous family presenting with encephalopathy, psychomotor delay, lactic acidosis and a single CI deficiency, a less severe phenotype than those previously reported in most NDUFS4 patients. One parent lacked the variant, and microsatellite genotyping showed complete paternal uniparental isodisomy of the non-imprinted chromosome 5. We demonstrated in patient's skeletal muscle and fibroblasts splicing abnormalities, low expression of NDUFS4, undetectable NDUFS4 protein, defects in cellular respiration (decreased oxygen consumption and ATP production), and impaired assembly or stability of mitochondrial supercomplexes containing CI. Our findings support that c.350 + 5G > A variant is pathogenic, and reinforce that UPD, although rare, should be considered as a possible cause of mitochondrial diseases in order to provide accurate genetic counselling.
    Keywords:  Genetic counselling; Mitochondrial complex I deficiency; Mitochondrial diseases; NDUFS4, mitochondrial Supercomplexes, Uniparental Disomy; RNA splicing
    DOI:  https://doi.org/10.1016/j.ymgme.2020.10.008
  12. Nat Cell Biol. 2020 Oct 19.
    PLCγ1 suppression promotes the adaptation of KRAS-mutant lung adenocarcinomas to hypoxia.
    Maria Saliakoura, Matteo Rossi Sebastiano, Chiara Pozzato, Florian H Heidel, Tina M Schnöder, Spasenija Savic Prince, Lukas Bubendorf, Paolo Pinton, Ralph A Schmid, Johanna Baumgartner, Stefan Freigang, Sabina A Berezowska, Alessandro Rimessi, Georgia Konstantinidou.
      Mutant KRAS modulates the metabolic plasticity of cancer cells to confer a growth advantage during hypoxia, but the molecular underpinnings are largely unknown. Using a lipidomic screen, we found that PLCγ1 is suppressed during hypoxia in KRAS-mutant human lung adenocarcinoma cancer cell lines. Suppression of PLCγ1 in hypoxia promotes a less oxidative cancer cell metabolism state, reduces the formation of mitochondrial reactive oxygen species and switches tumour bioenergetics towards glycolysis by impairing Ca2+ entry into the mitochondria. This event prevents lipid peroxidation, antagonizes apoptosis and increases cancer cell proliferation. Accordingly, loss of function of Plcg1 in a mouse model of KrasG12D-driven lung adenocarcinoma increased the expression of glycolytic genes, boosted tumour growth and reduced survival. In patients with KRAS-mutant lung adenocarcinomas, low PLCγ1 expression correlates with increased expression of hypoxia markers and predicts poor patient survival. Thus, our work reveals a mechanism of cancer cell adaptation to hypoxia with potential therapeutic value.
    DOI:  https://doi.org/10.1038/s41556-020-00592-8
  13. Cell Death Differ. 2020 Oct 23.
    Branched-chain amino acid aminotransferase 2 regulates ferroptotic cell death in cancer cells.
    Kang Wang, Zhengyang Zhang, Hsiang-I Tsai, Yanfang Liu, Jie Gao, Ming Wang, Lian Song, Xiongfeng Cao, Zhanxue Xu, Hongbo Chen, Aihua Gong, Dongqing Wang, Fang Cheng, Haitao Zhu.
      Ferroptosis, a form of iron-dependent cell death driven by cellular metabolism and iron-dependent lipid peroxidation, has been implicated as a tumor-suppressor function for cancer therapy. Recent advance revealed that the sensitivity to ferroptosis is tightly linked to numerous biological processes, including metabolism of amino acid and the biosynthesis of glutathione. Here, by using a high-throughput CRISPR/Cas9-based genetic screen in HepG2 hepatocellular carcinoma cells to search for metabolic proteins inhibiting ferroptosis, we identified a branched-chain amino acid aminotransferase 2 (BCAT2) as a novel suppressor of ferroptosis. Mechanistically, ferroptosis inducers (erastin, sorafenib, and sulfasalazine) activated AMPK/SREBP1 signaling pathway through iron-dependent ferritinophagy, which in turn inhibited BCAT2 transcription. We further confirmed that BCAT2 as the key enzyme mediating the metabolism of sulfur amino acid, regulated intracellular glutamate level, whose activation by ectopic expression specifically antagonize system Xc- inhibition and protected liver and pancreatic cancer cells from ferroptosis in vitro and in vivo. On the contrary, direct inhibition of BCAT2 by RNA interference, or indirect inhibition by blocking system Xc- activity, triggers ferroptosis. Finally, our results demonstrate the synergistic effect of sorafenib and sulfasalazine in downregulating BCAT2 expression and dictating ferroptotic death, where BCAT2 can also be used to predict the responsiveness of cancer cells to ferroptosis-inducing therapies. Collectively, these findings identify a novel role of BCAT2 in ferroptosis, suggesting a potential therapeutic strategy for overcoming sorafenib resistance.
    DOI:  https://doi.org/10.1038/s41418-020-00644-4
  14. Proc Natl Acad Sci U S A. 2020 Oct 19. pii: 201921223. [Epub ahead of print]
    Bifidobacterium alters the gut microbiota and modulates the functional metabolism of T regulatory cells in the context of immune checkpoint blockade.
    Shan Sun, Lingjie Luo, Wenhua Liang, Qian Yin, Jing Guo, Anthony M Rush, Zhibao Lv, Qiming Liang, Michael A Fischbach, Justin L Sonnenburg, Dylan Dodd, Mark M Davis, Feng Wang.
      Immune checkpoint-blocking antibodies that attenuate immune tolerance have been used to effectively treat cancer, but they can also trigger severe immune-related adverse events. Previously, we found that Bifidobacterium could mitigate intestinal immunopathology in the context of CTLA-4 blockade in mice. Here we examined the mechanism underlying this process. We found that Bifidobacterium altered the composition of the gut microbiota systematically in a regulatory T cell (Treg)-dependent manner. Moreover, this altered commensal community enhanced both the mitochondrial fitness and the IL-10-mediated suppressive functions of intestinal Tregs, contributing to the amelioration of colitis during immune checkpoint blockade.
    Keywords:  Bifidobacterium; immune checkpoint blockade; metabolism; microbiota; regulatory T cell
    DOI:  https://doi.org/10.1073/pnas.1921223117
  15. Pharm Dev Technol. 2020 Oct 18. 1-9
    Mitochondrial targeted doxorubicin derivatives delivered by ROS-responsive nanocarriers to breast tumor for overcoming of multidrug resistance.
    Xin-Cheng Zhong, Ming-Han Shi, Hui-Na Liu, Jie-Jian Chen, Tian-Tian Wang, Meng-Ting Lin, Zhen-Tao Zhang, Yi Zhou, Yi-Ying Lu, Wen-Hong Xu, Jian-Qing Gao, Dong-Hang Xu, Min Han, Yi-Ding Chen.
      Multidrug resistance (MDR) is a serious challenge in chemotherapy and also a major threat to breast cancer treatment. As an intracellular energy factory, mitochondria provide energy for drug efflux and are deeply involved in multidrug resistance. Mitochondrial targeted delivery of doxorubicin can overcome multidrug resistance by disrupting mitochondrial function. By incorporating a reactive oxygen species (ROS)-responsive hydrophobic group into the backbone structure of hyaluronic acid - a natural ligand for the highly expressed CD44 receptor on tumor surfaces, a novel ROS-responsive and CD44-targeting nano-carriers was constructed. In this study, mitochondria-targeted triphenylphosphine modified-doxorubicin (TPP-DOX) and amphipathic ROS-responsive hyaluronic acid derivatives (HA-PBPE) were synthesized and confirmed by 1H NMR. The nanocarriers TPP-DOX @ HA-PBPE was prepared in a regular shape and particle size of approximately 200 nm. Compared to free DOX, its antitumor activity in vitro and tumor passive targeting in vivo has been enhanced. The ROS-responsive TPP-DOX@HA-PBPE nanocarriers system provide a promising strategy for the reverse of MDR and efficient delivery of doxorubicin derivatives into drug-resistant cancer cells.
    Keywords:  Breast cancer; Hyaluronic acid; doxorubicin; mitochondrial target; multidrug resistance
    DOI:  https://doi.org/10.1080/10837450.2020.1832116
  16. Cell Death Dis. 2020 Oct 22. 11(10): 892
    TIMELESS regulates sphingolipid metabolism and tumor cell growth through Sp1/ACER2/S1P axis in ER-positive breast cancer.
    Shan Zhang, Peiqi Huang, Huijuan Dai, Qing Li, Lipeng Hu, Jing Peng, Shuheng Jiang, Yaqian Xu, Ziping Wu, Huizhen Nie, Zhigang Zhang, Wenjin Yin, Xueli Zhang, Jinsong Lu.
      Breast cancer is one of the most common female malignant cancers. Biorhythm disorder largely increases the risk of breast cancer. We aimed to investigate the biological functions and molecular mechanisms of circadian gene TIMELESS circadian regulator (TIM) in estrogen receptor (ER)-positive breast cancer and provide a new therapeutic target for breast cancer patients. Here, we explored that the expression of TIM was elevated in breast cancer, and high expression of TIM in cancer tissues was associated with poor prognosis, especially in the ER-positive breast cancer patients. In addition, we found that TIM promoted cell proliferation and enhanced mitochondrial respiration. TIM interacted with specificity protein 1 (Sp1) which contributes to upregulate the expression of alkaline ceramidase 2 (ACER2). Moreover, ACER2 is responsible for TIM-mediated promotive effects of cell growth and mitochondrial respiration. Collectively, our research unveiled a novel function of TIM in sphingolipid metabolism through interaction with Sp1. It provides a new theoretical explanation for the pathogenesis of breast cancer, and targeting TIM may serve as a potential therapeutic target for ER-positive breast cancer.
    DOI:  https://doi.org/10.1038/s41419-020-03106-4
  17. J Clin Endocrinol Metab. 2020 Oct 20. pii: dgaa751. [Epub ahead of print]
    Elevated plasma branched-chain amino acid levels correlate with type 2 diabetes-related metabolic disturbances.
    Froukje Vanweert, Marlies de Ligt, Joris Hoeks, Matthijs K C Hesselink, Patrick Schrauwen, Esther Phielix.
       CONTEXT: Patients with type 2 diabetes (T2DM) have elevated plasma branched-chain amino acid levels (BCAA). The underlying cause is however not known. Low mitochondrial oxidation of BCAA could contribute to higher plasma BCAA levels.
    OBJECTIVE: We aimed to investigate ex vivo muscle mitochondrial oxidative capacity and in vivo BCAA oxidation measured by whole-body leucine oxidation rates in patients with T2DM, first-degree relatives (FDR) and control participants (CON) with overweight or obesity.
    DESIGN AND SETTING: An observational, community-based study was conducted.
    PARTICIPANTS: Fifteen patients with T2DM, thirteen FDR and seventeen CON were included (age between 40-70 years and BMI ranging from 27-35 kg/m 2).
    MAIN OUTCOME MEASURES: High-resolution respirometry was used to examine ex vivo mitochondrial oxidative capacity in permeabilized muscle fibers. A subgroup of five T2DM and five CON underwent hyperinsulinemic-euglycemic clamps combined with 1- 13C leucine-infusion to determine whole-body leucine oxidation.
    RESULTS: Total BCAA levels were higher in patients with T2DM compared to CON, but not in FDR, and correlated negatively with muscle mitochondrial oxidative capacity (r = -0.44, p<0.001). Consistently, whole-body leucine oxidation rate was lower in patients with T2DM vs. CON under basal conditions (0.202 ± 0.049 vs. 0.275 ± 0.043 μmol kg -1 min -1, p<0.05) and tended to be lower during high insulin infusion (0.326 ± 0.024 vs. 0.382 ± 0.013 μmol kg -1 min -1, p=0.075).
    CONCLUSIONS: In patients with T2DM, a compromised whole-body leucine oxidation rate supports our hypothesis that higher plasma BCAA levels may at least originate partly from a low mitochondrial oxidative capacity.
    Keywords:  1- 13C leucine oxidation; branched-chain amino acids; first-degree relatives; insulin resistance; mitochondrial oxidative capacity; type 2 diabetes
    DOI:  https://doi.org/10.1210/clinem/dgaa751
  18. Transl Oncol. 2020 Oct 14. pii: S1936-5233(20)30397-1. [Epub ahead of print]14(1): 100905
    Targeting cancer-cell mitochondria and metabolism to improve radiotherapy response.
    Emma McCann, Jacintha O'Sullivan, Simone Marcone.
      Radiotherapy is a regimen that uses ionising radiation (IR) to treat cancer. Despite the availability of several therapeutic options, cancer remains difficult to treat and only a minor percentage of patients receiving radiotherapy show a complete response to the treatment due to development of resistance to IR (radioresistance). Therefore, radioresistance is a major clinical problem and is defined as an adaptive response of the tumour to radiation-induced damage by altering several cellular processes which sustain tumour growth including DNA damage repair, cell cycle arrest, alterations of oncogenes and tumour suppressor genes, autophagy, tumour metabolism and altered reactive oxygen species. Cellular organelles, in particular mitochondria, are key players in mediating the radiation response in tumour, as they regulate many of the cellular processes involved in radioresistance. In this article has been reviewed the recent findings describing the cellular and molecular mechanism by which cancer rewires the function of the mitochondria and cellular metabolism to enhance radioresistance, and the role that drugs targeting cellular bioenergetics have in enhancing radiation response in cancer patients.
    Keywords:  Cancer metabolism; Cancer treatment; Mitochondrial dysfunction; Radioresistance; Radiotherapy
    DOI:  https://doi.org/10.1016/j.tranon.2020.100905
  19. Membranes (Basel). 2020 Oct 21. pii: E299. [Epub ahead of print]10(10):
    Regulation of Cell Death by Mitochondrial Transport Systems of Calcium and Bcl-2 Proteins.
    Natalia Naumova, Radek Šachl.
      Mitochondria represent the fundamental system for cellular energy metabolism, by not only supplying energy in the form of ATP, but also by affecting physiology and cell death via the regulation of calcium homeostasis and the activity of Bcl-2 proteins. A lot of research has recently been devoted to understanding the interplay between Bcl-2 proteins, the regulation of these interactions within the cell, and how these interactions lead to the changes in calcium homeostasis. However, the role of Bcl-2 proteins in the mediation of mitochondrial calcium homeostasis, and therefore the induction of cell death pathways, remain underestimated and are still not well understood. In this review, we first summarize our knowledge about calcium transport systems in mitochondria, which, when miss-regulated, can induce necrosis. We continue by reviewing and analyzing the functions of Bcl-2 proteins in apoptosis. Finally, we link these two regulatory mechanisms together, exploring the interactions between the mitochondrial Ca2+ transport systems and Bcl-2 proteins, both capable of inducing cell death, with the potential to determine the cell death pathway-either the apoptotic or the necrotic one.
    Keywords:  Bax; Bcl-2 proteins; MCU; VDAC; apoptosis; calcium transport; mPTP; mitochondria; necrosis
    DOI:  https://doi.org/10.3390/membranes10100299
  20. J Biol Chem. 2020 Oct 21. pii: jbc.RA120.013716. [Epub ahead of print]
    PDE5 inhibition rescues mitochondrial dysfunction and angiogenic responses induced by Akt3 inhibition by promotion of PRC expression.
    Daniel G Corum, Dorea P Jenkins, James A Heslop, Lacey M Tallent, Gyda C Beeson, Jeremy L Barth, Rick G Schnellmann, Robin C Muise-Helmericks.
      Akt3 regulates mitochondrial content in endothelial cells through the inhibition of PGC-1α nuclear localization and is also required for angiogenesis. However, whether there is a direct link between mitochondrial function and angiogenesis is unknown. Here we show that Akt3 depletion in primary endothelial cells (EC) results in decreased uncoupled oxygen consumption, increased fission, decreased membrane potential and increased expression of the mitochondria-specific protein chaperones, HSP60 and HSP10, suggesting that Akt3 is required for mitochondrial homeostasis. Direct inhibition of mitochondrial homeostasis by the model oxidant paraquat results in decreased angiogenesis showing a direct link between angiogenesis and mitochondrial function. Next, in exploring functional links to PGC-1α, the master regulator of mitochondrial biogenesis, we searched for compounds that induce this process. We found that sildenafil, a phosphodiesterase 5 (PDE5) inhibitor induced mitochondrial biogenesis as measured by increased uncoupled oxygen consumption, mitochondrial DNA content and voltage-dependent anion channel protein expression.  Sildenafil rescued the effects on mitochondria by Akt3 depletion or pharmacological inhibition and promoted angiogenesis, further supporting that mitochondrial homeostasis is required for angiogenesis. Sildenafil also induces the expression of PGC-1 family member, PRC and can compensate for PGC-1α activity during mitochondrial stress by an Akt3-independent mechanism. The induction of PRC by sildenafil is dependent upon cAMP and the transcription factor CREB. Thus, PRC can functionally substitute during Akt3 depletion for absent PGC-1α activity to restore mitochondrial homeostasis and promote angiogenesis. These findings show that mitochondrial homeostasis as controlled by the PGC family of transcriptional activators is required for angiogenic responses.
    Keywords:  Akt PKB; Akt3; PRC; angiogenesis; mitochondria; peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1a)(PPARGC1A); phosphodiesterases
    DOI:  https://doi.org/10.1074/jbc.RA120.013716
  21. Front Mol Biosci. 2020 ;7 217
    Neutral Sphingomyelinase-2 (NSM 2) Controls T Cell Metabolic Homeostasis and Reprogramming During Activation.
    Maria Nathalia De Lira, Sudha Janaki Raman, Almut Schulze, Sibylle Schneider-Schaulies, Elita Avota.
      Neutral sphingomyelinase-2 (NSM2) is a member of a superfamily of enzymes responsible for conversion of sphingomyelin into phosphocholine and ceramide at the cytosolic leaflet of the plasma membrane. Upon specific ablation of NSM2, T cells proved to be hyper-responsive to CD3/CD28 co-stimulation, indicating that the enzyme acts to dampen early overshooting activation of these cells. It remained unclear whether hyper-reactivity of NSM2-deficient T cells is supported by a deregulated metabolic activity in these cells. Here, we demonstrate that ablation of NSM2 activity affects metabolism of the quiescent CD4+ T cells which accumulate ATP in mitochondria and increase basal glycolytic activity. This supports enhanced production of total ATP and metabolic switch early after TCR/CD28 stimulation. Most interestingly, increased metabolic activity in resting NSM2-deficient T cells does not support sustained response upon stimulation. While elevated under steady-state conditions in NSM2-deficient CD4+ T cells, the mTORC1 pathway regulating mitochondria size, oxidative phosphorylation, and ATP production is impaired after 24 h of stimulation. Taken together, the absence of NSM2 promotes a hyperactive metabolic state in unstimulated CD4+ T cells yet fails to support sustained T cell responses upon antigenic stimulation.
    Keywords:  ATP-adenosine triphosphate; Mitochondria; Seahorse XF; T cell receptor; neutral sphingomyelinase-2; oxidative phosphorylation
    DOI:  https://doi.org/10.3389/fmolb.2020.00217
  22. Mol Neurobiol. 2020 Oct 22.
    Effects of Novel Tacrine Derivatives on Mitochondrial Energy Metabolism and Monoamine Oxidase Activity-In Vitro Study.
    Jana Hroudová, Tereza Nováková, Jan Korábečný, Dávid Maliňák, Lukáš Górecki, Zdeněk Fišar.
      The trends of novel AD therapeutics are focused on multitarget-directed ligands (MTDLs), which combine cholinesterase inhibition with additional biological properties such as antioxidant properties to positively affect neuronal energy metabolism as well as mitochondrial function. We examined the in vitro effects of 10 novel MTDLs on the activities of mitochondrial enzymes (electron transport chain complexes and citrate synthase), mitochondrial respiration, and monoamine oxidase isoform (MAO-A and MAO-B) activity. The drug-induced effects of 7-MEOTA-adamantylamine heterodimers (K1011, K1013, K1018, K1020, and K1022) and tacrine/7-MEOTA/6-chlorotacrine-trolox heterodimers (K1046, K1053, K1056, K1060, and K1065) were measured in pig brain mitochondria. Most of the substances inhibited complex I- and complex II-linked respiration at high concentrations; K1046, K1053, K1056, and K1060 resulted in the least inhibition of mitochondrial respiration. Citrate synthase activity was not significantly inhibited by the tested substances; the least inhibition of complex I was observed for compounds K1060 and K1053, while both complex II/III and complex IV activity were markedly inhibited by K1011 and K1018. MAO-A was fully inhibited by K1018 and K1065, and MAO-B was fully inhibited by K1053 and K1065; the other tested drugs were partial inhibitors of both MAO-A and MAO-B. The tacrine/7-MEOTA/6-chlorotacrine-trolox heterodimers K1046, K1053, and K1060 seem to be the most suitable molecules for subsequent in vivo studies. These compounds had balanced inhibitory effects on mitochondrial respiration, with low complex I and complex II/III inhibition and full or partial inhibition of MAO-B activity.
    Keywords:  Alzheimer’s disease; Cholinesterase inhibitors; Electron transport chain complexes; Mitochondrial respiration; Monoamine oxidase; Multitarget-directed ligands
    DOI:  https://doi.org/10.1007/s12035-020-02172-1
  23. Redox Biol. 2020 Oct 14. pii: S2213-2317(20)30966-6. [Epub ahead of print]37 101761
    Stat2-Drp1 mediated mitochondrial mass increase is necessary for pro-inflammatory differentiation of macrophages.
    Weihua Yu, Xin Wang, Jiuzhou Zhao, Rui Liu, Jiangzheng Liu, Zhao Wang, Jie Peng, Hao Wu, Xiaodi Zhang, Zi Long, Deqin Kong, Wenli Li, Chunxu Hai.
      Macrophage recruitment and pro-inflammatory differentiation are hallmarks of various diseases, including infection and sepsis. Although studies suggest that mitochondria may regulate macrophage immune responses, it remains unclear whether mitochondrial mass affects macrophage pro-inflammatory differentiation. Here, we found that lipopolysaccharide (LPS)-activated macrophages possess higher mitochondrial mass than resting cells. Therefore, this study aimed to explore the functional role and molecular mechanisms of increased mitochondrial mass in pro-inflammatory differentiated macrophages. Results show that an increase in the mitochondrial mass of macrophages positively correlates with inflammatory cytokine generation in response to LPS. RNA-seq analysis revealed that LPS promotes signal transducers and activators of transcription 2 (Stat2) and dynamin-related protein 1 (Drp1) expression, which are enriched in positive mitochondrial fission regulation. Meanwhile, knockdown or pharmacological inhibition of Drp1 blunts LPS-induced mitochondrial mass increase and pro-inflammatory differentiation. Moreover, Stat2 boosts Drp1 phosphorylation at serine 616, required for Drp1-mediated mitochondrial fission. LPS also causes Stat2-and Drp1-dependent biogenesis, which contributes to the generation of additional mitochondria. However, these mitochondria are profoundly remodeled, displaying fragmented morphology, loose cristae, reduced Δψm, and metabolic programming. Furthermore, these remodeled mitochondria shift their function from ATP synthesis to reactive oxygen species (ROS) production, which drives NFκB-dependent inflammatory cytokine transcription. Interestingly, an increase in mitochondrial mass with constitutively active phosphomimetic mutant of Drp1 (Drp1S616E) boosted pro-inflammatory response in macrophages without LPS stimulation. In vivo, we also demonstrated that Mdivi-1 administration inhibits LPS-induced macrophage pro-inflammatory differentiation. Importantly, we observed Stat2 phosphorylation and Drp1-dependent mitochondrial mass increase in macrophages isolated from LPS-challenged mice. In conclusion, we comprehensively demonstrate that a Stat2-Drp1 dependent mitochondrial mass increase is necessary for pro-inflammatory differentiation of macrophages. Therefore, targeting the Stat2-Drp1 axis may provide novel therapeutic approaches for treating infection and inflammatory diseases.
    Keywords:  Drp1; Lipopolysaccharide; Mitochondrial mass; Pro-inflammatory macrophage; Reactive oxygen species; Stat2
    DOI:  https://doi.org/10.1016/j.redox.2020.101761
  24. Cell Calcium. 2020 Oct 16. pii: S0143-4160(20)30150-0. [Epub ahead of print]92 102308
    Mitochondria as the decision makers for cancer cell fate: from signaling pathways to therapeutic strategies.
    Ilaria Genovese, Bianca Vezzani, Alberto Danese, Lorenzo Modesti, Veronica Angela Maria Vitto, Virginia Corazzi, Stefano Pelucchi, Paolo Pinton, Carlotta Giorgi.
      As pivotal players in cellular metabolism, mitochondria have a double-faceted role in the final decision of cell fate. This is true for all cell types, but it is even more important and intriguing in the cancer setting. Mitochondria regulate cell fate in many diverse ways: through metabolism, by producing ATP and other metabolites deemed vital or detrimental for cancer cells; through the regulation of Ca2+ homeostasis, especially by the joint participation of the endoplasmic reticulum in a membranous tethering system for Ca2+ signaling called mitochondria-ER associated membranes (MAMs); and by regulating signaling pathways involved in the survival of cancer cells such as mitophagy. Recent studies have shown that mitochondria can also play a role in the regulation of inflammatory pathways in cancer cells, for example, through the release of mitochondrial DNA (mtDNA) involved in the activation of the cGAS-cGAMP-STING pathway. In this review, we aim to explore the role of mitochondria as decision makers in fostering cancer cell death or survival depending on the tumor cell stage and describe novel anticancer therapeutic strategies targeting mitochondria.
    Keywords:  Ca(2+) signaling; Mitochondria; bioenergetics; cGAS-cGAMP-STING pathway; cancer; mitophagy
    DOI:  https://doi.org/10.1016/j.ceca.2020.102308
  25. Nat Metab. 2020 Oct 19.
    Cytosolic pH regulates proliferation and tumour growth by promoting expression of cyclin D1.
    Lisa Maria Koch, Eivind Salmorin Birkeland, Stefania Battaglioni, Xiao Helle, Mayura Meerang, Stefanie Hiltbrunner, Alfredo J Ibáñez, Matthias Peter, Alessandra Curioni-Fontecedro, Isabelle Opitz, Reinhard Dechant.
      Enhanced growth and proliferation of cancer cells are accompanied by profound changes in cellular metabolism. These metabolic changes are also common under physiological conditions, and include increased glucose fermentation accompanied by elevated cytosolic pH (pHc)1,2. However, how these changes contribute to enhanced cell growth and proliferation is unclear. Here, we show that elevated pHc specifically orchestrates an E2F-dependent transcriptional programme to drive cell proliferation by promoting cyclin D1 expression. pHc-dependent transcription of cyclin D1 requires the transcription factors CREB1, ATF1 and ETS1, and the histone acetyltransferases p300 and CBP. Biochemical characterization revealed that the CREB1-p300/CBP interaction acts as a pH sensor and coincidence detector, integrating different mitotic signals to regulate cyclin D1 transcription. We also show that elevated pHc contributes to increased cyclin D1 expression in malignant pleural mesotheliomas (MPMs), and renders these cells hypersensitive to pharmacological reduction of pHc. Taken together, these data demonstrate that elevated pHc is a critical cellular signal regulating G1 progression, and provide a mechanism linking elevated pHc to oncogenic activation of cyclin D1 in MPMs, and possibly other cyclin D1~dependent tumours. Thus, an increase of pHc may represent a functionally important, early event in the aetiology of cancer that is amenable to therapeutic intervention.
    DOI:  https://doi.org/10.1038/s42255-020-00297-0
  26. Nat Commun. 2020 10 21. 11(1): 5338
    Single-cell derived tumor organoids display diversity in HLA class I peptide presentation.
    Laura C Demmers, Kai Kretzschmar, Arne Van Hoeck, Yotam E Bar-Epraïm, Henk W P van den Toorn, Mandy Koomen, Gijs van Son, Joost van Gorp, Apollo Pronk, Niels Smakman, Edwin Cuppen, Hans Clevers, Albert J R Heck, Wei Wu.
      Tumor heterogeneity is a major cause of therapeutic resistance. Immunotherapy may exploit alternative vulnerabilities of drug-resistant cells, where tumor-specific human leukocyte antigen (HLA) peptide ligands are promising leads to invoke targeted anti-tumor responses. Here, we investigate the variability in HLA class I peptide presentation between different clonal cells of the same colorectal cancer patient, using an organoid system. While clone-specific differences in HLA peptide presentation were observed, broad inter-clone variability was even more prevalent (15-25%). By coupling organoid proteomics and HLA peptide ligandomics, we also found that tumor-specific ligands from DNA damage control and tumor suppressor source proteins were prominently presented by tumor cells, coinciding likely with the silencing of such cytoprotective functions. Collectively, these data illustrate the heterogeneous HLA peptide presentation landscape even within one individual, and hint that a multi-peptide vaccination approach against highly conserved tumor suppressors may be a viable option in patients with low tumor-mutational burden.
    DOI:  https://doi.org/10.1038/s41467-020-19142-9
  27. Nat Rev Mol Cell Biol. 2020 Oct 22.
    Quality control of the mitochondrial proteome.
    Jiyao Song, Johannes M Herrmann, Thomas Becker.
      Mitochondria contain about 1,000-1,500 proteins that fulfil multiple functions. Mitochondrial proteins originate from two genomes: mitochondrial and nuclear. Hence, proper mitochondrial function requires synchronization of gene expression in the nucleus and in mitochondria and necessitates efficient import of mitochondrial proteins into the organelle from the cytosol. Furthermore, the mitochondrial proteome displays high plasticity to allow the adaptation of mitochondrial function to cellular requirements. Maintenance of this complex and adaptable mitochondrial proteome is challenging, but is of crucial importance to cell function. Defects in mitochondrial proteostasis lead to proteotoxic insults and eventually cell death. Different quality control systems monitor the mitochondrial proteome. The cytosolic ubiquitin-proteasome system controls protein transport across the mitochondrial outer membrane and removes damaged or mislocalized proteins. Concomitantly, a number of mitochondrial chaperones and proteases govern protein folding and degrade damaged proteins inside mitochondria. The quality control factors also regulate processing and turnover of native proteins to control protein import, mitochondrial metabolism, signalling cascades, mitochondrial dynamics and lipid biogenesis, further ensuring proper function of mitochondria. Thus, mitochondrial protein quality control mechanisms are of pivotal importance to integrate mitochondria into the cellular environment.
    DOI:  https://doi.org/10.1038/s41580-020-00300-2
  28. Free Radic Biol Med. 2020 Oct 16. pii: S0891-5849(20)31285-5. [Epub ahead of print]161 163-174
    Lung mitochondria adaptation to endurance training in rats.
    Wieslawa Jarmuszkiewicz, Karolina Dominiak, Lukasz Galganski, Hanna Galganska, Anna Kicinska, Joanna Majerczak, Jerzy A Zoladz.
      We elucidated the impact of eight weeks of endurance training on the oxidative metabolism of rat lungs. Adult 3.5-month-old male rats were randomly allocated to a treadmill training group or a sedentary group as control. In the lungs, endurance training raised the expression level of the oxygen sensors hypoxia inducible factor 1α (HIF1α) and lysine-specific demethylase 6A (KDM6A) as well as stimulated mitochondrial oxidative capacity and mitochondrial biogenesis, while lactate dehydrogenase activity was reduced. Endurance training enhanced antioxidant systems (the coenzyme Q content and superoxide dismutase) in lung tissue but decreased them (and uncoupling protein 2) in lung mitochondria. In the lung mitochondria of trained rats, the decreased Q content and Complex I (CI) activity and the enhanced cytochrome pathway activity (CIII + CIV) may account for the diminished Q reduction level, resulting in a general decrease in H2O2 formation by mitochondria. Endurance training enhanced oxidation of glutamate and fatty acids and caused opposite effects in functional mitochondrial properties during malate and succinate oxidation, which were related to reduced activity of CI and increased activity of CII, respectively. In addition, endurance training downregulated CI in supercomplexes and upregulated CIII in the CIII2+CIV supercomplex in the oxidative phosphorylation system. We concluded that the adaptive lung responses observed could be due to hypoxia and oxidative stress induced by strenuous endurance training.
    Keywords:  Endurance training and mitochondrial biogenesis; Hypoxia; Lung mitochondria function; Oxidative metabolism; Oxidative stress
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2020.10.011
  29. Cell Rep. 2020 Oct 20. pii: S2211-1247(20)31273-0. [Epub ahead of print]33(3): 108284
    A Regulation Loop between YAP and NR4A1 Balances Cell Proliferation and Apoptosis.
    Lingli He, Liang Yuan, Wentao Yu, Yang Sun, Dan Jiang, Xiaodong Wang, Xue Feng, Zuoyun Wang, Jinjin Xu, Ruizeng Yang, Wenxiang Zhang, Hua Feng, Hang-Zi Chen, Yi Arial Zeng, Lijian Hui, Qiao Wu, Yonglong Zhang, Lei Zhang.
      The Hippo signaling pathway maintains organ size and tissue homeostasis via orchestration of cell proliferation and apoptosis. How this pathway triggers cell apoptosis remains largely unexplored. Here, we identify NR4A1 as a target of the Hippo pathway that mediates the pro-apoptotic and anti-tumor effects of the Hippo pathway whereby YAP regulates the transcription, phosphorylation, and mitochondrial localization of NR4A1. NR4A1, in turn, functions as a feedback inhibitor of YAP to promote its degradation, thereby inhibiting the function of YAP during liver regeneration and tumorigenesis. Our studies elucidate a regulatory loop between NR4A1 and YAP to coordinate Hippo signaling activity during liver regeneration and tumorigenesis and highlight NR4A1 as a marker of Hippo signaling, as well as a therapeutic target for hepatocellular carcinoma.
    Keywords:  Hippo signaling pathway; NR4A1; apoptosis; hepatocellular carcinoma (HCC); liver regeneration
    DOI:  https://doi.org/10.1016/j.celrep.2020.108284
  30. Nat Cell Biol. 2020 Oct 19.
    ER-resident oxidoreductases are glycosylated and trafficked to the cell surface to promote matrix degradation by tumour cells.
    Manon Ros, Anh Tuan Nguyen, Joanne Chia, Son Le Tran, Xavier Le Guezennec, Ruth McDowall, Sergey Vakhrushev, Henrik Clausen, Martin James Humphries, Frederic Saltel, Frederic André Bard.
      Tumour growth and invasiveness require extracellular matrix (ECM) degradation and are stimulated by the GALA pathway, which induces protein O-glycosylation in the endoplasmic reticulum (ER). ECM degradation requires metalloproteases, but whether other enzymes are required is unclear. Here, we show that GALA induces the glycosylation of the ER-resident calnexin (Cnx) in breast and liver cancer. Glycosylated Cnx and its partner ERp57 are trafficked to invadosomes, which are sites of ECM degradation. We find that disulfide bridges are abundant in connective and liver ECM. Cell surface Cnx-ERp57 complexes reduce these extracellular disulfide bonds and are essential for ECM degradation. In vivo, liver cancer cells but not hepatocytes display cell surface Cnx. Liver tumour growth and lung metastasis of breast and liver cancer cells are inhibited by anti-Cnx antibodies. These findings uncover a moonlighting function of Cnx-ERp57 at the cell surface that is essential for ECM breakdown and tumour development.
    DOI:  https://doi.org/10.1038/s41556-020-00590-w
  31. Cell Stem Cell. 2020 Oct 10. pii: S1934-5909(20)30493-8. [Epub ahead of print]
    Mitochondrial Potentiation Ameliorates Age-Related Heterogeneity in Hematopoietic Stem Cell Function.
    Els Mansell, Valgardur Sigurdsson, Elitza Deltcheva, John Brown, Chela James, Kenichi Miharada, Shamit Soneji, Jonas Larsson, Tariq Enver.
      Aging is associated with reduced fitness and increased myeloid bias of the hematopoietic stem cell (HSC) compartment, causing increased risk of immune compromise, anemia, and malignancy. We show that mitochondrial membrane potential (MMP) can be used to prospectively isolate chronologically old HSCs with transcriptional features and functional attributes characteristic of young HSCs, including a high rate of transcription and balanced lineage-affiliated programs. Strikingly, MMP is a stronger determinant of the quantitative and qualitative transcriptional state of HSCs than chronological age, and transcriptional consequences of manipulation of MMP in HSCs within their native niche suggest a causal relationship. Accordingly, we show that pharmacological enhancement of MMP in old HSCs in vivo increases engraftment potential upon transplantation and reverses myeloid-biased peripheral blood output at steady state. Our results demonstrate that MMP is a source of heterogeneity in old HSCs, and its pharmacological manipulation can alter transcriptional programs with beneficial consequences for function.
    Keywords:  Aging; Hematopoietc Stem Cell; Lineage bias; Mitochondria; Mitochondrial Membrane Potential; Mitoquinol; Transcription Rate
    DOI:  https://doi.org/10.1016/j.stem.2020.09.018
  32. Sci Adv. 2020 Oct;pii: eaaz4452. [Epub ahead of print]6(43):
    HSB-1/HSF-1 pathway modulates histone H4 in mitochondria to control mtDNA transcription and longevity.
    Surojit Sural, Chung-Yi Liang, Feng-Yung Wang, Tsui-Ting Ching, Ao-Lin Hsu.
      Heat shock factor-1 (HSF-1) is a master regulator of stress responses across taxa. Overexpression of HSF-1 or genetic ablation of its conserved negative regulator, heat shock factor binding protein 1 (HSB-1), results in robust life-span extension in Caenorhabditis elegans Here, we found that increased HSF-1 activity elevates histone H4 levels in somatic tissues during development, while knockdown of H4 completely suppresses HSF-1-mediated longevity. Moreover, overexpression of H4 is sufficient to extend life span. Ablation of HSB-1 induces an H4-dependent increase in micrococcal nuclease protection of both nuclear chromatin and mitochondrial DNA (mtDNA), which consequently results in reduced transcription of mtDNA-encoded complex IV genes, decreased respiratory capacity, and a mitochondrial unfolded protein response-dependent life-span extension. Collectively, our findings reveal a previously unknown role of HSB-1/HSF-1 signaling in modulation of mitochondrial function via mediating histone H4-dependent regulation of mtDNA gene expression and concomitantly acting as a determinant of organismal longevity.
    DOI:  https://doi.org/10.1126/sciadv.aaz4452
  33. Mol Cancer Ther. 2020 Oct 21. pii: molcanther.0182.2020. [Epub ahead of print]
    Inhibition of Lysosomal Function Mitigates Protective Mitophagy and Augments Ceramide Nanoliposome-Induced Cell Death in Head and Neck Squamous Cell Carcinoma.
    Jeremy Jp Shaw, Timothy L Boyer, Emily Venner, Patrick J Beck, Tristen Slamowitz, Tara Caste, Alexandra Hickman, Michael H Raymond, Pedro Costa-Pinheiro, Mark J Jameson, Todd E Fox, Mark Kester.
      Therapies for Head and Neck Squamous Cell Carcinoma (HNSCC) are, at best, moderately effective, underscoring the need for new therapeutic strategies. Ceramide treatment leads to cell death as a consequence of mitochondrial damage by generating oxidative stress and causing mitochondrial permeability. However, HNSCC cells are able to resist cell death through mitochondria repair via mitophagy. Through the use of the C6-ceramide nanoliposome (CNL) to deliver therapeutic levels of bioactive ceramide, we demonstrate that the effects of CNL are mitigated in drug-resistant HNSCC via an autophagic/mitophagic response. We also demonstrate that inhibitors of lysosomal function, including chloroquine (CQ), significantly augment CNL-induced death in HNSCC cell lines. Mechanistically, the combination of CQ and CNL results in dysfunctional lysosomal processing of damaged mitochondria. We further demonstrate that exogenous addition of Methyl Pyruvate rescues cells from CNL+CQ-dependent cell death by restoring mitochondrial functionality via the reduction of CNL- and CQ-induced generation of reactive oxygen species and mitochondria permeability. Taken together, inhibition of late-stage protective autophagy/mitophagy augments the efficacy of CNL through preventing mitochondrial repair. Moreover, the combination of inhibitors of lysosomal function with CNL may provide an efficacious treatment modality for HNSCC.
    DOI:  https://doi.org/10.1158/1535-7163.MCT-20-0182
  34. Mol Cell Proteomics. 2020 Oct 19. pii: mcp.RA120.002150. [Epub ahead of print]
    Systematic Proteome and Lysine Succinylome Analysis Reveals the Enhanced Cell Migration by Hyposuccinylation in Esophageal Squamous Cell Cancer.
    Zhenchang Guo, Feng Pan, Liu Peng, Shanshan Tian, Jiwei Jiao, Liandi Liao, Congcong Lu, Guijin Zhai, Zhiyong Wu, Hanyang Dong, Xiue Xu, Jianyi Wu, Pu Chen, Xue Bai, Dechen Lin, Li-Yan Xu, En-Min Li, Kai Zhang.
      Esophageal squamous cell cancer (ESCC) is an aggressive malignancy with poor therapeutic outcomes. However, the alterations in proteins and post-translational modifications (PTMs) leading to the pathogenesis of ESCC remains unclear. Here, we provide the comprehensive characterization of the proteome, phosphorylome, lysine acetylome and succinylome for ESCC and matched control cells using quantitative proteomic approach. We identify abnormal protein and post-translational modification (PTM) pathways, including significantly downregulated lysine succinylation sites in cancer cells. Focusing on hyposuccinylation, we reveal that this altered PTM was enriched on enzymes of metabolic pathways inextricably linked with cancer metabolism. Importantly, ESCC malignant behaviors such as cell migration are inhibited once the level of succinylation was restored in vitro or in vivo This effect was further verified by mutations to disrupt succinylation sites in candidate proteins. Meanwhile, we found that succinylation has a negative regulatory effect on histone methylation to promote cancer migration. Finally, hyposuccinylation is confirmed in primary ESCC specimens. Our findings together demonstrate that lysine succinylation may alter ESCC metabolism and migration, providing new insights into the functional significance of PTM in cancer biology.
    Keywords:  Acetylation*; Cancer Biology*; Cell Migration; Cell biology*; Esophageal Squamous Cell Cancer; Histones*; Lysine succinylation; Mass Spectrometry; Post-translational modifications*; Proteomics; SILAC; post-translational modifications
    DOI:  https://doi.org/10.1074/mcp.RA120.002150
  35. Cancer Res. 2020 Oct 22. pii: canres.0831.2020. [Epub ahead of print]
    Autofluorescence imaging of 3D tumor-macrophage microscale cultures resolves spatial and temporal dynamics of macrophage metabolism.
    Tiffany M Heaster, Mouhita Humayun, Jiaquan Yu, David J Beebe, Melissa C Skala.
      Macrophages within the tumor microenvironment (TME) exhibit a spectrum of pro-tumor and anti-tumor functions, yet it is unclear how the TME regulates this macrophage heterogeneity. Standard methods to measure macrophage heterogeneity require destructive processing, limiting spatiotemporal studies of function within the live, intact 3D TME. Here we demonstrate two-photon autofluorescence imaging of NAD(P)H and FAD to non-destructively resolve spatiotemporal metabolic heterogeneity of individual macrophages within 3D microscale TME models. Fluorescence lifetimes and intensities of NAD(P)H and FAD were acquired at 24, 48, and 72 hours post-stimulation for mouse macrophages (RAW 264.7) stimulated with IFN-γ or IL-4 plus IL-13 in 2D culture, confirming that autofluorescence measurements capture known metabolic phenotypes. To quantify metabolic dynamics of macrophages within the TME, mouse macrophages or human monocytes (RAW264.7 or THP-1) were cultured alone or with breast cancer cells (mouse PyVMT or primary human IDC) in 3D microfluidic platforms. Human monocytes and mouse macrophages in tumor co-cultures exhibited significantly different FAD mean lifetimes and greater migration than monocultures at 24, 48, and 72 hours post-seeding. In co-cultures with primary human cancer cells, actively-migrating monocyte-derived macrophages had greater redox ratios (NAD(P)H/FAD intensity) compared to passively-migrating monocytes at 24 and 48 hours post-seeding, reflecting metabolic heterogeneity in this sub-population of monocytes. Genetic analyses further confirmed this metabolic heterogeneity. These results establish label-free autofluorescence imaging to quantify dynamic metabolism, polarization, and migration of macrophages at single-cell resolution within 3D microscale models. This combined culture and imaging system provides unique insights into spatiotemporal tumor-immune crosstalk within the 3D TME.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-20-0831
  36. Int J Mol Sci. 2020 Oct 16. pii: E7674. [Epub ahead of print]21(20):
    Deferasirox-Dependent Iron Chelation Enhances Mitochondrial Dysfunction and Restores p53 Signaling by Stabilization of p53 Family Members in Leukemic Cells.
    Chiara Calabrese, Cristina Panuzzo, Serena Stanga, Giacomo Andreani, Silvia Ravera, Alessandro Maglione, Lucrezia Pironi, Jessica Petiti, Muhammad Shahzad Shahzad Ali, Patrizia Scaravaglio, Francesca Napoli, Carmen Fava, Marco De De Gobbi, Francesco Frassoni, Giuseppe Saglio, Enrico Bracco, Barbara Pergolizzi, Daniela Cilloni.
      Iron is crucial to satisfy several mitochondrial functions including energy metabolism and oxidative phosphorylation. Patients affected by Myelodysplastic Syndromes (MDS) and acute myeloid leukemia (AML) are frequently characterized by iron overload (IOL), due to continuous red blood cell (RBC) transfusions. This event impacts the overall survival (OS) and it is associated with increased mortality in lower-risk MDS patients. Accordingly, the oral iron chelator Deferasirox (DFX) has been reported to improve the OS and delay leukemic transformation. However, the molecular players and the biological mechanisms laying behind remain currently mostly undefined. The aim of this study has been to investigate the potential anti-leukemic effect of DFX, by functionally and molecularly analyzing its effects in three different leukemia cell lines, harboring or not p53 mutations, and in human primary cells derived from 15 MDS/AML patients. Our findings indicated that DFX can lead to apoptosis, impairment of cell growth only in a context of IOL, and can induce a significant alteration of mitochondria network, with a sharp reduction in mitochondrial activity. Moreover, through a remarkable reduction of Murine Double Minute 2 (MDM2), known to regulate the stability of p53 and p73 proteins, we observed an enhancement of p53 transcriptional activity after DFX. Interestingly, this iron depletion-triggered signaling is enabled by p73, in the absence of p53, or in the presence of a p53 mutant form. In conclusion, we propose a mechanism by which the increased p53 family transcriptional activity and protein stability could explain the potential benefits of iron chelation therapy in terms of improving OS and delaying leukemic transformation.
    Keywords:  Deferasirox; MDM2; chelation; iron; leukemia; mitochondria; p21; p53; p73
    DOI:  https://doi.org/10.3390/ijms21207674
  37. Mol Oncol. 2020 Oct 17.
    Deubiquitinase OTUD6A promotes proliferation of cancer cells via regulating Drp1 stability and mitochondrial fission.
    Le Shi, Jing Liu, Yunhua Peng, Jinfang Zhang, Xiangpeng Dai, Shuangxi Zhang, Yongyao Wang, Jiankang Liu, Jiangang Long.
      Dynamin-related protein 1 (Drp1) is a cytosolic protein responsible for mitochondrial fission and is essential in the initiation and development of several human diseases, including cancer. However, the regulation of Drp1, especially of its ubiquitination, remains unclear. In this study, we report that the ovarian tumor-associated protease deubiquitinase 6A (OTUD6A) deubiquitylates and stabilizes Drp1, thereby facilitating regulation of mitochondrial morphology and tumorigenesis. OTUD6A is upregulated in human patients with colorectal cancer. Depletion of OTUD6A leads to lower Drp1 levels and suppressed mitochondrial fission and the affected cells are consequently less prone to tumorigenesis. Conversely, overexpression of OTUD6A increases Drp1 levels and its protein half-life and enhances cancer cell growth. Therefore, our results reveal a novel upstream protein of Drp1, and its role in tumorigenesis that is played, in part, through the activation of mitochondrial fission mediated by Drp1.
    Keywords:  Drp1; OTUD6A; cancer cell growth; deubiquitination; mitochondrial fission
    DOI:  https://doi.org/10.1002/1878-0261.12825
  38. Mol Ther. 2020 Oct 19. pii: S1525-0016(20)30550-5. [Epub ahead of print]
    Combinatorial Approaches to Enhance DNA Damage Following Enzyme-mediated Depletion of L-Cyst(e)ine for Treatment of Pancreatic Cancer.
    Achinto Saha, Shengyuan Zhao, Zhao Chen, George Georgiou, Everett Stone, Dawit Kidane, John DiGiovanni.
      Pancreatic ductal adenocarcinoma (PDAC) represents one of the deadliest forms of cancer with very few available therapeutic options. We previously reported that an engineered human enzyme, Cyst(e)inase, that degrades L-cysteine and cystine, inhibits growth of multiple cancer cells including PDAC both in vitro and in vivo. Here, we show that Cyst(e)inase treatment leads to increased clustered oxidative DNA damage, DNA single strand breaks, apurinic/apyrimidinic sites and DNA double strand breaks (DSBs) in PDAC cells sensitive to intracellular depletion of L-Cys that is associated with reduced survival. BRCA2 deficient PDAC cells exhibited increased DSBs and enhanced sensitivity to Cyst(e)inase. Blocking a second antioxidant pathway (thioredoxin/thioredoxin reductase) using Auranofin or inhibiting DNA repair using the PARP inhibitor, Olaparib, led to significant increases in DSBs following Cyst(e)inase treatment in all PDAC cells examined. Cyst(e)inase plus Olaparib also synergistically inhibited growth of sensitive and resistant PDAC cells in both xenograft and allograft tumor models. Collectively, these results demonstrate an important role for oxidative DNA damage and ultimately DNA DSBs in the anticancer action of Cyst(e)inase. The data further show the potential for combining agents that target alternate antioxidant pathways or by targeting DNA repair pathways or genetic liabilities in DNA repair pathways to enhance the therapeutic action of Cyst(e)inase for PDAC. Cyst(e)inase is an engineered human enzyme shown to inhibit growth of multiple cancer cells. In this study, Saha et al. found that combining agents that target alternate antioxidant pathways or by targeting DNA repair pathways or genetic liabilities in DNA repair pathways improves therapeutic action of Cyst(e)inase in pancreatic cancer.
    DOI:  https://doi.org/10.1016/j.ymthe.2020.10.016
  39. Chembiochem. 2020 Oct 20.
    Hydrogen Sulfide Oxidation by Sulfide Quinone Oxidoreductase.
    Aaron P Landry, David P Ballou, Ruma Banerjee.
      Hydrogen sulfide (H 2 S) is an environmental toxin and a heritage of ancient microbial metabolism, which has stimulated new interest following its discovery as a neuromodulator. While many physiological responses have been attributed to low H 2 S levels, higher levels inhibit complex IV in the electron transport chain. To prevent respiratory poisoning, a dedicated set of enzymes comprising the mitochondrial sulfide oxidation pathway exists to clear H 2 S. The committed step in this pathway is catalyzed by sulfide quinone oxidoreductase (SQOR), which couples sulfide oxidation to coenzyme Q 10 reduction in the electron transport chain. The SQOR reaction prevents H 2 S accumulation and generates highly reactive persulfide species as products, which can be further oxidized or can modify cysteine residues in proteins via persulfidation. Here, we review the kinetic and structural characteristics of human SQOR, and how its unconventional redox cofactor configuration and substrate promiscuity lead to sulfide clearance and potentially expand the signaling potential of H 2 S. This dual role of SQOR makes it a promising target for H 2 S-based therapeutics.
    Keywords:  protein structure, sulfide, flavin, redox chemistry, metabolism
    DOI:  https://doi.org/10.1002/cbic.202000661
  40. Cell Mol Life Sci. 2020 Oct 19.
    The connection between the dynamic remodeling of the mitochondrial network and the regulation of muscle mass.
    Vanina Romanello, Marco Sandri.
      The dynamic coordination of processes controlling the quality of the mitochondrial network is crucial to maintain the function of mitochondria in skeletal muscle. Changes of mitochondrial proteolytic system, dynamics (fusion/fission), and mitophagy induce pathways that affect muscle mass and performance. When muscle mass is lost, the risk of disease onset and premature death is dramatically increased. For instance, poor quality of muscles correlates with the onset progression of several age-related disorders such as diabetes, obesity, cancer, and aging sarcopenia. To date, there are no drug therapies to reverse muscle loss, and exercise remains the best approach to improve mitochondrial health and to slow atrophy in several diseases. This review will describe the principal mechanisms that control mitochondrial quality and the pathways that link mitochondrial dysfunction to muscle mass regulation.
    Keywords:  Atrophy; Autophagy; FGF21; Fission; Fusion; Mitochondria; Mitochondrial proteostasis; Mitophagy; Myokines; Skeletal muscle
    DOI:  https://doi.org/10.1007/s00018-020-03662-0
  41. Cancers (Basel). 2020 Oct 17. pii: E3023. [Epub ahead of print]12(10):
    Dissecting the Crosstalk between NRF2 Signaling and Metabolic Processes in Cancer.
    Janine M DeBlasi, Gina M DeNicola.
      The transcription factor NRF2 (nuclear factor-erythroid 2 p45-related factor 2 or NFE2L2) plays a critical role in response to cellular stress. Following an oxidative insult, NRF2 orchestrates an antioxidant program, leading to increased glutathione levels and decreased reactive oxygen species (ROS). Mounting evidence now implicates the ability of NRF2 to modulate metabolic processes, particularly those at the interface between antioxidant processes and cellular proliferation. Notably, NRF2 regulates the pentose phosphate pathway, NADPH production, glutaminolysis, lipid and amino acid metabolism, many of which are hijacked by cancer cells to promote proliferation and survival. Moreover, deregulation of metabolic processes in both normal and cancer-based physiology can stabilize NRF2. We will discuss how perturbation of metabolic pathways, including the tricarboxylic acid (TCA) cycle, glycolysis, and autophagy can lead to NRF2 stabilization, and how NRF2-regulated metabolism helps cells deal with these metabolic stresses. Finally, we will discuss how the negative regulator of NRF2, Kelch-like ECH-associated protein 1 (KEAP1), may play a role in metabolism through NRF2 transcription-independent mechanisms. Collectively, this review will address the interplay between the NRF2/KEAP1 complex and metabolic processes.
    Keywords:  KEAP1; NADPH; NRF2; amino acids; cancer metabolism; lipids; oxidative stress
    DOI:  https://doi.org/10.3390/cancers12103023
  42. Am J Physiol Gastrointest Liver Physiol. 2020 Oct 21.
    Production of hydrogen sulfide by the intestinal microbiota and epithelial cells and consequences for the colonic and rectal mucosa.
    Francois Blachier, Mireille Andriamihaja, Pierre Larraufie, Eunyeong Ahn, Annaig Lan, Eunjung Kim.
      Among bacterial metabolites, hydrogen sulfide (H2S) has received increasing attention. The epithelial cells of the large intestine are exposed to two sources of H2S. The main one is the luminal source that results from specific bacteria metabolic activity towards sulfur-containing substrates. The other source in colonocytes is from the intracellular production mainly through cystathionine beta-synthase (CBS) activity. H2S is oxidized by the mitochondrial sulfide oxidation unit, resulting in ATP synthesis, and thus establishing this compound as the first mineral energy substrate in colonocytes. However, when the intracellular H2S concentration exceeds the colonocyte capacity for its oxidation, it inhibits the mitochondrial respiratory chain, thus affecting energy metabolism. Higher luminal H2S concentration affects the integrity of the mucus layer and displays pro-inflammatory effects. However, a low/minimal amount of endogenous H2S exerts an anti-inflammatory effect on the colon mucosa pointing out the ambivalent effect of H2S depending on its intracellular concentration. Regarding colorectal carcinogenesis, forced CBS expression in late adenoma-like colonocytes increased their proliferative activity, bioenergetics capacity, and tumorigenicity; while genetic ablation of CBS in mice resulted in a reduced number of mutagen-induced aberrant crypt foci. Activation of endogenous H2S production and low H2S extracellular concentration enhance cancerous colorectal cells proliferation. Higher exogenous H2S concentrations markedly reduce mitochondrial ATP synthesis and proliferative capacity in cancerous cells, enhance glycolysis, but do not affect their ATP cell content nor viability. Thus, it appears that, notably through an effect on colonocyte energy metabolism, endogenous and microbiota-derived H2S are involved in the host intestinal physiology and physiopathology.
    Keywords:  colorectal carcinogenesis; energy metabolism; hydrogen sulfide; inflammatory bowel diseases
    DOI:  https://doi.org/10.1152/ajpgi.00261.2020
  43. J Clin Invest. 2020 Oct 20. pii: 139929. [Epub ahead of print]
    Guanosine triphosphate links MYC-dependent metabolic and ribosome programs in small cell lung cancer.
    Fang Huang, Kenneth Huffman, Zixi Wang, Xun Wang, Kailong Li, Feng Cai, Chendong Yang, Ling Cai, Terry S Shih, Lauren G Zacharias, Andrew S Chung, Qian Yang, Milind D Chalishazar, Abbie S Ireland, C Allison Stewart, Kasey R Cargill, Luc Girard, Yi Liu, Min Ni, Jian Xu, Xudong Wu, Hao Zhu, Benjamin J Drapkin, Lauren A Byers, Trudy G Oliver, Adi Gazdar, John Minna, Ralph DeBerardinis.
      MYC stimulates both metabolism and protein synthesis, but it is unknown how cells coordinate these complementary programs. Previous work reported that in a subset of small cell lung cancer (SCLC) cell lines, MYC activates guanosine triphosphate (GTP) synthesis and results in sensitivity to inhibitors of the GTP synthesis enzyme inosine monophosphate dehydrogenase (IMPDH). Here we demonstrated that primary MYCHigh human SCLC tumors also contain abundant guanosine nucleotides. We also found that elevated MYC in SCLCs with acquired chemoresistance rendered these otherwise recalcitrant tumors dependent on IMPDH. Unexpectedly, our data indicated that IMPDH links the metabolic and protein synthesis outputs of oncogenic MYC. Co-expression analysis placed IMPDH within the MYC-driven ribosome program, and GTP depletion prevented RNA Polymerase I (Pol I) from localizing to ribosomal DNA. Furthermore, the GTPases GPN1 and GPN3 were upregulated by MYC and directed Pol I to ribosomal DNA. Constitutively GTP-bound GPN1/3 mutants mitigated the effect of GTP depletion on Pol I, protecting chemoresistant SCLC cells from IMPDH inhibition. GTP therefore functions as a metabolic gate tethering MYC-dependent ribosome biogenesis to nucleotide sufficiency through GPN1 and GPN3. IMPDH dependence is a targetable vulnerability in chemoresistant, MYCHigh SCLC.
    Keywords:  Intermediary metabolism; Lung cancer; Metabolism; Oncogenes; Oncology
    DOI:  https://doi.org/10.1172/JCI139929
  44. Proc Natl Acad Sci U S A. 2020 Oct 23. pii: 202009899. [Epub ahead of print]
    Targeted CRISPR screening identifies PRMT5 as synthetic lethality combinatorial target with gemcitabine in pancreatic cancer cells.
    Xiaolong Wei, Jiekun Yang, Sara J Adair, Harun Ozturk, Cem Kuscu, Kyung Yong Lee, William J Kane, Patrick E O'Hara, Denis Liu, Yusuf Mert Demirlenk, Alaa Hamdi Habieb, Ebru Yilmaz, Anindya Dutta, Todd W Bauer, Mazhar Adli.
      Pancreatic ductal adenocarcinoma (PDAC) remains one of the most challenging cancers to treat. Due to the asymptomatic nature of the disease and lack of curative treatment modalities, the 5-y survival rate of PDAC patients is one of the lowest of any cancer type. The recurrent genetic alterations in PDAC are yet to be targeted. Therefore, identification of effective drug combinations is desperately needed. Here, we performed an in vivo CRISPR screen in an orthotopic patient-derived xenograft (PDX) model to identify gene targets whose inhibition creates synergistic tumor growth inhibition with gemcitabine (Gem), a first- or second-line chemotherapeutic agent for PDAC treatment. The approach revealed protein arginine methyltransferase gene 5 (PRMT5) as an effective druggable candidate whose inhibition creates synergistic vulnerability of PDAC cells to Gem. Genetic depletion and pharmacological inhibition indicate that loss of PRMT5 activity synergistically enhances Gem cytotoxicity due to the accumulation of excessive DNA damage. At the molecular level, we show that inhibition of PRMT5 results in RPA depletion and impaired homology-directed DNA repair (HDR) activity. The combination (Gem + PRMT5 inhibition) creates conditional lethality and synergistic reduction of PDAC tumors in vivo. The findings demonstrate that unbiased genetic screenings combined with a clinically relevant model system is a practical approach in identifying synthetic lethal drug combinations for cancer treatment.
    Keywords:  CRISPR screening; cancer genomics and epigenomics; combinatorial drugs targets; pancreatic cancer; synthetic lethality
    DOI:  https://doi.org/10.1073/pnas.2009899117
  45. Nat Med. 2020 Oct 19.
    Midkine rewires the melanoma microenvironment toward a tolerogenic and immune-resistant state.
    Daniela Cerezo-Wallis, Marta Contreras-Alcalde, Kevin Troulé, Xavier Catena, Cynthia Mucientes, Tonantzin G Calvo, Estela Cañón, Cristina Tejedo, Paula C Pennacchi, Sabrina Hogan, Peter Kölblinger, Héctor Tejero, Andrew X Chen, Nuria Ibarz, Osvaldo Graña-Castro, Lola Martinez, Javier Muñoz, Pablo Ortiz-Romero, José L Rodriguez-Peralto, Gonzalo Gómez-López, Fátima Al-Shahrour, Raúl Rabadán, Mitchell P Levesque, David Olmeda, María S Soengas.
      An open question in aggressive cancers such as melanoma is how malignant cells can shift the immune system to pro-tumorigenic functions. Here we identify midkine (MDK) as a melanoma-secreted driver of an inflamed, but immune evasive, microenvironment that defines poor patient prognosis and resistance to immune checkpoint blockade. Mechanistically, MDK was found to control the transcriptome of melanoma cells, allowing for coordinated activation of nuclear factor-κB and downregulation of interferon-associated pathways. The resulting MDK-modulated secretome educated macrophages towards tolerant phenotypes that promoted CD8+ T cell dysfunction. In contrast, genetic targeting of MDK sensitized melanoma cells to anti-PD-1/anti-PD-L1 treatment. Emphasizing the translational relevance of these findings, the expression profile of MDK-depleted tumors was enriched in key indicators of a good response to immune checkpoint blockers in independent patient cohorts. Together, these data reveal that MDK acts as an internal modulator of autocrine and paracrine signals that maintain immune suppression in aggressive melanomas.
    DOI:  https://doi.org/10.1038/s41591-020-1073-3
  46. Mitochondrion. 2020 Oct 15. pii: S1567-7249(20)30200-2. [Epub ahead of print]
    Complex IV- the regulatory center of mitochondrial oxidative phosphorylation.
    Bernhard Kadenbach.
      ATP, the universal energy currency in all living cells, is mainly synthesized in mitochondria by oxidative phosphorylation (OXPHOS). The final and rate limiting step of the respiratory chain is cytochrome c oxidase (COX) which represents the regulatory center of OXPHOS. COX is regulated through binding of various effectors to its ,supernumerary" subunits, by reversible phosphorylation, and by expression of subunit isoforms. Of particular interest is its feedback inhibition by ATP, the final product of OXPHOS. This ,allosteric ATP-inhibition" of phosphorylated and dimeric COX maintains a low and healthy mitochondrial membrane potential (relaxed state), and prevents the formation of ROS (reactive oxygen species) which are known to cause numerous diseases. Excessive work and stress abolish this feedback inhibition of COX by Ca2+-activated dephosphorylation which leads to monomerization and movement of NDUFA4 from complex I to COX with higher rates of COX activity and ATP synthesis (active state) but increased ROS formation and decreased efficiency.
    Keywords:  ROS; allosteric ATP-inhibition; cytochrome c oxidase; efficiency; membrane potential; oxidative phosphorylation; respiratory control
    DOI:  https://doi.org/10.1016/j.mito.2020.10.004
  47. Nat Commun. 2020 10 21. 11(1): 5332
    Vestigial-like 1 is a shared targetable cancer-placenta antigen expressed by pancreatic and basal-like breast cancers.
    Sherille D Bradley, Amjad H Talukder, Ivy Lai, Rebecca Davis, Hector Alvarez, Herve Tiriac, Minying Zhang, Yulun Chiu, Brenda Melendez, Kyle R Jackson, Arjun Katailiha, Heather M Sonnemann, Fenge Li, Yaan Kang, Na Qiao, Bih-Fang Pan, Philip L Lorenzi, Mark Hurd, Elizabeth A Mittendorf, Christine B Peterson, Milind Javle, Christopher Bristow, Michael Kim, David A Tuveson, David Hawke, Scott Kopetz, Robert A Wolff, Patrick Hwu, Anirban Maitra, Jason Roszik, Cassian Yee, Gregory Lizée.
      Cytotoxic T lymphocyte (CTL)-based cancer immunotherapies have shown great promise for inducing clinical regressions by targeting tumor-associated antigens (TAA). To expand the TAA landscape of pancreatic ductal adenocarcinoma (PDAC), we performed tandem mass spectrometry analysis of HLA class I-bound peptides from 35 PDAC patient tumors. This identified a shared HLA-A*0101 restricted peptide derived from co-transcriptional activator Vestigial-like 1 (VGLL1) as a putative TAA demonstrating overexpression in multiple tumor types and low or absent expression in essential normal tissues. Here we show that VGLL1-specific CTLs expanded from the blood of a PDAC patient could recognize and kill in an antigen-specific manner a majority of HLA-A*0101 allogeneic tumor cell lines derived not only from PDAC, but also bladder, ovarian, gastric, lung, and basal-like breast cancers. Gene expression profiling reveals VGLL1 as a member of a unique group of cancer-placenta antigens (CPA) that may constitute immunotherapeutic targets for patients with multiple cancer types.
    DOI:  https://doi.org/10.1038/s41467-020-19141-w
  48. Mol Cancer Ther. 2020 Oct 21. pii: molcanther.0271.2020. [Epub ahead of print]
    Glutaminase inhibitors induce thiol-mediated oxidative stress and radio-sensitization in treatment resistant cervical cancers.
    Ramachandran Rashmi, Kay Jayachandran, Jin Zhang, Vishnu Menon, Naoshad Muhammad, Michael Zahner, Fiona Ruiz, Sisi Zhang, Kevin Cho, Yuting Wang, Xiaojing Huang, Yi Huang, Michael L McCormick, Buck E Rogers, Douglas R Spitz, Gary J Patti, Julie K Schwarz.
      The purpose of the study was to determine if radiation resistant cervical cancers are dependent upon glutamine metabolism driven by activation of the PI3K pathway and test whether PI3K pathway mutation predicts radio-sensitization by inhibition of glutamine metabolism. Cervical cancer cell lines with and without PI3K pathway mutations, including SiHa and SiHa PTEN-/- cells engineered by CRISPR/Cas9, were used for mechanistic studies performed in vitro in the presence and absence of glutamine starvation and the glutaminase inhibitor, telaglenastat (CB-839). These studies included cell survival, proliferation, quantification of oxidative stress parameters, metabolic tracing with stable isotope labeled substrates, metabolic rescue and combination studies with L-buthionine sulfoximine (BSO), auranofin (AUR), and radiation (RT). In vivo studies of telaglenastat ± RT were performed using CaSki and SiHa xenografts grown in immune compromised mice. PI3K activated cervical cancer cells were selectively sensitive to glutamine deprivation through a mechanism that included thiol-mediated oxidative stress. Telaglenastat treatment decreased total glutathione pools, increased the percent glutathione disulfide, and caused clonogenic cell killing that was reversed by treatment with the thiol antioxidant, N-acetylcysteine. Telaglenastat also sensitized cells to killing by glutathione depletion with BSO, thioredoxin reductase inhibition with AUR, and RT. Glutamine dependent PI3K activated cervical cancer xenografts were sensitive to telaglenastat monotherapy, and telaglenastat selectively radio-sensitized cervical cancer cells in vitro and in vivo. These novel preclinical data support the utility of telaglenastat for glutamine dependent radio-resistant cervical cancers and demonstrate that PI3K pathway mutations may be used as a predictive biomarker for telaglenastat sensitivity.
    DOI:  https://doi.org/10.1158/1535-7163.MCT-20-0271
  49. Commun Biol. 2020 Oct 21. 3(1): 596
    Phosphodiesterase 2A2 regulates mitochondria clearance through Parkin-dependent mitophagy.
    Miguel J Lobo, Laia Reverte-Salisa, Ying-Chi Chao, Andreas Koschinski, Frank Gesellchen, Gunasekaran Subramaniam, He Jiang, Samuel Pace, Natasha Larcom, Ester Paolocci, Alexander Pfeifer, Sara Zanivan, Manuela Zaccolo.
      Programmed degradation of mitochondria by mitophagy, an essential process to maintain mitochondrial homeostasis, is not completely understood. Here we uncover a regulatory process that controls mitophagy and involves the cAMP-degrading enzyme phosphodiesterase 2A2 (PDE2A2). We find that PDE2A2 is part of a mitochondrial signalosome at the mitochondrial inner membrane where it interacts with the mitochondrial contact site and organizing system (MICOS). As part of this compartmentalised signalling system PDE2A2 regulates PKA-mediated phosphorylation of the MICOS component MIC60, resulting in modulation of Parkin recruitment to the mitochondria and mitophagy. Inhibition of PDE2A2 is sufficient to regulate mitophagy in the absence of other triggers, highlighting the physiological relevance of PDE2A2 in this process. Pharmacological inhibition of PDE2 promotes a 'fat-burning' phenotype to retain thermogenic beige adipocytes, indicating that PDE2A2 may serve as a novel target with potential for developing therapies for metabolic disorders.
    DOI:  https://doi.org/10.1038/s42003-020-01311-7
  50. Nat Commun. 2020 10 22. 11(1): 5342
    Type III ATP synthase is a symmetry-deviated dimer that induces membrane curvature through tetramerization.
    Rasmus Kock Flygaard, Alexander Mühleip, Victor Tobiasson, Alexey Amunts.
      Mitochondrial ATP synthases form functional homodimers to induce cristae curvature that is a universal property of mitochondria. To expand on the understanding of this fundamental phenomenon, we characterized the unique type III mitochondrial ATP synthase in its dimeric and tetrameric form. The cryo-EM structure of a ciliate ATP synthase dimer reveals an unusual U-shaped assembly of 81 proteins, including a substoichiometrically bound ATPTT2, 40 lipids, and co-factors NAD and CoQ. A single copy of subunit ATPTT2 functions as a membrane anchor for the dimeric inhibitor IF1. Type III specific linker proteins stably tie the ATP synthase monomers in parallel to each other. The intricate dimer architecture is scaffolded by an extended subunit-a that provides a template for both intra- and inter-dimer interactions. The latter results in the formation of tetramer assemblies, the membrane part of which we determined to 3.1 Å resolution. The structure of the type III ATP synthase tetramer and its associated lipids suggests that it is the intact unit propagating the membrane curvature.
    DOI:  https://doi.org/10.1038/s41467-020-18993-6
  51. EMBO Mol Med. 2020 Oct 19. e13001
    Altered bioenergetics and mitochondrial dysfunction of monocytes in patients with COVID-19 pneumonia.
    Lara Gibellini, Sara De Biasi, Annamaria Paolini, Rebecca Borella, Federica Boraldi, Marco Mattioli, Domenico Lo Tartaro, Lucia Fidanza, Alfredo Caro-Maldonado, Marianna Meschiari, Vittorio Iadisernia, Erica Bacca, Giovanni Riva, Luca Cicchetti, Daniela Quaglino, Giovanni Guaraldi, Stefano Busani, Massimo Girardis, Cristina Mussini, Andrea Cossarizza.
      In patients infected by SARS-CoV-2 who experience an exaggerated inflammation leading to pneumonia, monocytes likely play a major role but have received poor attention. Thus, we analyzed peripheral blood monocytes from patients with COVID-19 pneumonia and found that these cells show signs of altered bioenergetics and mitochondrial dysfunction, had a reduced basal and maximal respiration, reduced spare respiratory capacity and decreased proton leak. Basal extracellular acidification rate was also diminished, suggesting reduced capability to perform aerobic glycolysis. Although COVID-19 monocytes had a reduced ability to perform oxidative burst, they were still capable of producing TNF and IFN-g,in vitro. A significantly high amount of monocytes had depolarized mitochondria and abnormal mitochondrial ultrastructure. A redistribution of monocyte subsets, with a significant expansion of intermediate/pro-inflammatory cells, and high amounts of immature monocytes were found, along with a concomitant compression of classical monocytes, and an increased expression of inhibitory checkpoints like PD-1/PD-L1. High plasma levels of several inflammatory cytokines and chemokines, including GM-CSF, IL-18, CCL2, CXCL10 and osteopontin, finally confirm the importance of monocytes in COVID-19 immunopathogenesis.
    Keywords:  COVID-19; OXPHOS; inhibitory checkpoints; mitochondria; monocytes
    DOI:  https://doi.org/10.15252/emmm.202013001
  52. Cell Mol Life Sci. 2020 Oct 21.
    Mitochondrial microRNA (MitomiRs) in cancer and complex mitochondrial diseases: current status and future perspectives.
    Paresh Kumar Purohit, Neeru Saini.
      Mitochondria are not only important for cellular bioenergetics but also lie at the heart of critical metabolic pathways. They can rapidly adjust themselves in response to changing conditions and the metabolic needs of the cell. Mitochondrial involvement as well as its dysfunction has been found to be associated with variety of pathological processes and diseases. mitomiRs are class of miRNA(s) that regulate mitochondrial gene expression and function. This review sheds light on the role of mitomiRs in regulating different biological processes-mitochondrial dynamics, oxidative stress, cell metabolism, chemoresistance, apoptosis,and their relevance in metabolic diseases, neurodegenerative disorders, and cancer. Insilico analysis of predicted targets of mitomiRs targeting energy metabolism identified several significantly altered pathways (needs in vivo validations) that may provide a new therapeutic approach for the treatment of human diseases. Last part of the review discusses about the clinical aspects of miRNA(s) and mitomiRs in Medicine.
    Keywords:  Cancer; Cardiovascular disease; Clinical medicine; Diabetes; Metabolic disorders; Neurodegenerative disorders; microRNA; mitomiR
    DOI:  https://doi.org/10.1007/s00018-020-03670-0
  53. Cell Rep. 2020 Oct 20. pii: S2211-1247(20)31267-5. [Epub ahead of print]33(3): 108278
    PPARα Inhibition Overcomes Tumor-Derived Exosomal Lipid-Induced Dendritic Cell Dysfunction.
    Xiaozhe Yin, Wenfeng Zeng, Bowen Wu, Luoyang Wang, Zihao Wang, Hongjian Tian, Luyao Wang, Yunhan Jiang, Ryan Clay, Xiuli Wei, Yan Qin, Fayun Zhang, Chunling Zhang, Lingtao Jin, Wei Liang.
      Dendritic cells (DCs) orchestrate the initiation, programming, and regulation of anti-tumor immune responses. Emerging evidence indicates that the tumor microenvironment (TME) induces immune dysfunctional tumor-infiltrating DCs (TIDCs), characterized with both increased intracellular lipid content and mitochondrial respiration. The underlying mechanism, however, remains largely unclear. Here, we report that fatty acid-carrying tumor-derived exosomes (TDEs) induce immune dysfunctional DCs to promote immune evasion. Mechanistically, peroxisome proliferator activated receptor (PPAR) α responds to the fatty acids delivered by TDEs, resulting in excess lipid droplet biogenesis and enhanced fatty acid oxidation (FAO), culminating in a metabolic shift toward mitochondrial oxidative phosphorylation, which drives DC immune dysfunction. Genetic depletion or pharmacologic inhibition of PPARα effectively attenuates TDE-induced DC-based immune dysfunction and enhances the efficacy of immunotherapy. This work uncovers a role for TDE-mediated immune modulation in DCs and reveals that PPARα lies at the center of metabolic-immune regulation of DCs, suggesting a potential immunotherapeutic target.
    Keywords:  DC; PPARα; dendritic cell; immune dysfunction; lipid metabolism; tumor-derived exosome
    DOI:  https://doi.org/10.1016/j.celrep.2020.108278
  54. iScience. 2020 Oct 23. 23(10): 101601
    MitoSegNet: Easy-to-use Deep Learning Segmentation for Analyzing Mitochondrial Morphology.
    Christian A Fischer, Laura Besora-Casals, Stéphane G Rolland, Simon Haeussler, Kritarth Singh, Michael Duchen, Barbara Conradt, Carsten Marr.
      While the analysis of mitochondrial morphology has emerged as a key tool in the study of mitochondrial function, efficient quantification of mitochondrial microscopy images presents a challenging task and bottleneck for statistically robust conclusions. Here, we present Mitochondrial Segmentation Network (MitoSegNet), a pretrained deep learning segmentation model that enables researchers to easily exploit the power of deep learning for the quantification of mitochondrial morphology. We tested the performance of MitoSegNet against three feature-based segmentation algorithms and the machine-learning segmentation tool Ilastik. MitoSegNet outperformed all other methods in both pixelwise and morphological segmentation accuracy. We successfully applied MitoSegNet to unseen fluorescence microscopy images of mitoGFP expressing mitochondria in wild-type and catp-6 ATP13A2 mutant C. elegans adults. Additionally, MitoSegNet was capable of accurately segmenting mitochondria in HeLa cells treated with fragmentation inducing reagents. We provide MitoSegNet in a toolbox for Windows and Linux operating systems that combines segmentation with morphological analysis.
    Keywords:  Artificial Intelligence; Automation in Bioinformatics; Bioinformatics; Cell Biology
    DOI:  https://doi.org/10.1016/j.isci.2020.101601
  55. Autophagy. 2020 Oct 19.
    Mammalian Atg8-family proteins are upstream regulators of the lysosomalsystem by controlling MTOR and TFEB.
    Suresh Kumar, Ashish Jain, Seong Won Choi, Gustavo Peixoto Duarte da Silva, Lee Allers, Michal H Mudd, Ryan Scott Peters, Jan Haug Anonsen, Tor-Erik Rusten, Michael Lazarou, Vojo Deretic.
      Macroautophagy/autophagy delivers cytoplasmic cargo to lysosomes for degradation. In yeast, the single Atg8 protein plays a role in the formation of autophagosomes whereas in mammalian cells there are five to seven paralogs, referred to as mammalian Atg8s (mAtg8s: GABARAP, GABARAPL1, GABARAPL2, LC3A, LC3B, LC3B2 and LC3C) with incompletely defined functions. Here we show that a subset of mAtg8s directly control lysosomal biogenesis. This occurs at the level of TFEB, the principal regulator of the lysosomal transcriptional program. mAtg8s promote TFEB's nuclear translocation in response to stimuli such as starvation. GABARAP interacts directly with TFEB, whereas RNA-Seq analyses reveal that knockout of six genes encoding mAtg8s, or a triple knockout of the genes encoding all GABARAPs, diminishes the TFEB transcriptional program. We furthermore show that GABARAPs in cooperation with other proteins, IRGM, a factor implicated in tuberculosis and Crohn disease, and STX17, are required during starvation for optimal inhibition of MTOR, an upstream kinase of TFEB, and activation of the PPP3/calcineurin phosphatase that dephosphorylates TFEB, thus promoting its nuclear translocation. In conclusion, mAtg8s, IRGM and STX17 control lysosomal biogenesis by their combined or individual effects on MTOR, TFEB, and PPP3/calcineurin, independently of their roles in the formation of autophagosomal membranes.
    Keywords:  Crohn’s disease; GABARAP; HIV; LC3; MTOR; Mycobacterium tuberculosis; TFEB; autophagy; lysosome; metabolism
    DOI:  https://doi.org/10.1080/15548627.2020.1837423
  56. Oncotarget. 2020 Oct 06. 11(40): 3621-3632
    Deconstructing tumor heterogeneity: the stromal perspective.
    Renee E Vickman, Douglas V Faget, Philip Beachy, David Beebe, Neil A Bhowmick, Edna Cukierman, Wu-Min Deng, James G Granneman, Jeffrey Hildesheim, Raghu Kalluri, Ken S Lau, Ernst Lengyel, Joakim Lundeberg, Jorge Moscat, Peter S Nelson, Kristian Pietras, Katerina Politi, Ellen Puré, Ruth Scherz-Shouval, Mara H Sherman, David Tuveson, Ashani T Weeraratna, Richard M White, Melissa H Wong, Elisa C Woodhouse, Ying Zheng, Simon W Hayward, Sheila A Stewart.
      Significant advances have been made towards understanding the role of immune cell-tumor interplay in either suppressing or promoting tumor growth, progression, and recurrence, however, the roles of additional stromal elements, cell types and/or cell states remain ill-defined. The overarching goal of this NCI-sponsored workshop was to highlight and integrate the critical functions of non-immune stromal components in regulating tumor heterogeneity and its impact on tumor initiation, progression, and resistance to therapy. The workshop explored the opposing roles of tumor supportive versus suppressive stroma and how cellular composition and function may be altered during disease progression. It also highlighted microenvironment-centered mechanisms dictating indolence or aggressiveness of early lesions and how spatial geography impacts stromal attributes and function. The prognostic and therapeutic implications as well as potential vulnerabilities within the heterogeneous tumor microenvironment were also discussed. These broad topics were included in this workshop as an effort to identify current challenges and knowledge gaps in the field.
    Keywords:  cellular plasticity; extracellular matrix; stromal heterogeneity; therapy resistance; tumor microenvironment
    DOI:  https://doi.org/10.18632/oncotarget.27736
  57. iScience. 2020 Oct 23. 23(10): 101548
    The Loss of Nuclear PTEN Increases Tumorigenesis in a Preclinical Mouse Model for Hepatocellular Carcinoma.
    Takashi Kato, Tatsuya Yamada, Hideki Nakamura, Atsushi Igarashi, Robert A Anders, Hiromi Sesaki, Miho Iijima.
      The PTEN gene is highly mutated in many cancers, including hepatocellular carcinoma. The PTEN protein is located at different subcellular regions-PTEN at the plasma membrane suppresses PI3-kinase signaling in cell growth, whereas PTEN in the nucleus maintains genome integrity. Here, using nuclear PTEN-deficient mice, we analyzed the role of PTEN in the nucleus in hepatocellular carcinoma that is induced by carcinogen and oxidative stress-producing hepatotoxin. Upon oxidative stress, PTEN was accumulated in the nucleus of the liver, and this accumulation promoted repair of DNA damage in wild-type mice. In contrast, nuclear PTEN-deficient mice had increased DNA damage and accelerated hepatocellular carcinoma formation. Both basal and oxidative stress-induced localization of PTEN in the nucleus require ubiquitination of lysine 13 in PTEN. Taken together, these data suggest the critical role of nuclear PTEN in the protection from DNA damage and tumorigenesis in vivo.
    Keywords:  Cancer; Cell Biology
    DOI:  https://doi.org/10.1016/j.isci.2020.101548
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