bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2020‒03‒08
thirty-nine papers selected by
Christian Frezza
University of Cambridge, MRC Cancer Unit


  1. Cell Metab. 2020 Mar 03. pii: S1550-4131(20)30059-0. [Epub ahead of print]31(3): 564-579.e7
    Shats I, Williams JG, Liu J, Makarov MV, Wu X, Lih FB, Deterding LJ, Lim C, Xu X, Randall TA, Lee E, Li W, Fan W, Li JL, Sokolsky M, Kabanov AV, Li L, Migaud ME, Locasale JW, Li X.
      Nicotinamide adenine dinucleotide (NAD), a cofactor for hundreds of metabolic reactions in all cell types, plays an essential role in metabolism, DNA repair, and aging. However, how NAD metabolism is impacted by the environment remains unclear. Here, we report an unexpected trans-kingdom cooperation between bacteria and mammalian cells wherein bacteria contribute to host NAD biosynthesis. Bacteria confer resistance to inhibitors of NAMPT, the rate-limiting enzyme in the amidated NAD salvage pathway, in cancer cells and xenograft tumors. Mechanistically, a microbial nicotinamidase (PncA) that converts nicotinamide to nicotinic acid, a precursor in the alternative deamidated NAD salvage pathway, is necessary and sufficient for this protective effect. Using stable isotope tracing and microbiota-depleted mice, we demonstrate that this bacteria-mediated deamidation contributes substantially to the NAD-boosting effect of oral nicotinamide and nicotinamide riboside supplementation in several tissues. Collectively, our findings reveal an important role of bacteria-enabled deamidated pathway in host NAD metabolism.
    Keywords:  NAMPT inhibitors; cancer cells; deamidated NAD synthesis; germ-free mice; host-microbe interaction; microbial nicotinamidase; mycoplasma; nicotinic acid; oral nicotinamide riboside supplementation
    DOI:  https://doi.org/10.1016/j.cmet.2020.02.001
  2. Biochem Pharmacol. 2020 Feb 26. pii: S0006-2952(20)30113-1. [Epub ahead of print] 113885
    Rizza S, Di Leo L, Mandatori S, De Zio D, Filomeni G.
      The downregulation of the denitrosylating enzyme S-nitrosoglutathione reductase (GSNOR, EC:1.1.1.284), is a feature of hepatocellular carcinoma (HCC). This condition causes mitochondrial rearrangements that sensitize these tumors to mitochondrial toxins, in particular to the mitochondrial complex II inhibitor alpha-tocopheryl succinate (αTOS). It has also been reported the GSNOR depletion impairs the selective degradation of mitochondria through mitophagy; however, if this contributes to GSNOR-deficient HCC cell sensitivity to αTOS and can be applied to anticancer therapies, is still not known. Here, we provide evidence that GSNOR-deficient HCC cells show defective mitophagy which contributes to αTOS toxicity. Mitophagy inhibition by Parkin (EC: 2.3.2.31) depletion enhances αTOS anticancer effects, thus suggesting that this drug could be effective in treating mitophagy-defective tumors.
    Keywords:  Alpha-tocopheryl succinate; GSNOR; Hepatocellular carcinoma; Mitophagy; S-nitrosylation
    DOI:  https://doi.org/10.1016/j.bcp.2020.113885
  3. EMBO J. 2020 Mar 05. e103334
    Schwörer S, Berisa M, Violante S, Qin W, Zhu J, Hendrickson RC, Cross JR, Thompson CB.
      The production and secretion of matrix proteins upon stimulation of fibroblasts by transforming growth factor-beta (TGFβ) play a critical role in wound healing. How TGFβ supports the bioenergetic cost of matrix protein synthesis is not fully understood. Here, we show that TGFβ promotes protein translation at least in part by increasing the mitochondrial oxidation of glucose and glutamine carbons to support the bioenergetic demand of translation. Surprisingly, we found that in addition to stimulating the entry of glucose and glutamine carbon into the TCA cycle, TGFβ induced the biosynthesis of proline from glutamine in a Smad4-dependent fashion. Metabolic manipulations that increased mitochondrial redox generation promoted proline biosynthesis, while reducing mitochondrial redox potential and/or ATP synthesis impaired proline biosynthesis. Thus, proline biosynthesis acts as a redox vent, preventing the TGFβ-induced increase in mitochondrial glucose and glutamine catabolism from generating damaging reactive oxygen species (ROS) when TCA cycle activity exceeds the ability of oxidative phosphorylation to convert mitochondrial redox potential into ATP. In turn, the enhanced synthesis of proline supports TGFβ-induced production of matrix proteins.
    Keywords:  TGFβ; collagen; fibrosis; metabolism; proline
    DOI:  https://doi.org/10.15252/embj.2019103334
  4. Proteomics. 2020 Mar 04. e1800404
    Natarajan V, Chawla R, Mah T, Vivekanandan R, Tan SY, Sato PY, Mallilankaraman K.
      Ageing is a natural biological process in living organisms characterized by receding bioenergetics. Mitochondria are crucial for cellular bioenergetics and thus an important contributor to age-related energetics deterioration. In addition, mitochondria play a major role in calcium signaling, redox homeostasis, and thermogenesis making this organelle a major cellular component that dictates the fate of a cell. To maintain its quantity and quality, mitochondria undergo multiple processes such as fission, fusion and mitophagy to eliminate or replace damaged mitochondria. While this bioenergetics machinery is properly protected, the functional decline associated with age and age-related metabolic diseases are mostly a result of a failure in such protective mechanisms. In addition, metabolic byproducts like the reactive oxygen species also aid in this destructive pathway. Mitochondrial dysfunction has always been thought to be associated with diseases. Moreover, studies in recent years have pointed that ageing contributes to the decay of mitochondrial health by promoting imbalances in key mitochondrial-regulated pathways. Thus, it is crucial to understand the nexus of mitochondrial dysfunction and age-related diseases. This review focuses on various aspects of basic mitochondrial biology and its status in ageing and age-related metabolic diseases. This article is protected by copyright. All rights reserved.
    Keywords:  ageing; diabetes; metabolic diseases; mitochondrial calcium uniporter; mitochondrial dysfunction; mitophagy; obesity
    DOI:  https://doi.org/10.1002/pmic.201800404
  5. Oncogene. 2020 Mar 02.
    Khan A, Valli E, Lam H, Scott DA, Murray J, Hanssen KM, Eden G, Gamble LD, Pandher R, Flemming CL, Allan S, Osterman AL, Haber M, Norris MD, Fletcher JI, Yu DMT.
      Amplification of the MYCN oncogene occurs in ~25% of primary neuroblastomas and is the single most powerful biological marker of poor prognosis in this disease. MYCN transcriptionally regulates a range of biological processes important for cancer, including cell metabolism. The MYCN-regulated metabolic gene SLC16A1, encoding the lactate transporter monocarboxylate transporter 1 (MCT1), is a potential therapeutic target. Treatment of neuroblastoma cells with the MCT1 inhibitor SR13800 increased intracellular lactate levels, disrupted the nicotinamide adenine dinucleotide (NADH/NAD+) ratio, and decreased intracellular glutathione levels. Metabolite tracing with 13C-glucose and 13C-glutamine following MCT1 inhibitor treatment revealed increased quantities of tricarboxylic acid (TCA) cycle intermediates and increased oxygen consumption rate. MCT1 inhibition was highly synergistic with vincristine and LDHA inhibition under cell culture conditions, but this combination was ineffective against neuroblastoma xenografts. Posttreatment xenograft tumors had increased synthesis of the MCT1 homolog MCT4/SLC16A, a known resistance factor to MCT1 inhibition. We found that MCT4 was negatively regulated by MYCN in luciferase reporter assays and its synthesis in neuroblastoma cells was increased under hypoxic conditions and following hypoxia-inducible factor (HIF1) induction, suggesting that MCT4 may contribute to resistance to MCT1 inhibitor treatment in hypoxic neuroblastoma tumors. Co-treatment of neuroblastoma cells with inhibitors of MCT1 and LDHA, the enzyme responsible for lactate production, resulted in a large increase in intracellular pyruvate and was highly synergistic in decreasing neuroblastoma cell viability. These results highlight the potential of targeting MCT1 in neuroblastoma in conjunction with strategies that involve disruption of pyruvate homeostasis and indicate possible resistance mechanisms.
    DOI:  https://doi.org/10.1038/s41388-020-1235-2
  6. Int Rev Cell Mol Biol. 2020 ;pii: S1937-6448(19)30104-2. [Epub ahead of print]350 119-196
    Perrone M, Caroccia N, Genovese I, Missiroli S, Modesti L, Pedriali G, Vezzani B, Vitto VAM, Antenori M, Lebiedzinska-Arciszewska M, Wieckowski MR, Giorgi C, Pinton P.
      Mitochondria and endoplasmic reticulum (ER) are fundamental in the control of cell physiology regulating several signal transduction pathways. They continuously communicate exchanging messages in their contact sites called MAMs (mitochondria-associated membranes). MAMs are specific microdomains acting as a platform for the sorting of vital and dangerous signals. In recent years increasing evidence reported that multiple scaffold proteins and regulatory factors localize to this subcellular fraction suggesting MAMs as hotspot signaling domains. In this review we describe the current knowledge about MAMs' dynamics and processes, which provided new correlations between MAMs' dysfunctions and human diseases. In fact, MAMs machinery is strictly connected with several pathologies, like neurodegeneration, diabetes and mainly cancer. These pathological events are characterized by alterations in the normal communication between ER and mitochondria, leading to deep metabolic defects that contribute to the progression of the diseases.
    Keywords:  Autophagy; Calcium transfer apoptosis; Cancer; Diabetes; Inflammation and antiviral response; Lipid trafficking and metabolism; Mitochondrial dynamics; Neurodegenerative diseases; ROS
    DOI:  https://doi.org/10.1016/bs.ircmb.2019.11.002
  7. Cell Metab. 2020 Mar 03. pii: S1550-4131(20)30062-0. [Epub ahead of print]31(3): 642-653.e6
    Pak VV, Ezeriņa D, Lyublinskaya OG, Pedre B, Tyurin-Kuzmin PA, Mishina NM, Thauvin M, Young D, Wahni K, Martínez Gache SA, Demidovich AD, Ermakova YG, Maslova YD, Shokhina AG, Eroglu E, Bilan DS, Bogeski I, Michel T, Vriz S, Messens J, Belousov VV.
      Hydrogen peroxide (H2O2) is a key redox intermediate generated within cells. Existing probes for H2O2 have not solved the problem of detection of the ultra-low concentrations of the oxidant: these reporters are not sensitive enough, or pH-dependent, or insufficiently bright, or not functional in mammalian cells, or have poor dynamic range. Here we present HyPer7, the first bright, pH-stable, ultrafast, and ultrasensitive ratiometric H2O2 probe. HyPer7 is fully functional in mammalian cells and in other higher eukaryotes. The probe consists of a circularly permuted GFP integrated into the ultrasensitive OxyR domain from Neisseria meningitidis. Using HyPer7, we were able to uncover the details of H2O2 diffusion from the mitochondrial matrix, to find a functional output of H2O2 gradients in polarized cells, and to prove the existence of H2O2 gradients in wounded tissue in vivo. Overall, HyPer7 is a probe of choice for real-time H2O2 imaging in various biological contexts.
    Keywords:  D-amino acid oxidase; H(2)O(2); H(2)O(2) gradients; HyPer7; cell migration; chemogenetics; genetically encoded probes; hydrogen peroxide; mitochondria; redox signaling
    DOI:  https://doi.org/10.1016/j.cmet.2020.02.003
  8. Nat Rev Mol Cell Biol. 2020 Mar 06.
    Lee P, Chandel NS, Simon MC.
      Molecular oxygen (O2) sustains intracellular bioenergetics and is consumed by numerous biochemical reactions, making it essential for most species on Earth. Accordingly, decreased oxygen concentration (hypoxia) is a major stressor that generally subverts life of aerobic species and is a prominent feature of pathological states encountered in bacterial infection, inflammation, wounds, cardiovascular defects and cancer. Therefore, key adaptive mechanisms to cope with hypoxia have evolved in mammals. Systemically, these adaptations include increased ventilation, cardiac output, blood vessel growth and circulating red blood cell numbers. On a cellular level, ATP-consuming reactions are suppressed, and metabolism is altered until oxygen homeostasis is restored. A critical question is how mammalian cells sense oxygen levels to coordinate diverse biological outputs during hypoxia. The best-studied mechanism of response to hypoxia involves hypoxia inducible factors (HIFs), which are stabilized by low oxygen availability and control the expression of a multitude of genes, including those involved in cell survival, angiogenesis, glycolysis and invasion/metastasis. Importantly, changes in oxygen can also be sensed via other stress pathways as well as changes in metabolite levels and the generation of reactive oxygen species by mitochondria. Collectively, this leads to cellular adaptations of protein synthesis, energy metabolism, mitochondrial respiration, lipid and carbon metabolism as well as nutrient acquisition. These mechanisms are integral inputs into fine-tuning the responses to hypoxic stress.
    DOI:  https://doi.org/10.1038/s41580-020-0227-y
  9. Annu Rev Anal Chem (Palo Alto Calif). 2020 Mar 02.
    Zhang Z, Cheng X, Zhao Y, Yang Y.
      As the core component of cell metabolism, central carbon metabolism, consisting of glycolysis, the pentose phosphate pathway, and the tricarboxylic acid cycle converts nutrients into metabolic precursors for biomass and energy to sustain the life of virtually all extant species. The metabolite levels or distributions in central carbon metabolism often change dynamically with cell fates, development, and disease progression. However, traditional biochemical methods require cell lysis, making it challenging to obtain spatiotemporal information about metabolites in living cells and in vivo. Genetically encoded fluorescent sensors allow the rapid, sensitive, specific, and real-time readout of metabolite dynamics in living organisms, thereby offering the potential to fill the gap in current techniques. In this review, we introduce recent progress made in the development of genetically encoded fluorescent sensors for central carbon metabolism and discuss their advantages, disadvantages, and applications. Moreover, several future directions of metabolite sensors are also proposed. Expected final online publication date for the Annual Review of Analytical Chemistry, Volume 13 is June 12, 2020. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
    DOI:  https://doi.org/10.1146/annurev-anchem-091619-091306
  10. Front Cell Dev Biol. 2020 ;8 8
    Refolo G, Vescovo T, Piacentini M, Fimia GM, Ciccosanti F.
      In the last years, proteomics has represented a valuable approach to elucidate key aspects in the regulation of type I/III interferons (IFNs) and autophagy, two main processes involved in the response to viral infection, to unveil the molecular strategies that viruses have evolved to counteract these processes. Besides their main metabolic roles, mitochondria are well recognized as pivotal organelles in controlling signaling pathways essential to restrain viral infections. In particular, a major role in antiviral defense is played by mitochondrial antiviral signaling (MAVS) protein, an adaptor protein that coordinates the activation of IFN inducing pathways and autophagy at the mitochondrial level. Here, we provide an overview of how mass spectrometry-based studies of protein-protein interactions and post-translational modifications (PTMs) have fostered our understanding of the molecular mechanisms that control the mitochondria-mediated antiviral immunity.
    Keywords:  RNA virus infection; mitochondria; mitochondrial antiviral signaling protein; proteomics; retinoic acid-inducible gene I
    DOI:  https://doi.org/10.3389/fcell.2020.00008
  11. Semin Cell Dev Biol. 2020 Feb 28. pii: S1084-9521(19)30136-3. [Epub ahead of print]
    Carroll B.
      The mechanistic (or mammalian) Target of Rapamycin Complex 1 (mTORC1) is a central regulator of cell growth and metabolism. By integrating mitogenic signals, mTORC1-dependent phosphorylation of substrates dictates the balance between anabolic, pro-growth and catabolic, recycling processes in the cell. The discovery that amino acids activate mTORC1 by promoting its translocation to the lysosome was a fundamental advance in the understanding of mTORC1 signalling. It has since become clear that the lysosome-cytoplasm shuttling of mTORC1 represents just one layer of spatial control of this signalling pathway. This review will focus on exploring the subcellular localisation of mTORC1 and its regulators to multiple sites within the cell. We will discuss how these spatially distinct regions such as endoplasmic reticulum, plasma membrane and the endosomal pathway co-operate to transduce nutrient availability to mTORC1, allowing for tight control of cell growth.
    Keywords:  Amino acids; Autophagy; Endoplasmic reticulum; Endosome; Golgi; Lysosome; Rheb; Trafficking
    DOI:  https://doi.org/10.1016/j.semcdb.2020.02.007
  12. Cell Rep. 2020 Mar 03. pii: S2211-1247(20)30203-5. [Epub ahead of print]30(9): 2889-2899.e6
    Ramstead AG, Wallace JA, Lee SH, Bauer KM, Tang WW, Ekiz HA, Lane TE, Cluntun AA, Bettini ML, Round JL, Rutter J, O'Connell RM.
      Metabolic pathways regulate T cell development and function, but many remain understudied. Recently, the mitochondrial pyruvate carrier (MPC) was identified as the transporter that mediates pyruvate entry into mitochondria, promoting pyruvate oxidation. Here we find that deleting Mpc1, an obligate MPC subunit, in the hematopoietic system results in a specific reduction in peripheral αβ T cell numbers. MPC1-deficient T cells have defective thymic development at the β-selection, intermediate single positive (ISP)-to-double-positive (DP), and positive selection steps. We find that early thymocytes deficient in MPC1 display alterations to multiple pathways involved in T cell development. This results in preferred escape of more activated T cells. Finally, mice with hematopoietic deletion of Mpc1 are more susceptible to experimental autoimmune encephalomyelitis. Altogether, our study demonstrates that pyruvate oxidation by T cell precursors is necessary for optimal αβ T cell development and that its deficiency results in reduced but activated peripheral T cell populations.
    DOI:  https://doi.org/10.1016/j.celrep.2020.02.042
  13. BMJ Open Diabetes Res Care. 2020 Mar;pii: e000923. [Epub ahead of print]8(1):
    Abbade J, Klemetti MM, Farrell A, Ermini L, Gillmore T, Sallais J, Tagliaferro A, Post M, Caniggia I.
      INTRODUCTION: Gestational diabetes mellitus (GDM), a common pregnancy disorder, increases the risk of fetal overgrowth and later metabolic morbidity in the offspring. The placenta likely mediates these sequelae, but the exact mechanisms remain elusive. Mitochondrial dynamics refers to the joining and division of these organelles, in attempts to maintain cellular homeostasis in stress conditions or alterations in oxygen and fuel availability. These remodeling processes are critical to optimize mitochondrial function, and their disturbances characterize diabetes and obesity.METHODS AND RESULTS: Herein we show that placental mitochondrial dynamics are tilted toward fusion in GDM, as evidenced by transmission electron microscopy and changes in the expression of key mechanochemical enzymes such as OPA1 and active phosphorylated DRP1. In vitro experiments using choriocarcinoma JEG-3 cells demonstrated that increased exposure to insulin, which typifies GDM, promotes mitochondrial fusion. As placental ceramide induces mitochondrial fission in pre-eclampsia, we also examined ceramide content in GDM and control placentae and observed a reduction in placental ceramide enrichment in GDM, likely due to an insulin-dependent increase in ceramide-degrading ASAH1 expression.
    CONCLUSIONS: Placental mitochondrial fusion is enhanced in GDM, possibly as a compensatory response to maternal and fetal metabolic derangements. Alterations in placental insulin exposure and sphingolipid metabolism are among potential contributing factors. Overall, our results suggest that GDM has profound impacts on placental mitochondrial dynamics and metabolism, with plausible implications for the short-term and long-term health of the offspring.
    Keywords:  GDM; mitochondria; placenta
    DOI:  https://doi.org/10.1136/bmjdrc-2019-000923
  14. Redox Biol. 2020 Feb 09. pii: S2213-2317(20)30042-2. [Epub ahead of print] 101454
    Brooks GA.
      Mistakenly thought to be the consequence of oxygen lack in contracting skeletal muscle we now know that the L-enantiomer of the lactate anion is formed under fully aerobic conditions and is utilized continuously in diverse cells, tissues, organs and at the whole-body level. By shuttling between producer (driver) and consumer (recipient) cells lactate fulfills at least three purposes: 1] a major energy source for mitochondrial respiration; 2] the major gluconeogenic precursor; and 3] a signaling molecule. Working by mass action, cell redox regulation, allosteric binding, and reprogramming of chromatin by lactylation of lysine residues on histones, lactate has major influences in energy substrate partitioning. The physiological range of tissue [lactate] is 0.5-20 mM and the cellular Lactate/Pyruvate ratio (L/P) can range from 10 to >500; these changes during exercise and other stress-strain responses dwarf other metabolic signals in magnitude and span. Hence, lactate dynamics have rapid and major short- and long-term effects on cell redox and other control systems. By inhibiting lipolysis in adipose via HCAR-1, and muscle mitochondrial fatty acid uptake via malonyl-CoA and CPT1, lactate controls energy substrate partitioning. Repeated lactate exposure from regular exercise results in major effects on the expression of regulatory enzymes of glycolysis and mitochondrial respiration. Lactate is the fulcrum of metabolic regulation in vivo.
    Keywords:  Aerobic; Anaerobic; Cell-cell signaling; Energy substrate partitioning; Exercise; Gluconeogenesis; Glycolysis; HCAR1; Histone lactylation; Mitochondrial biogenesis; Oxidative metabolism; PGC-1α; PPAR-γ; SIRT activation; TGFβ
    DOI:  https://doi.org/10.1016/j.redox.2020.101454
  15. J Immunol. 2020 Mar 06. pii: ji1900740. [Epub ahead of print]
    Høgh RI, Droujinine A, Møller SH, Jepsen SD, Mellergaard M, Andresen L, Skov S.
      Fumarate is a tricarboxylic acid cycle metabolite whose intracellular accumulation is linked to inflammatory signaling and development of cancer. In this study, we demonstrate that endogenous fumarate accumulation upregulates surface expression of the immune stimulatory NK group 2, member D (NKG2D) ligands ULBP2 and ULBP5. In agreement with this, accumulation of fumarate by the therapeutic drug dimethyl fumarate (DMF) also promotes ULBP2/5 surface expression. Mechanistically, we found that the increased ULBP2/5 expression was dependent on oxidative stress and the antioxidants N-acetylcysteine and glutathione (GSH) abrogated ULBP2/5 upregulated by DMF. Fumarate can complex with GSH and thereby exhaust cells of functional GSH capacity. In line with this, inhibition of GSH reductase (GR), the enzyme responsible for GSH recycling, promoted ULBP2/5 surface expression. Loss of the tricarboxylic acid cycle enzyme fumarate hydratase (FH) associates with a malignant form of renal cancer characterized by fumarate accumulation and increased production of reactive oxygen species, highlighting fumarate as an oncometabolite. Interestingly, FH-deficient renal cancer cells had low surface expression of ULBP2/5 and were unresponsive to DMF treatment, suggesting that the fumarate-stimulating ULBP2/5 pathway is abrogated in these cells as an immune-evasive strategy. Together, our data show that ULBP2/5 expression can be upregulated by accumulation of fumarate, likely by depleting cells of GSH antioxidant capacity. Given that DMF is an approved human therapeutic drug, our findings support a broader use of DMF in treatment of cancers and inflammatory conditions.
    DOI:  https://doi.org/10.4049/jimmunol.1900740
  16. Autophagy. 2020 Mar 04. 1-3
    Evans CS, Holzbaur ELF.
      Damaged mitochondria are selectively removed from the cell in a process termed mitophagy. This mitochondrial quality control mechanism is important for neuronal homeostasis, and mutations in pathway components are causative for Parkinson disease and amyotrophic lateral sclerosis (ALS). Here, we discuss our recent work using a novel mild induction paradigm to investigate the spatiotemporal dynamics of mitophagy in primary neurons. Using live-cell imaging, we find that mitophagy-associated proteins translocate to depolarized mitochondrial fragments. These mitophagic events were primarily localized to somatodendritic compartments, suggesting neuronal mitophagy is primarily a somal quality control mechanism. Damaged mitochondria were efficiently sequestered within autophagosomes, but lysosomal fusion or acidification was significantly delayed. Surprisingly, engulfed mitochondria persisted in non-acidified vesicular compartments for hours to days after initial damage. Expression of an ALS-associated mutation disrupted the membrane potential of the mitochondrial network, and oxidative stress exacerbated this effect. Importantly, our results highlight the slow kinetics of mitophagy and suggest that slow turnover of damaged mitochondria may increase neuronal susceptibility to neurodegeneration.
    Keywords:  Autophagy; lysosome; mitochondria; mitophagy; neurodegenerative diseases
    DOI:  https://doi.org/10.1080/15548627.2020.1734330
  17. Biogerontology. 2020 Mar 03.
    Sedlackova L, Korolchuk VI.
      Cellular adaptation to various types of stress requires a complex network of steps that altogether lead to reconstitution of redox balance, degradation of damaged macromolecules and restoration of cellular metabolism. Advances in our understanding of the interplay between cellular signalling and signal translation paint a complex picture of multi-layered paths of regulation. In this review we explore the link between cellular adaptation to metabolic and oxidative stresses by activation of autophagy, a crucial cellular catabolic pathway. Metabolic stress can lead to changes in the redox state of nicotinamide adenine dinucleotide (NAD), a co-factor in a variety of enzymatic reactions and thus trigger autophagy that acts to sequester intracellular components for recycling to support cellular growth. Likewise, autophagy is activated by oxidative stress to selectively recycle damaged macromolecules and organelles and thus maintain cellular viability. Multiple proteins that help regulate or execute autophagy are targets of post-translational modifications (PTMs) that have an effect on their localization, binding affinity or enzymatic activity. These PTMs include acetylation, a reversible enzymatic modification of a protein's lysine residues, and oxidation, a set of reversible and irreversible modifications by free radicals. Here we highlight the latest findings and outstanding questions on the interplay of autophagy with metabolic stress, presenting as changes in NAD levels, and oxidative stress, with a focus on autophagy proteins that are regulated by both, oxidation and acetylation. We further explore the relevance of this multi-layered signalling to healthy human ageing and their potential role in human disease.
    Keywords:  Acetylation; Ageing; Autophagy; NAD; ROS; Sirtuins
    DOI:  https://doi.org/10.1007/s10522-020-09864-0
  18. J Inherit Metab Dis. 2020 Mar 02.
    Gancheva S, Caspari D, Bierwagen A, Jelenik T, Caprio S, Santoro N, Rothe M, Markgraf DF, Herebian D, Hwang JH, Öner-Sieben S, Mennenga J, Pacini G, Thimm E, Schlune A, Meissner T, Vom Dahl S, Klee D, Mayatepek E, Roden M, Ensenauer R.
      BACKGROUND: Classical organic acidemias (OAs) result from defective mitochondrial catabolism of branched-chain amino acids (BCAAs). Abnormal mitochondrial function relates to oxidative stress, ectopic lipids and insulin resistance (IR). We investigated whether genetically impaired function of mitochondrial BCAA catabolism associates with cardiometabolic risk factors, altered liver and muscle energy metabolism, and IR.PATIENTS AND METHODS: In this case-control study, 31 children and young adults with propionic acidemia (PA), methylmalonic acidemia (MMA) or isovaleric acidemia (IVA) were compared with 30 healthy young humans using comprehensive metabolic phenotyping including in vivo 31 P/1 H magnetic resonance spectroscopy of liver and skeletal muscle.
    RESULTS: Among all OAs, patients with PA exhibited abdominal adiposity, IR, fasting hyperglycemia and hypertriglyceridemia as well as increased liver fat accumulation, despite dietary energy intake within recommendations for age and sex. In contrast, patients with MMA more frequently featured higher energy intake than recommended and had a different phenotype including hepatomegaly and mildly lower skeletal muscle ATP content. In skeletal muscle of patients with PA, slightly lower inorganic phosphate levels were found. However, hepatic ATP and inorganic phosphate concentrations were not different between all OA patients and controls. In patients with IVA, no abnormalities were detected.
    CONCLUSIONS: Impaired BCAA catabolism in PA, but not in MMA or IVA, was associated with a previously unrecognized, metabolic syndrome-like phenotype with abdominal adiposity potentially resulting from ectopic lipid storage. These findings suggest the need for early cardiometabolic risk factor screening in PA. This article is protected by copyright. All rights reserved.
    Keywords:  Organic acidemia; cardiometabolic; fatty liver; metabolic syndrome; mitochondria; oxidative stress
    DOI:  https://doi.org/10.1002/jimd.12231
  19. Nat Cancer. 2020 Feb;1(2): 249-263
    Degasperi A, Amarante TD, Czarnecki J, Shooter S, Zou X, Glodzik D, Morganella S, Nanda AS, Badja C, Koh G, Momen SE, Georgakopoulos-Soares I, Dias JML, Young J, Memari Y, Davies H, Nik-Zainal S.
      Mutational signatures are patterns of mutations that arise during tumorigenesis. We present an enhanced, practical framework for mutational signature analyses. Applying these methods on 3,107 whole genome sequenced (WGS) primary cancers of 21 organs reveals known signatures and nine previously undescribed rearrangement signatures. We highlight inter-organ variability of signatures and present a way of visualizing that diversity, reinforcing our findings in an independent analysis of 3,096 WGS metastatic cancers. Signatures with a high level of genomic instability are dependent on TP53 dysregulation. We illustrate how uncertainty in mutational signature identification and assignment to samples affects tumor classification, reinforcing that using multiple orthogonal mutational signature data is not only beneficial, it is essential for accurate tumor stratification. Finally, we present a reference web-based tool for cancer and experimentally-generated mutational signatures, called Signal (https://signal.mutationalsignatures.com), that also supports performing mutational signature analyses.
    Keywords:  Mutational signatures; homologous recombination deficiency; somatic variants; whole genome sequencing
    DOI:  https://doi.org/10.1038/s43018-020-0027-5
  20. Nat Cell Biol. 2020 Mar;22(3): 310-320
    Davis RT, Blake K, Ma D, Gabra MBI, Hernandez GA, Phung AT, Yang Y, Maurer D, Lefebvre AEYT, Alshetaiwi H, Xiao Z, Liu J, Locasale JW, Digman MA, Mjolsness E, Kong M, Werb Z, Lawson DA.
      Although metastasis remains the cause of most cancer-related mortality, mechanisms governing seeding in distal tissues are poorly understood. Here, we establish a robust method for the identification of global transcriptomic changes in rare metastatic cells during seeding using single-cell RNA sequencing and patient-derived-xenograft models of breast cancer. We find that both primary tumours and micrometastases display transcriptional heterogeneity but micrometastases harbour a distinct transcriptome program conserved across patient-derived-xenograft models that is highly predictive of poor survival of patients. Pathway analysis revealed mitochondrial oxidative phosphorylation as the top pathway upregulated in micrometastases, in contrast to higher levels of glycolytic enzymes in primary tumour cells, which we corroborated by flow cytometric and metabolomic analyses. Pharmacological inhibition of oxidative phosphorylation dramatically attenuated metastatic seeding in the lungs, which demonstrates the functional importance of oxidative phosphorylation in metastasis and highlights its potential as a therapeutic target to prevent metastatic spread in patients with breast cancer.
    DOI:  https://doi.org/10.1038/s41556-020-0477-0
  21. Mol Cell. 2020 Mar 05. pii: S1097-2765(20)30105-2. [Epub ahead of print]77(5): 1107-1123.e10
    Phu L, Rose CM, Tea JS, Wall CE, Verschueren E, Cheung TK, Kirkpatrick DS, Bingol B.
      Mitochondria import nearly their entire proteome from the cytoplasm by translocating precursor proteins through the translocase of the outer membrane (TOM) complex. Here, we show dynamic regulation of mitochondrial import by the ubiquitin system. Acute pharmacological inhibition or genetic ablation of the mitochondrial deubiquitinase (DUB) USP30 triggers accumulation of Ub-substrates that are normally localized inside the mitochondria. Mitochondrial import of USP30 substrates is impaired in USP30 knockout (KO) cells, suggesting that deubiquitination promotes efficient import. Upstream of USP30, the E3 ligase March5 ubiquitinates mitochondrial proteins whose eventual import depends on USP30. In USP30 KOs, exogenous March5 expression induces accumulation of unimported translocation intermediates that are degraded by the proteasomes. In USP30 KO mice, TOM subunits have reduced abundance across multiple tissues. Together these data highlight how protein import into a subcellular compartment can be regulated by ubiquitination and deubiquitination by E3 ligase and DUB machinery positioned at the gate.
    Keywords:  Deubiquitinase; E3 Ubiquitin Ligase; Mitochondria; Mitochondrial Import; TOM complex; Ubiquitin System
    DOI:  https://doi.org/10.1016/j.molcel.2020.02.012
  22. Adv Exp Med Biol. 2020 ;1219 109-123
    Schoonjans CA, Gallez B.
      Dysregulated metabolism is a key hallmark of cancer cells and an enticing target for cancer treatment. Since the last 10 years, research on cancer metabolism has moved from pathway attention to network consideration. This metabolic complexity continuously adapt to new constraints in the tumor microenvironment. In this review, we will highlight striking changes in cancer cell metabolism compared to normal cells. Understanding this tumor metabolic plasticity suggests potential new targets and innovative combinatorial treatments for fighting cancer.
    Keywords:  Acidosis; Amino acid; Bioenergetics; Combined therapies; Fatty acid; Glycolysis; Hypoxia; Metabolic reprogramming; Mitochondria
    DOI:  https://doi.org/10.1007/978-3-030-34025-4_6
  23. Semin Nephrol. 2020 Jan;pii: S0270-9295(19)30112-3. [Epub ahead of print]40(1): 2-13
    Wettersten HI.
      Metabolic reprogramming is one of the major steps that tumor cells take during cancer progression. This process allows the cells to survive in a nutrient- and oxygen-deprived environment, to become stress tolerant, and to metastasize to different sites. Recent studies have shown that reprogramming happens in stromal cells and involves the cross-talk of the cancer cell/tumor microenvironment. There are similarities between the metabolic reprogramming that occurs in both noncancerous kidney diseases and renal cell carcinoma (RCC), suggesting that such reprogramming is a means by which renal epithelial cells survive injury and repair the tissue, and that RCC cells hijack this system. This article reviews reprogramming of major metabolism pathways in RCC, highlighting similarities and differences from kidney diseases and potential therapeutic strategies against it.
    Keywords:  Renal cell carcinoma; energy metabolism; immune evasion; kidney injury; metabolic reprogramming
    DOI:  https://doi.org/10.1016/j.semnephrol.2019.12.002
  24. EMBO J. 2020 Mar 05. e102166
    Maffei B, Laverrière M, Wu Y, Triboulet S, Perrinet S, Duchateau M, Matondo M, Hollis RL, Gourley C, Rupp J, Keillor JW, Subtil A.
      Transglutaminase 2 (TG2) is a ubiquitously expressed enzyme with transamidating activity. We report here that both expression and activity of TG2 are enhanced in mammalian epithelial cells infected with the obligate intracellular bacteria Chlamydia trachomatis. Genetic or pharmacological inhibition of TG2 impairs bacterial development. We show that TG2 increases glucose import by up-regulating the transcription of the glucose transporter genes GLUT-1 and GLUT-3. Furthermore, TG2 activation drives one specific glucose-dependent pathway in the host, i.e., hexosamine biosynthesis. Mechanistically, we identify the glucosamine:fructose-6-phosphate amidotransferase (GFPT) among the substrates of TG2. GFPT modification by TG2 increases its enzymatic activity, resulting in higher levels of UDP-N-acetylglucosamine biosynthesis and protein O-GlcNAcylation. The correlation between TG2 transamidating activity and O-GlcNAcylation is disrupted in infected cells because host hexosamine biosynthesis is being exploited by the bacteria, in particular to assist their division. In conclusion, our work establishes TG2 as a key player in controlling glucose-derived metabolic pathways in mammalian cells, themselves hijacked by C. trachomatis to sustain their own metabolic needs.
    Keywords:   Chlamydia ; GFPT ; O-GlcNAcylation; hexosamine biosynthesis; transglutaminase 2
    DOI:  https://doi.org/10.15252/embj.2019102166
  25. Nature. 2020 Mar 04.
    Guo X, Aviles G, Liu Y, Tian R, Unger BA, Lin YT, Wiita AP, Xu K, Correia MA, Kampmann M.
      In mammalian cells, mitochondrial dysfunction triggers the integrated stress response, in which the phosphorylation of eukaryotic translation initiation factor 2α (eIF2α) results in the induction of the transcription factor ATF41-3. However, how mitochondrial stress is relayed to ATF4 is unknown. Here we show that HRI is the eIF2α kinase that is necessary and sufficient for this relay. In a genome-wide CRISPR interference screen, we identified factors upstream of HRI: OMA1, a mitochondrial stress-activated protease; and DELE1, a little-characterized protein that we found was associated with the inner mitochondrial membrane. Mitochondrial stress stimulates OMA1-dependent cleavage of DELE1 and leads to the accumulation of DELE1 in the cytosol, where it interacts with HRI and activates the eIF2α kinase activity of HRI. In addition, DELE1 is required for ATF4 translation downstream of eIF2α phosphorylation. Blockade of the OMA1-DELE1-HRI pathway triggers an alternative response in which specific molecular chaperones are induced. The OMA1-DELE1-HRI pathway therefore represents a potential therapeutic target that could enable fine-tuning of the integrated stress response for beneficial outcomes in diseases that involve mitochondrial dysfunction.
    DOI:  https://doi.org/10.1038/s41586-020-2078-2
  26. Biol Chem. 2020 Mar 01. pii: /j/bchm.just-accepted/hsz-2020-0106/hsz-2020-0106.xml. [Epub ahead of print]
    Mokranjac D.
      Biogenesis of mitochondria relies on import of over 1000 different proteins from the cytosol. About 70% of these proteins follow the presequence pathway - they are synthesized with cleavable N-terminal extensions called presequences and reach the final place of their function within the organelle with the help of the TOM and TIM23 complexes in the outer and inner membranes, respectively. The translocation of proteins along the presequence pathway is powered by the import motor of the TIM23 complex. The import motor of the TIM23 complex is localized at the matrix face of the inner membrane and is likely the most complicated Hsp70-based system identified to date. How it converts the energy of ATP hydrolysis into unidirectional translocation of proteins into mitochondria remains one of the biggest mysteries of this translocation pathway. Here, I discuss the knowns and the unknowns of the mitochondrial protein import motor.
    Keywords:  Hsp70; J protein; chaperone; mitochondria; protein translocation
    DOI:  https://doi.org/10.1515/hsz-2020-0106
  27. Cell Calcium. 2020 Feb 24. pii: S0143-4160(20)30028-2. [Epub ahead of print]87 102186
    Basso V, Marchesan E, Ziviani E.
      The outer mitochondrial membrane protein VDAC interacts with the ER protein IP3R via chaperone Grp75 to form a molecular complex that couples mitochondria to the ER and contributes to functional mitochondria-ER contacts (MERCs), essential for efficient calcium (Ca2+) transfer. A new study by Liu et al. identifies the PD protein DJ-1 as a component of the IP3R-Grp75-VDAC complex. DJ-1 ablation impairs mitochondria-ER association and Ca2+ crosstalk, and impacts the stability of the trio.
    Keywords:  Calcium (Ca(2+)); DJ-1; MERCs; Parkinson’s disease
    DOI:  https://doi.org/10.1016/j.ceca.2020.102186
  28. J Diabetes. 2020 Mar 03.
    Jayakumari NR, Rajendran RS, Sivasailam A, Vimala SS, Nanda S, Manjunatha S, Pillai VV, Karunakaran J, Gopala S.
      BACKGROUND: The cardiovascular complications associated with type 2 diabetes mellitus could be attributed to changes in myocardial mitochondrial metabolism. Though it is a known fact that permeabilized cardiac muscle fibres as well as isolated mitochondria are metabolically compromised in Caucasian population, studies in Asian Indian myocardial mitochondrial function are lacking. Thus, the objective of the present study was to analyze if there is altered cardiac mitochondrial substrate utilization in diabetic Asian Indians.METHODS: Mitochondrial substrate utilization was measured using high-resolution respirometry in isolated mitochondria prepared from right atrial appendage tissues of diabetic and non-diabetic subjects undergoing coronary artery bypass graft surgery. Western blotting and densitometric analysis were also done to compare the levels of proteins involved in fatty acid metabolism and regulation.
    RESULTS: Mitochondrial oxygen consumption rate for fatty acid substrate was shown to be decreased between diabetic and non-diabetic subjects along with unvaried mitochondrial DNA copy number and uniform levels of electron transport chain complex proteins and proteins involved in fatty acid metabolism and regulation. Decreased glutamate but unchanged pyruvate-mediated state 3 respiration were also observed in diabetic subjects.
    CONCLUSION: The current study reports deranged cardiac mitochondrial fatty acid-mediated complex I respiration in type 2 diabetic Asian Indians with comparable levels of regulators of fatty acid oxidation to that of non-diabetic myocardium. Altered glutamate-mediated mitochondrial respiration also point towards possible alterations in mitochondrial complex I activity. When compared with previous reports on other ethnic populations, the current study suggests that Asian Indian population too have altered cardiac mitochondrial substrate utilization.
    Keywords:  Asian Indians,cardiac mitochondria,fatty acid metabolism; sirtuins; type 2 diabetes mellitus
    DOI:  https://doi.org/10.1111/1753-0407.13031
  29. Front Biosci (Landmark Ed). 2020 Mar 01. 25 1058-1109
    Ilango S, Paital B, Jayachandran P, Padma PR, Nirmaladevi R.
      Genetic and epigenetic modifications in DNA contribute to altered gene expression in aging and cancer. In human cancers, epigenetic changes such as DNA methylation, histone modifications, micro RNAs and nucleosome remodelling all control gene expression. The link between the genetics and epigenetics in cancer is further shown by existence of aberrant metabolism and biochemical pathways in cancer or mutation in genes that are epigenetic players. Reversal of these epigenetic changes has been clearly shown to have therapeutic value in various forms of lymphoma and preleukemia and similar results are appearing for the treatment of solid tumors. In this review, we discuss the functional effects of epigenetic changes inducible by hypoxia, the epigenetic alterations in cancer and how they contribute to tumor progression and their relevance to epigenetic therapy.
  30. EMBO Rep. 2020 Mar 05. e48183
    Wang B, Ye Y, Yang X, Liu B, Wang Z, Chen S, Jiang K, Zhang W, Jiang H, Mustonen H, Puolakkainen P, Wang S, Luo J, Shen Z.
      Protein lysine acetylation affects colorectal cancer (CRC) distant metastasis through multiple pathways. In a previous proteomics screen, we found that isocitrate dehydrogenase 1 (IDH1) is hyperacetylated in CRC primary tumors and liver metastases. Here, we further investigate the function of IDH1 hyperacetylation at lysine 224 in CRC progression. We find that IDH1 K224 deacetylation promotes its enzymatic activity and the production of α-KG, and we identify sirtuin-2 (SIRT2) as a major deacetylase for IDH1. SIRT2 overexpression significantly inhibits CRC cell proliferation, migration, and invasion. IDH1 acetylation is modulated in response to intracellular metabolite concentration and regulates cellular redox hemostasis. Moreover, IDH1 acetylation reversely regulates HIF1α-dependent SRC transcription which in turn controls CRC progression. Physiologically, our data indicate that IDH1 deacetylation represses CRC cell invasion and migration in vitro and in vivo, while the hyperacetylation of IDH1 on K224 is significantly correlated to distant metastasis and poor survival of colorectal cancer patients. In summary, our study uncovers a novel mechanism through which SIRT2-dependent IDH1 deacetylation regulates cellular metabolism and inhibits liver metastasis of colorectal cancer.
    Keywords:  IDH1; SIRT2; acetylation; colorectal cancer; metastasis
    DOI:  https://doi.org/10.15252/embr.201948183
  31. Oncoimmunology. 2020 ;9(1): 1726556
    Xiao Z, Locasale JW, Dai Z.
      The metabolism of both cancer and immune cells in the tumor microenvironment (TME) is poorly understood since most studies have focused on analysis in bulk samples and ex vivo cell culture models. Our recent analyses of single-cell RNA sequencing data suggest that the metabolic features of single cells within TME differ greatly from those of the bulk measurements. Here, we discuss some key findings about metabolism in cancer and immune cells and discuss possible relevance to immunotherapy.
    Keywords:  Cancer metabolism; immunometabolism; single-cell RNA sequencing; tumor microenvironment
    DOI:  https://doi.org/10.1080/2162402X.2020.1726556
  32. Elife. 2020 Mar 06. pii: e53917. [Epub ahead of print]9
    Arce-Molina R, Cortés-Molina F, Sandoval PY, Galaz A, Alegría K, Schirmeier S, Barros LF, San Martín A.
      Mitochondria generate ATP and building blocks for cell growth and regeneration, using pyruvate as the main substrate. Here we introduce PyronicSF, a user-friendly GFP-based sensor of improved dynamic range that enables real-time subcellular quantitation of mitochondrial pyruvate transport, concentration and flux. We report that cultured mouse astrocytes maintain mitochondrial pyruvate in the low micromolar range, below cytosolic pyruvate, which means that the mitochondrial pyruvate carrier MPC is poised to exert ultrasensitive control on the balance between respiration and anaplerosis/gluconeogenesis. The functionality of the sensor in living tissue is demonstrated in the brain of Drosophila melanogaster larvae. Mitochondrial subpopulations are known to coexist within a given cell, which differ in their morphology, mobility, membrane potential, and vicinity to other organelles. The present tool can be used to investigate how mitochondrial diversity relates to metabolism, to study the role of MPC in disease, and to screen for small-molecule MPC modulators.
    Keywords:  D. melanogaster; cell biology; mouse
    DOI:  https://doi.org/10.7554/eLife.53917
  33. Cell Metab. 2020 Mar 03. pii: S1550-4131(20)30064-4. [Epub ahead of print]31(3): 441-442
    Puleston DJ, Pearce EL.
      Engulfment of dying cells by phagocytes is essential to maintain tissue function and promote injury resolution and repair. This process, termed efferocytosis, requires persistent corpse engulfment and remains a poorly understood mechanism. Here, we preview findings from Yurdagul et al. (2020) that detail how continual efferocytosis is supported by metabolites derived from the dying cell itself.
    DOI:  https://doi.org/10.1016/j.cmet.2020.02.005
  34. Nature. 2020 Mar 04.
    Fessler E, Eckl EM, Schmitt S, Mancilla IA, Meyer-Bender MF, Hanf M, Philippou-Massier J, Krebs S, Zischka H, Jae LT.
      Mitochondrial fidelity is tightly linked to overall cellular homeostasis and is compromised in ageing and various pathologies1-3. Mitochondrial malfunction needs to be relayed to the cytosol, where an integrated stress response is triggered by the phosphorylation of eukaryotic translation initiation factor 2α (eIF2α) in mammalian cells4,5. eIF2α phosphorylation is mediated by the four eIF2α kinases GCN2, HRI, PERK and PKR, which are activated by diverse types of cellular stress6. However, the machinery that communicates mitochondrial perturbation to the cytosol to trigger the integrated stress response remains unknown1,2,7. Here we combine genome engineering and haploid genetics to unbiasedly identify genes that affect the induction of C/EBP homologous protein (CHOP), a key factor in the integrated stress response. We show that the mitochondrial protease OMA1 and the poorly characterized protein DELE1, together with HRI, constitute the missing pathway that is triggered by mitochondrial stress. Mechanistically, stress-induced activation of OMA1 causes DELE1 to be cleaved into a short form that accumulates in the cytosol, where it binds to and activates HRI via its C-terminal portion. Obstruction of this pathway can be beneficial or adverse depending on the type of mitochondrial perturbation. In addition to the core pathway components, our comparative genetic screening strategy identifies a suite of additional regulators. Together, these findings could be used to inform future strategies to modulate the cellular response to mitochondrial dysfunction in the context of human disease.
    DOI:  https://doi.org/10.1038/s41586-020-2076-4
  35. EMBO Rep. 2020 Mar 05. e48791
    Goldbraikh D, Neufeld D, Eid-Mutlak Y, Lasry I, Gilda JE, Parnis A, Cohen S.
      PI3K-Akt-FoxO-mTOR signaling is the central pathway controlling growth and metabolism in all cells. Ubiquitination of the protein kinase Akt prior to its phosphorylation is required for PI3K-Akt activity. Here, we found that the deubiquitinating (DUB) enzyme USP1 removes K63-linked polyubiquitin chains on Akt to restrict PI3K-Akt-FoxO signaling in mouse muscle during prolonged starvation. DUB screening platform identified USP1 as a direct DUB for Akt, and USP1 depletion in mouse muscle increased Akt ubiquitination, PI3K-Akt-FoxO signaling, and glucose uptake during fasting. Co-immunoprecipitation and mass spectrometry identified disabled homolog-2 (Dab2), the tuberous sclerosis complex TSC1/TSC2, and PHLPP1 as USP1 bound proteins. During starvation, Dab2 is essential for Akt recruitment to USP1-TSC1-PHLPP1 complex, and for PI3K-Akt-FoxO inhibition. Surprisingly, USP1 limits TSC1 levels to sustain mTOR-mediated basal protein synthesis rates and maintain its own protein levels. We propose that Dab2 recruits Akt to USP1-TSC1-PHLPP1 complex to efficiently terminate the transmission of growth signals when cellular energy level is low.
    Keywords:  Dab2; PI3K-Akt signaling; USP1; fasting; muscle atrophy
    DOI:  https://doi.org/10.15252/embr.201948791
  36. Proc Natl Acad Sci U S A. 2020 Mar 02. pii: 201920413. [Epub ahead of print]
    Hermans D, Gautam S, García-Cañaveras JC, Gromer D, Mitra S, Spolski R, Li P, Christensen S, Nguyen R, Lin JX, Oh J, Du N, Veenbergen S, Fioravanti J, Ebina-Shibuya R, Bleck C, Neckers LM, Rabinowitz JD, Gattinoni L, Leonard WJ.
      Interleukin (IL)-2 and IL-21 dichotomously shape CD8+ T cell differentiation. IL-2 drives terminal differentiation, generating cells that are poorly effective against tumors, whereas IL-21 promotes stem cell memory T cells (TSCM) and antitumor responses. Here we investigated the role of metabolic programming in the developmental differences induced by these cytokines. IL-2 promoted effector-like metabolism and aerobic glycolysis, robustly inducing lactate dehydrogenase (LDH) and lactate production, whereas IL-21 maintained a metabolically quiescent state dependent on oxidative phosphorylation. LDH inhibition rewired IL-2-induced effects, promoting pyruvate entry into the tricarboxylic acid cycle and inhibiting terminal effector and exhaustion programs, including mRNA expression of members of the NR4A family of nuclear receptors, as well as Prdm1 and Xbp1 While deletion of Ldha prevented development of cells with antitumor effector function, transient LDH inhibition enhanced the generation of memory cells capable of triggering robust antitumor responses after adoptive transfer. LDH inhibition did not significantly affect IL-21-induced metabolism but caused major transcriptomic changes, including the suppression of IL-21-induced exhaustion markers LAG3, PD1, 2B4, and TIM3. LDH inhibition combined with IL-21 increased the formation of TSCM cells, resulting in more profound antitumor responses and prolonged host survival. These findings indicate a pivotal role for LDH in modulating cytokine-mediated T cell differentiation and underscore the therapeutic potential of transiently inhibiting LDH during adoptive T cell-based immunotherapy, with an unanticipated cooperative antitumor effect of LDH inhibition and IL-21.
    Keywords:  IL-2; IL-21; LDH; adoptive immunotherapy; immunometabolism
    DOI:  https://doi.org/10.1073/pnas.1920413117
  37. Sci Rep. 2020 Mar 03. 10(1): 3924
    Wacquier B, Combettes L, Dupont G.
      Mitochondria play an essential role in bioenergetics and cellular Ca[Formula: see text] handling. The mitochondrial permeability transition pore (mPTP) is a non-specific channel located in the inner mitochondrial membrane. Long-lasting openings of the pore allow the rapid passage of ions and large molecules, which can result in cell death. The mPTP also exhibits transient, low conductance openings that contribute to Ca[Formula: see text] homeostasis. Although many regulators of the pore have been identified, none of them uniquely governs the passage between the two operating modes, which thus probably relies on a still unidentified network of interactions. By developing a core computational model for mPTP opening under the control of mitochondrial voltage and Ca[Formula: see text], we uncovered the existence of a positive feedback loop leading to bistability. The characteristics of the two stable steady-states correspond to those of the two opening states. When inserted in a full model of Ca[Formula: see text] handling by mitochondria, our description of the pore reproduces observations in mitochondrial suspensions. Moreover, the model predicted the occurrence of hysteresis in the switching between the two modes, upon addition and removal of free Ca[Formula: see text] in the extra-mitochondrial medium. Stochastic simulations then confirmed that the pore can undergo transient openings resembling those observed in intact cells.
    DOI:  https://doi.org/10.1038/s41598-020-60177-1
  38. Adv Exp Med Biol. 2020 ;1219 51-74
    Pereira-Nunes A, Afonso J, Granja S, Baltazar F.
      Reprogramming of energy metabolism is a key hallmark of cancer. Most cancer cells display a glycolytic phenotype, with increased glucose consumption and glycolysis rates, and production of lactate as the end product, independently of oxygen concentrations. This phenomenon, known as "Warburg Effect", provides several survival advantages to cancer cells and modulates the metabolism and function of neighbour cells in the tumour microenvironment. However, due to the presence of metabolic heterogeneity within a tumour, cancer cells can also display an oxidative phenotype, and corruptible cells from the microenvironment become glycolytic, cooperating with oxidative cancer cells to boost tumour growth. This phenomenon is known as "Reverse Warburg Effect". In either way, lactate is a key mediator in the metabolic crosstalk between cancer cells and the microenvironment, and lactate transporters are expressed differentially by existing cell populations, to support this crosstalk.In this review, we will focus on lactate and on lactate transporters in distinct cells of the tumour microenvironment, aiming at a better understanding of their role in the acquisition and maintenance of the direct/reverse "Warburg effect" phenotype, which modulate cancer progression.
    Keywords:  Cancer-associated fibroblasts; Endothelial cells; Glycolysis; Immune cells; Lactate; Lactate shuttles; Monocarboxylate transporters; Reverse Warburg effect; Warburg effect
    DOI:  https://doi.org/10.1007/978-3-030-34025-4_3
  39. J Biol Chem. 2020 Mar 05. pii: jbc.RA119.012376. [Epub ahead of print]
    Geck RC, Foley JR, Murray Stewart T, Asara JM, Casero RA, Toker A.
      Treatment of patients with triple-negative breast cancer (TNBC) is limited by a lack of effective molecular therapies targeting this disease. Recent studies have identified metabolic alterations in cancer cells that can be targeted to improve responses to standard-of-care chemotherapy regimens. Using MDA-MB-468 and SUM-159PT TNBC cells, along with LC-MS/MS and HPLC metabolomics profiling, we found here that exposure of TNBC cells to the cytotoxic chemotherapy drugs cisplatin and doxorubicin alter arginine and polyamine metabolites. This alteration was due to a reduction in the levels and activity of a rate-limiting polyamine biosynthetic enzyme, ornithine decarboxylase (ODC). Using gene silencing and inhibitor treatments, we determined that the reduction in ODC was mediated by its negative regulator, antizyme, targeting ODC to the proteasome for degradation. Treatment with the ODC inhibitor difluoromethylornithine (DFMO) sensitized TNBC cells to chemotherapy, but this was not observed in receptor-positive breast cancer cells. Moreover, TNBC cell lines had greater sensitivity to single-agent DFMO, and ODC levels were elevated in TNBC patient samples. The alterations in polyamine metabolism in response to chemotherapy, as well as DFMO-induced, preferential sensitization of TNBC cells to chemotherapy, reported here suggest that ODC may be a targetable metabolic vulnerability in TNBC.
    Keywords:  DNA damage; amino acid; antizyme; breast cancer; difluoromethylornithine; metabolomics; ornithine decarboxylase (ODC); polyamine; triple-negative breast cancer (TNBC)
    DOI:  https://doi.org/10.1074/jbc.RA119.012376