bims-camemi Biomed news
on Mitochondrial metabolism in cancer
Issue of 2018‒11‒04
twelve papers selected by
Christian Frezza
University of Cambridge, MRC Cancer Unit


  1. Mol Genet Metab. 2018 Oct 16. pii: S1096-7192(18)30605-X. [Epub ahead of print]
    El-Hattab AW, Suleiman J, Almannai M, Scaglia F.
      Mitochondria are dynamic organelles that undergo fusion, fission, movement, and mitophagy. These processes are essential to maintain the normal mitochondrial morphology, distribution, and function. Mitochondrial fusion allows the exchange of intramitochondrial material, whereas the fission process is required to replicate the mitochondria during cell division, facilitate the transport and distribution of mitochondria, and allow the isolation of damaged organelles. Mitochondrial mobility is essential for mitochondrial distribution depending on the cellular metabolic demands. Mitophagy is needed for the elimination of dysfunctional and damaged mitochondria to maintain a healthy mitochondrial population. The mitochondrial dynamic processes are mediated by a number of nuclear-encoded proteins that function in mitochondrial transport, fusion, fission, and mitophagy. Disorders of mitochondrial dynamics are caused by pathogenic variants in the genes encoding these proteins. These diseases have a high clinical variability, and range in severity from isolated optic atrophy to lethal encephalopathy. These disorders include defects in mitochondrial fusion (caused by pathogenic variants in MFN2, OPA1, YME1L1, MSTO1, and FBXL4), mitochondrial fission (caused by pathogenic variants in DNM1L and MFF), and mitochondrial autophagy (caused by pathogenic variants in PINK1 and PRKN). In this review, the molecular machinery and biological roles of mitochondrial dynamic processes are discussed. Subsequently, the currently known diseases related to mitochondrial dynamic defects are presented.
    Keywords:  DNM1L; FBXL4; MFF; MFN2; MSTO1; Mitochondrial fission; Mitochondrial fusion; Mitophagy; OPA1; PINK1; PRKN; YME1L1
    DOI:  https://doi.org/10.1016/j.ymgme.2018.10.003
  2. Metabolism. 2018 Oct 22. pii: S0026-0495(18)30213-0. [Epub ahead of print]
    Okamoto S, Asgar NF, Yokota S, Saito K, Minokoshi Y.
      BACKGROUND: AMP-activated protein kinase (AMPK), a heterotrimer with α1 or α2 catalytic subunits, acts as an energy sensor and regulates cellular homeostasis. Whereas AMPKα1 is necessary for myogenesis in skeletal muscle, the role of AMPKα2 in myogenic differentiation and energy metabolism-related gene expressions has remained unclear. We here examined the specific roles of AMPKα1 and AMPKα2 in the myogenic differentiation and mitochondria and energy metabolism-related gene expressions in C2C12 cells.MATERIALS AND METHODS: Stable C2C12 cell lines expressing a scramble short hairpin RNA (shRNA) or shRNAs specific for AMPKα1 (shAMPKα1), AMPKα2 (shAMPKα2), or both AMPKα1 and AMPKα2 (shPanAMPK) were generated by lentivirus infection. Lentiviruses encoding wild-type AMPKα2 (WT-AMPKα2) or AMPKα2 with a mutated nuclear localization signal (ΔNLS-AMPKα2) were also constructed for introduction into myoblasts. Myogenesis was induced by culture of C2C12 myoblasts for 6 days in differentiation medium.
    RESULTS: The amount of AMPKα2 increased progressively, whereas that of AMPKα1 remained constant, during the differentiation of myoblasts into myotubes. Expression of shPanAMPK or shAMPKα1, but not that of shAMPKα2, attenuated the proliferation of myoblasts as well as the phosphorylation of both acetyl-CoA carboxylase and the autophagy-initiating kinase ULK1 in myotubes. Up-regulation of myogenin mRNA, a marker for the middle stage of myogenesis, was attenuated in differentiating myotubes expressing shPanAMPK or shAMPKα1. In contrast, up-regulation of gene expression for muscle creatine kinase (MCK), a late-stage differentiation marker, as well as for genes related to mitochondrial biogenesis including the transcriptional coactivator peroxisome proliferator-activated receptor-γ coactivator-1α1 and α4 (PGC-1α1 and PGC-1α4) and mitochondria-specific genes such as cytochrome c was attenuated in myotubes expressing shAMPKα2 or shPanAMPK. The diameter of myotubes expressing shPanAMPK or shAMPKα2 was reduced, whereas that of those expressing shAMPKα1 was increased, compared with myotubes expressing scramble shRNA. A portion of AMPKα2 became localized to the nucleus during myogenic differentiation. The AMPK activator AICAR (5-aminoimidazole-4-carboxamide ribonucleotide) and 2-deoxyglucose (2DG) each induced the nuclear translocation of WT-AMPKα2, but not that of ΔNLS-AMPKα2. Finally, expression of WT-AMPKα2 increased the mRNA abundance of PGC-1α1 and MCK mRNAs as well as cell diameter and tended to increase that of PGC-1α4, whereas that of ΔNLS-AMPKα2 increased only the abundance of MCK mRNA, in myotubes depleted of endogenous AMPKα2.
    CONCLUSION: AMPKα1 and AMPKα2 have distinct roles in myogenic differentiation of C2C12 cells, with AMPKα1 contributing to the middle stage of myogenesis and AMPKα2 to the late stage. AMPKα2 regulates gene expressions including MCK, PGC-1α1 and PGC-1α4 and mitochondria-specific genes such as cytochrome c during the late stage of differentiation. Furthermore, the nuclear translocation of AMPKα2 is necessary for maintenance of PGC-1α1 mRNA during myogenesis.
    Keywords:  AMP-activated protein kinase (AMPK); C2C12 cells; Muscle creatine kinase; Muscle differentiation; Nuclear localization signal; PGC-1α
    DOI:  https://doi.org/10.1016/j.metabol.2018.10.003
  3. Pharmaceuticals (Basel). 2018 Oct 23. pii: E114. [Epub ahead of print]11(4):
    Santana-Codina N, Mancias JD.
      Nuclear receptor coactivator 4 (NCOA4) is a selective cargo receptor that mediates the autophagic degradation of ferritin ("ferritinophagy"), the cytosolic iron storage complex. NCOA4-mediated ferritinophagy maintains intracellular iron homeostasis by facilitating ferritin iron storage or release according to demand. Ferritinophagy is involved in iron-dependent physiological processes such as erythropoiesis, where NCOA4 mediates ferritin iron release for mitochondrial heme synthesis. Recently, ferritinophagy has been shown to regulate ferroptosis, a newly described form of iron-dependent cell death mediated by excess lipid peroxidation. Dysregulation of iron metabolism and ferroptosis have been described in neurodegeneration, cancer, and infection, but little is known about the role of ferritinophagy in the pathogenesis of these diseases. Here, we will review the biochemical regulation of NCOA4, its contribution to physiological processes and its role in disease. Finally, we will discuss the potential of activating or inhibiting ferritinophagy and ferroptosis for therapeutic purposes.
    Keywords:  NCOA4; cancer; erythropoiesis; ferritinophagy; ferroptosis; iron homeostasis
    DOI:  https://doi.org/10.3390/ph11040114
  4. Cell Physiol Biochem. 2018 Oct 25. 50(4): 1574-1584
    Yang XY, Tse MCL, Hu X, Jia WH, Du GH, Chan CB.
      BACKGROUND/AIMS: Fibronectin type III domain-containing protein 5 (FNDC5), also known as irisin, is a myokine secreted from muscle in response to exercise. However, the molecular mechanisms that regulate FNDC5 expression and the functional significance of irisn in skeletal muscle remain unknown. In this study, we explored the potential pathways that induce FNDC5 expression and delineated the metabolic effects of irisin on skeletal muscle.METHODS: C2C12 myotubes were treated with drugs at various concentrations and durations. The expression and activation of genes were measured by real-time polymerase chain reaction (qRT-PCR) and Western blotting. Oxidative phosphorylation was quantified by measuring the oxygen consumption rate (OCR).
    RESULTS: We found that the exercise-mimicking treatment (cAMP, forskolin and isoproterenol) increased Fndc5 expression in C2C12 myotubes. CREB over-expressed C2C12 myotubes displayed higher Fndc5 expression. CREB over-expression also promoted peroxisome proliferator-activated receptor gamma coactivator 1α (PGC-1α) expression. PGC-1α-induced Fndc5 expression was blocked when the dominant negative form of CREB (S133A) was present. PGC-1α mutation (S570A) also decreased Fndc5 expression. Immunoprecipitation showed that overexpressed PGC-1α complexed with CREB in HEK293 cells. C2C12 myotubes treated with forskolin also increased endogenous CREB and PGC-1α binding. Functionally, irisin treatment increased mitochondrial respiration, enhanced ATP production, promoted fatty acid oxidation but decreased glycolysis in myotubes.
    CONCLUSION: Our observation indicates that cAMP-mediated PGC-1α/CREB interaction triggers Fndc5 expression, which acts as an autocrine/paracrine to shape the metabolic phenotype of myotubes.
    Keywords:  C2C12; FNDC5; Glucose; Irisin; Myokine; PGC-1α; Skeletal muscle
    DOI:  https://doi.org/10.1159/000494655
  5. Mol Genet Metab. 2018 Oct 16. pii: S1096-7192(18)30395-0. [Epub ahead of print]
    Newell C, Hume S, Greenway SC, Podemski L, Shearer J, Khan A.
      BACKGROUND: Mitochondrial diseases are a clinically heterogeneous group of diseases caused by mutations in either nuclear or mitochondrial DNA (mtDNA). The diagnosis is challenging and has frequently required a tissue biopsy to obtain a sufficient quantity of mtDNA. Less-invasive sources mtDNA, such as peripheral blood leukocytes, urine sediment, or buccal swab, contain a lower quantity of mtDNA compared to tissue sources which may reduce sensitivity. Cellular apoptosis of tissues and hematopoetic cells releases fragments of DNA and mtDNA into the circulation and these molecules can be extracted from plasma as cell-free DNA (cfDNA). However, entire mtDNA has not been successfully identified from the cell free fraction previously. We hypothesized that the circular nature of mtDNA would prevent its degradation and a higher sensitivity method, such as next generation sequencing, could identify intact cf-mtDNA from human plasma.METHODS: Plasma was obtained from patients with mitochondrial disease diagnosed from skeletal muscle biopsy (n = 7) and healthy controls (n = 7) using a specially cfDNA collection tube (Streck Inc.; La Vista, NE). To demonstrate the presence of mtDNA within these samples, we amplified the isolated DNA using custom PCR primers specific to overlapping fragments of mtDNA. cfDNA samples were then sequenced using the Illumina MiSeq sequencing platform.
    RESULTS: We confirmed the presence of mtDNA, demonstrating that the full mitochondrial genome is in fact present within the cell-free plasma fraction of human blood. Sequencing identified the mitochondrial haplogroup matching with the tissue specimen for all patients.
    CONCLUSION: We report the existence of full length mtDNA in cell-free human plasma that was successfully used to perform haplogroup matching. Clinical applications for this work include patient monitoring for heteroplasmy status after mitochondrially-targeted therapies or haplogroup monitoring as a measure of stem cell transplantation.
    Keywords:  Cell-free mitochondrial DNA; Mitochondrial disease; mtDNA Haplotype; mtDNA Mutations
    DOI:  https://doi.org/10.1016/j.ymgme.2018.10.002
  6. J Mol Biol. 2018 Oct 22. pii: S0022-2836(18)30970-7. [Epub ahead of print]
    Nicholas Laribee R.
      Nutrient availability impacts health such that nutrient excess states can dysregulate epigenetic and transcriptional pathways to cause many diseases. Increasing evidence implicates aberrant regulation of nutrient signaling cascades as one means of communicating nutrient information to the epigenetic and transcriptional regulatory machinery. One such signaling cascade, the mechanistic target of rapamycin complex 1 (mTORC1), is conserved from yeast to man, and it is deregulated in diverse disease states. The catalytic subunit of the mTORC1 kinase complex (Tor1 or Tor2 in budding yeast and mTor in mammals) phosphorylates several downstream effectors regulating transcriptional and translational responses controlling growth and proliferation. Delineating mechanisms of cytoplasmic nutrient mTORC1 activation continues to be a major research focus. However, Tor kinases localize not only to the cytoplasm, but they also are found in the nucleus where they selectively bind and regulate genes controlling cellular metabolism and anabolism. The nuclear mTORC1 functions are now beginning to be defined, and they suggest that mTORC1 has a critical role in regulating the complex transcriptional activities required for ribosomal biogenesis. The mTORC1 pathway also interacts with epigenetic regulators required for modifying chromatin structure and function to control gene expression. Because altered nutrient states exert both individual and transgenerational phenotypic changes, mTORC1 signaling to chromatin effectors may have a significant role in mediating the effects of diet and nutrients on the epigenome. This article will discuss the recent inroads into the function of nuclear mTORC1 and its role in epigenetic and transcriptional regulation.
    DOI:  https://doi.org/10.1016/j.jmb.2018.10.008
  7. Arch Biochem Biophys. 2018 Oct 22. pii: S0003-9861(18)30736-7. [Epub ahead of print]
    Szeto HH, Liu S.
      It has been proposed that a loss of bioenergetic capacity of cells contributes to the progressive loss of biological function with age. Aging is associated with loss of mitochondrial cristae membranes and inhibition of ATP production. Despite the many approaches being pursued for improving mitochondrial function, none of them directly targets the electron transport chain to improve ATP production. Recent studies have brought attention to cardiolipin as a unique target for promoting mitochondrial efficiency. Cardiolipin is important for cristae curvatures and is necessary for optimal activity of the respiratory complexes and the assembly of supercomplexes. Here we describe the discovery of a class of cell-penetrating aromatic-cationic tetrapeptides that selectively target cardiolipin and increase coupling efficiency while reducing reactive oxygen species production. These compounds can rejuvenate mitochondrial bioenergetics, remodel mitochondrial cristae structure, repair cellular structure, and restore organ function during aging.
    Keywords:  Mitochondrial cristae; Mitochondrial dynamics; Respiratory supercomplexes; SS-31; Szeto-schiller peptides
    DOI:  https://doi.org/10.1016/j.abb.2018.10.013
  8. Genome Biol. 2018 Oct 25. 19(1): 174
    Ma X, Ezer D, Adryan B, Stevens TJ.
      BACKGROUND: Transcription factor (TF) binding to regulatory DNA sites is a key determinant of cell identity within multi-cellular organisms and has been studied extensively in relation to site affinity and chromatin modifications. There has been a strong focus on the inference of TF-gene regulatory networks and TF-TF physical interaction networks. Here, we present a third type of TF network, the spatial network of co-localized TF binding sites within the three-dimensional genome.RESULTS: Using published canonical Hi-C data and single-cell genome structures, we assess the spatial proximity of a genome-wide array of potential TF-TF co-localizations in human and mouse cell lines. For individual TFs, the abundance of occupied binding sites shows a positive correspondence with their clustering in three dimensions, and this is especially apparent for weak TF binding sites and at enhancer regions. An analysis between different TF proteins identifies significantly proximal pairs, which are enriched in reported physical interactions. Furthermore, clustering of different TFs based on proximity enrichment identifies two partially segregated co-localization sub-networks, involving different TFs in different cell types. Using data from both human lymphoblastoid cells and mouse embryonic stem cells, we find that these sub-networks are enriched within, but not exclusive to, different chromosome sub-compartments that have been identified previously in Hi-C data.
    CONCLUSIONS: This suggests that the association of TFs within spatial networks is closely coupled to gene regulatory networks. This applies to both differentiated and undifferentiated cells and is a potential causal link between lineage-specific TF binding and chromosome sub-compartment segregation.
    Keywords:  Chromatin conformational capture; Chromosome compartment; Genome structure; Hi-C; Nuclear organization; Proximity network; Transcription factor
    DOI:  https://doi.org/10.1186/s13059-018-1558-2
  9. Cancer Biol Ther. 2018 Oct 25. 1-11
    Wang SQ, Cui SX, Qu XJ.
      Although a mountain of papers have showed that metformin plays a role in inhibiting cancers, but the mechanism underpinning this has not yet fully elucidated. Herein, we used AOM/DSS model, the clinicopathological features are similar to those found in humans, to investigate the effects of metformin as well as combination with 5-FU in the prevention of colitis and colitis associated cancer (CAC). Oral metformin significantly inhibited DSS-induced ulcerative colitis and AOM/DSS-induced CAC. Metformin also ameliorated 5-FU-induced colorectal gastrointestinal symptoms in mice. Metformin combination with 5-FU strongly inhibited colorectal cancer. Metformin reduced levels of the NFκB signaling components p-IKKα/β, p-NFκB, p-IκBα in colorectal mucosal cells. Transmission electron microscopy analysis suggested that the inhibition of metformin on colitis and CAC might associate with its biological activity of protecting mitochondrial structures of colorectal epithelial cells. Further analysis by Mito Tracker Red staining assay indicated that metformin prevented H2O2-induced mitochondrial fission correlated with a decrease of mitochondrial perimeter. In addition, metformin increased the level of NDUFA9, a Q-module subunit required for complex I assembly, in colorectal epithelial cells. These observations of metformin in the inhibition of colitis and CAC might associate with its activity of activating the LKB1/AMPK pathway in colorectal epithelial cells. In conclusion, metformin inhibited colitis and CAC through protecting the mitochondrial structures of colorectal epithelial cells.
    Keywords:  Colitis; LKB1/AMPK pathway; Mitochondria; colorectal cancer; metformin
    DOI:  https://doi.org/10.1080/15384047.2018.1529108
  10. Nutrients. 2018 Oct 23. pii: E1564. [Epub ahead of print]10(11):
    Cruzat V, Macedo Rogero M, Noel Keane K, Curi R, Newsholme P.
      Glutamine is the most abundant and versatile amino acid in the body. In health and disease, the rate of glutamine consumption by immune cells is similar or greater than glucose. For instance, in vitro and in vivo studies have determined that glutamine is an essential nutrient for lymphocyte proliferation and cytokine production, macrophage phagocytic plus secretory activities, and neutrophil bacterial killing. Glutamine release to the circulation and availability is mainly controlled by key metabolic organs, such as the gut, liver, and skeletal muscles. During catabolic/hypercatabolic situations glutamine can become essential for metabolic function, but its availability may be compromised due to the impairment of homeostasis in the inter-tissue metabolism of amino acids. For this reason, glutamine is currently part of clinical nutrition supplementation protocols and/or recommended for immune suppressed individuals. However, in a wide range of catabolic/hypercatabolic situations (e.g., ill/critically ill, post-trauma, sepsis, exhausted athletes), it is currently difficult to determine whether glutamine supplementation (oral/enteral or parenteral) should be recommended based on the amino acid plasma/bloodstream concentration (also known as glutaminemia). Although the beneficial immune-based effects of glutamine supplementation are already established, many questions and evidence for positive in vivo outcomes still remain to be presented. Therefore, this paper provides an integrated review of how glutamine metabolism in key organs is important to cells of the immune system. We also discuss glutamine metabolism and action, and important issues related to the effects of glutamine supplementation in catabolic situations.
    Keywords:  amino acids; gut; leukocytes; liver; nutrition; skeletal muscle
    DOI:  https://doi.org/10.3390/nu10111564
  11. Curr Cancer Drug Targets. 2018 Oct 15.
    Wang G, Wang JJ, Guan R, Sun Y, Shi F, Gao J, Fu XL.
      Colorectal cancer is a heterogeneous group of diseases that result from the accumulation of different sets of genomic alterations, together with epigenomic alterations, and it is influenced by tumor-host interactions, leading to tumor cell growth and glycolytic imbalances. This review summarizes recent findings that involve multiple signaling molecules and downstream genes in the dysregulated glycolytic pathway. This paper further discusses the role of the dysregulated glycolytic pathway in the tumor initiation, progression and the concomitant systemic immunosuppression commonly observed in colorectal cancer patients. Moreover, the relationship between colorectal cancer cells and T cells, especially CD8+ T cells, is discussed, while different aspects of metabolic pathway regulation in cancer cell proliferation are comprehensively defined. Furthermore, this study elaborates on metabolism in colorectal cancer, specifically key metabolic modulators together with regulators, glycolytic enzymes, and glucose deprivation induced by tumor cells and how they inhibit T-cell glycolysis and immunogenic functions. Moreover, metabolic pathways that are integral to T cell function, differentiation, and activation are described. Selective metabolic inhibitors or immune-modulation agents targeting these pathways may be clinically useful to increase effector T cell responses for colorectal cancer treatment. However, there is a need to identify specific antigens using a cancer patient-personalized approach and combination strategies with other therapeutic agents to effectively target tumor metabolic pathways.
    DOI:  https://doi.org/10.2174/1568009618666181015150138
  12. Int J Mol Sci. 2018 Oct 22. pii: E3284. [Epub ahead of print]19(10):
    Singh BK, Sinha RA, Yen PM.
      The thyroid hormone plays a key role in energy and nutrient metabolisms in many tissues and regulates the transcription of key genes in metabolic pathways. It has long been believed that thyroid hormones (THs) exerted their effects primarily by binding to nuclear TH receptors (THRs) that are associated with conserved thyroid hormone response elements (TREs) located on the promoters of target genes. However, recent transcriptome and ChIP-Seq studies have challenged this conventional view as discordance was observed between TH-responsive genes and THR binding to DNA. While THR association with other transcription factors bound to DNA, TH activation of THRs to mediate effects that do not involve DNA-binding, or TH binding to proteins other than THRs have been invoked as potential mechanisms to explain this discrepancy, it appears that additional novel mechanisms may enable TH to regulate the mRNA expression. These include activation of transcription factors by SIRT1 via metabolic actions by TH, the post-translational modification of THR, the THR co-regulation of transcription with other nuclear receptors and transcription factors, and the microRNA (miR) control of RNA transcript expression to encode proteins involved in the cellular metabolism. Together, these novel mechanisms enlarge and diversify the panoply of metabolic genes that can be regulated by TH.
    Keywords:  SIRT1; estrogen-related receptor alpha (ERRα; forkhead box protein O1 (FOXO1); gene transcription; lipid metabolism; metabolism; microRNAs; microRNAs (miRs); non-alcoholic fatty liver disease (NAFLD); thyroid hormone
    DOI:  https://doi.org/10.3390/ijms19103284