bims-camemi 2018-08-26 papers

bims-camemi

Biomed News

on Mitochondrial metabolism in cancer

Issue of 2018–08–26
seven papers selected by
Christian Frezza, , University of Cambridge, MRC Cancer Unit

Acute oral administration of L-leucine upregulates slow-fiber- and mitochondria-related genes in skeletal muscle of rats.
Thioredoxin overexpression in both the cytosol and mitochondria accelerates age-related disease and shortens lifespan in male C57BL/6 mice.
Ensemble Properties of Bax Determine Its Function.
APD-Containing Cyclolipodepsipeptides Target Mitochondrial Function in Hypoxic Cancer Cells.
Variety is the spice of life: how to explore a redox-dependent heterogeneity in genomically identical cellular populations.
Microenvironmental control of glucose metabolism in tumors by regulation of pyruvate dehydrogenase.
A Role for De Novo Purine Metabolic Enzyme PAICS in Bladder Cancer Progression.

Nutr Res. 2018 Sep;pii: S0271-5317(18)30227-6. [Epub ahead of print]57 36-44

Acute oral administration of L-leucine upregulates slow-fiber- and mitochondria-related genes in skeletal muscle of rats.

Yoriko Sato, Yusuke Sato, Kodwo Amuzuah Obeng, Fumiaki Yoshizawa.

  Branched-chain amino acids promote both protein and mRNA synthesis through mechanistic target of rapamycin (mTOR) signaling. A previous report demonstrated that chronic branched-chain amino acid supplementation increased mitochondrial biogenesis in the skeletal muscle of middle-aged mice through activation of mTOR signaling. In this study, we hypothesized that the acute oral administration of L-leucine alone has the ability to alter the gene expression related to fiber type and metabolism in skeletal muscle of young rats through the activation of mTOR signaling. Although the gene expression of representative glycolytic enzymes (Hk2 and Eno3) was not altered, L-leucine administration (135 mg/100 g body weight) upregulated the expression of slow-fiber-related genes (Myh7, Myl3, and Tnni1) and a mitochondrial biogenesis-related gene (Ppargc1a) in the soleus and extensor digitorum longus muscles compared with the control. In addition, L-leucine treatment also upregulated the slow-fiber genes and mitochondrial gene expression in cultured C2C12 myotubes, whereas rapamycin inhibited the effects of L-leucine. However, L-alanine, L-phenylalanine, and L-valine treatment did not alter the expression of the fiber type- and metabolism-related genes as observed in L-leucine. Our results suggest that L-leucine may have the ability to alter skeletal muscle fiber type toward slow fiber and oxidative metabolism by upregulation of gene expression through mTOR signaling.

Keywords:  C2C12; L-Leucine; Metabolism; Muscle fiber type; Rat; Skeletal muscle; mTOR

DOI:  https://doi.org/10.1016/j.nutres.2018.05.006
Geroscience. 2018 Aug 18.

Thioredoxin overexpression in both the cytosol and mitochondria accelerates age-related disease and shortens lifespan in male C57BL/6 mice.

Geneva M Cunningham, Lisa C Flores, Madeline G Roman, Christie Cheng, Sara Dube, Colton Allen, Joseph M Valentine, Gene B Hubbard, Yidong Bai, Thomas L Saunders, Yuji Ikeno.

  To investigate the role of increased levels of thioredoxin (Trx) in both the cytosol (Trx1) and mitochondria (Trx2) on aging, we have conducted a study to examine survival and age-related diseases using male mice overexpressing Trx1 and Trx2 (TXNTg × TXN2Tg). Our study demonstrated that the upregulation of Trx in both the cytosol and mitochondria in male TXNTg × TXN2Tg C57BL/6 mice resulted in a significantly shorter lifespan compared to wild-type (WT) mice. Cross-sectional pathology data showed a slightly higher incidence of neoplastic diseases in TXNTg × TXN2Tg mice than WT mice. The incidence of lymphoma, a major neoplastic disease in C57BL/6 mice, was slightly higher in TXNTg × TXN2Tg mice than in WT mice, and more importantly, the severity of lymphoma was significantly higher in TXNTg × TXN2Tg mice compared to WT mice. Furthermore, the total number of histopathological changes in the whole body (disease burden) was significantly higher in TXNTg × TXN2Tg mice compared to WT mice. Therefore, our study suggests that overexpression of Trx in both the cytosol and mitochondria resulted in deleterious effects on aging and accelerated the development of age-related diseases, especially cancer, in male C57BL/6 mice.

Keywords:  Aging; Cancer; Oxidative stress; Thioredoxin; Transgenic mouse

DOI:  https://doi.org/10.1007/s11357-018-0039-6
Structure. 2018 Aug 04. pii: S0969-2126(18)30252-1. [Epub ahead of print]

Ensemble Properties of Bax Determine Its Function.

Adeline Y Robin, Sweta Iyer, Richard W Birkinshaw, Jarrod Sandow, Ahmad Wardak, Cindy S Luo, Melissa Shi, Andrew I Webb, Peter E Czabotar, Ruth M Kluck, Peter M Colman.

  BAX and BAK are essential mediators of intrinsic apoptosis that permeabilize the mitochondrial outer membrane. BAX activation requires its translocation from cytosol to mitochondria where conformational changes cause its oligomerization. To better understand the critical step of translocation, we examined its blockade by mutation near the C terminus (P168G) or by antibody binding near the N terminus. Similarities in the crystal structures of wild-type and BAX P168G but significant other differences suggest that cytosolic BAX exists as an ensemble of conformers, and that the distribution of conformers within the ensemble determines the different functions of wild-type and mutant proteins. We also describe the structure of BAX in complex with an antibody, 3C10, that inhibits cytosolic BAX by limiting exposure of the membrane-associating helix α9, as does the P168G mutation. Our data for both means of BAX inhibition argue for an allosteric model of BAX regulation that derives from properties of the ensemble of conformers.

Keywords:  BAX; allostery; apoptosis; translocation

DOI:  https://doi.org/10.1016/j.str.2018.07.006
Cell Chem Biol. 2018 Aug 09. pii: S2451-9456(18)30262-9. [Epub ahead of print]

APD-Containing Cyclolipodepsipeptides Target Mitochondrial Function in Hypoxic Cancer Cells.

Kristian Mark Jacobsen, Nikolaj Lilholm Villadsen, Thomas Tørring, Camilla Bak Nielsen, Trine Salomón, Morten Muhlig Nielsen, Michail Tsakos, Christian Sibbersen, Carsten Scavenius, Rikke Nielsen, Erik Ilsø Christensen, Paula Fernandez Guerra, Peter Bross, Jakob Skou Pedersen, Jan Johannes Enghild, Mogens Johannsen, Jørgen Frøkiær, Jens Overgaard, Michael R Horsman, Morten Busk, Thomas B Poulsen.

  The natural product family of macrocyclic lipodepsipeptides containing the 4-amido-2,4-pentadienoate functionality possesses intriguing cytotoxic selectivity toward hypoxic cancer cells. These subpopulations of cancer cells display increased metastatic potential and resistance to chemo- and radiotherapy. In this paper, we present studies on the mechanism of action of these natural products in hypoxic cancer cells and show that this involves rapid and hypoxia-selective collapse of mitochondrial integrity and function. These events drive a regulated cell death process that potentially could function as a powerful tool in the fight against chemo- and radiotherapy-resistant cancer cells. Toward that end, we demonstrate activity in two different mouse tumor models.

Keywords:  ROS; cell death; mitochondria; mode of action; natural products; tumor hypoxia

DOI:  https://doi.org/10.1016/j.chembiol.2018.07.010
Curr Genet. 2018 Aug 18.

Variety is the spice of life: how to explore a redox-dependent heterogeneity in genomically identical cellular populations.

Meytal Radzinski, Dana Reichmann.

  Cellular heterogeneity is a widespread phenomenon, existing across organisms and serving a crucial role in evolution and cell survival. Genetically identical cells may as a result present in a variety of forms with different gene and protein expressions, as well as oxidation level. As a result, a wide range of methodologies and techniques for dissecting different types of genetic, proteomic, and phenotypic heterogeneous traits have emerged in recent years in an effort to better understand how diversity exists within a single population and its effects therein. A key area of interest seeks to establish the ways in which cellular heterogeneity and aging processes interact with each other. Here, we discuss recent developments in defining cellular heterogeneity, specifically focusing on redox-dependent heterogeneity, its characterization, quantification, and behavior. We further expand on potential applications of a cell sorting-based methodology for distinguishing between cells harboring different redox statuses. As an example, we use organelle-specific fluorescence protein-based probes to examine the crosstalk between cytosol and mitochondria in a yeast strain lacking glutathione reductase. Together, these may have wide-reaching implications for future research into redox-associated factors, as well as mechanisms of redox-dependent heterogeneity and its influence on organelles and the cell at large.

Keywords:  Cell-to-cell diversity; Heterogeneity; Redox biology; Redox sensors; glr1; roGFP

DOI:  https://doi.org/10.1007/s00294-018-0878-9
Int J Cancer. 2018 Aug 19.

Microenvironmental control of glucose metabolism in tumors by regulation of pyruvate dehydrogenase.

Tereza Golias, Martin Kery, Silvia Radenkovic, Ioanna Papandreou.

  During malignant progression cancer cells undergo a series of changes, which promote their survival, invasiveness and metastatic process. One of them is a change in glucose metabolism. Unlike normal cells, which mostly rely on the tricarboxylic acid cycle (TCA), many cancer types rely on glycolysis. Pyruvate dehydrogenase complex (PDC) is the gatekeeper enzyme between these two pathways and is responsible for converting pyruvate to acetyl-CoA, which can then be processed further in the TCA cycle. Its activity is regulated by PDP (pyruvate dehydrogenase phosphatases) and PDHK (pyruvate dehydrogenase kinases). Pyruvate dehydrogenase kinase exists in 4 tissue specific isoforms (PDHK1-4), the activities of which are regulated by different factors, including hormones, hypoxia, and nutrients. PDHK1 and PDHK3 are active in the hypoxic tumor microenvironment and inhibit PDC, resulting in a decrease of mitochondrial function and activation of the glycolytic pathway. High PDHK1/3 expression is associated with worse prognosis in patients, which makes them a promising target for cancer therapy. However, a better understanding of PDC's enzymatic regulation in vivo and of the mechanisms of PDHK-mediated malignant progression is necessary for the design of better PDHK inhibitors and the selection of patients most likely to benefit from such inhibitors. This article is protected by copyright. All rights reserved.

Keywords:  glycolytic cancer metabolism; hypoxia; pyruvate dehydrogenase complex; pyruvate dehydrogenase kinase

DOI:  https://doi.org/10.1002/ijc.31812
Neoplasia. 2018 Aug 14. pii: S1476-5586(18)30184-2. [Epub ahead of print]20(9): 894-904

A Role for De Novo Purine Metabolic Enzyme PAICS in Bladder Cancer Progression.

Balabhadrapatruni V S K Chakravarthi, Maria Del Carmen Rodriguez Pena, Sumit Agarwal, Darshan S Chandrashekar, Sai Akshaya Hodigere Balasubramanya, Fayez J Jabboure, Andres Matoso, Trinity J Bivalacqua, Katayoon Rezaei, Alcides Chaux, William E Grizzle, Guru Sonpavde, Jennifer Gordetsky, George J Netto, Sooryanarayana Varambally.

Genomic and transcriptome sequencing of bladder cancer (BLCA) has identified multiple molecular alterations during cancer progression. Many of these identified genetic and epigenetic changes play a role in the progression of this disease. Studies have identified molecular subtypes in muscle-invasive bladder cancer (MIBC) with different sensitivities to frontline therapy suggesting the heterogeneity in these tumors and the importance of molecular characterization of MIBC to provide effective treatment. Specifically, it has become increasingly evident, as demonstrated by The Cancer Genome Atlas project, that metabolic enzymes are commonly dysregulated in BLCA. Elevated expression of multiple metabolic enzymes is due to the increased demand from rapidly proliferating BLCA cells requiring extensive nucleotide synthesis. Cancer cells utilize the de novo purine and pyrimidine biosynthetic pathway as a source of their nucleotide needs. In this study, we show that phosphoribosyl aminoimidazole succinocarboxamide synthetase (PAICS), an enzyme involved in de novo purine biosynthetic pathway, is significantly overexpressed in BLCA. Immunohistochemical staining of paraffin-embedded tissue sections showed that PAICS is overexpressed in MIBC. Furthermore, we found that tumor suppressor miR-128 negatively regulated PAICS expression by binding to its 3'-untranslated region. We also found that PAICS induces EMT by positively regulating SNAI1 and by a reduction in E-cadherin expression. Additionally, our in vitro functional studies and in vivo chicken chorioallantoic membrane assay show that PAICS plays a critical role in BLCA cell proliferation, invasion, and tumor growth. Collectively, our data suggest that targeting PAICS may provide a therapeutic option in BLCA.

DOI: https://doi.org/10.1016/j.neo.2018.07.006