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Human Molecular GeneticsVolume 24, Issue 7, 28 October 2014, Pages 1977-1990

OXPHOS dysfunction regulates integrin-β1 modifications and enhances cell motility and migration(Article)(Open Access)

  • Nunes, J.B.,
  • Peixoto, J.,
  • Soares, P.,
  • Maximo, V.,
  • Carvalho, S.,
  • Pinho, S.S.,
  • Vieira, A.F.,
  • Paredes, J.,
  • Rego, A.C.,
  • Ferreira, I.L.,
  • Gomez-Lazaro, M.,
  • Sobrinho-Simoes, M.,
  • Singh, K.K.,
  • Lima, J.
  • View Correspondence (jump link)
  • aInstitute of Molecular Pathology and Immunology, The University of Porto (IPATIMUP), Porto, Portugal
  • bMedical Faculty, University of Porto, Porto, Portugal
  • cIMAGE-Bioimaging Centre for Biomaterials and Regenerative Therapies, Institute of Biomedical Engineering (INEB), University of Porto, Porto, Portugal
  • dCenter for Neuroscience and Cell Biology (CNC), University of Coimbra-Pólo III, Coimbra, 3000-354, Portugal
  • eFaculty of Medicine, University of Coimbra-Pólo III, Coimbra, 3000-354, Portugal
  • fInstitute for Interdisciplinary Research (IIIUC), University of Coimbra, Coimbra, 3030-789, Portugal
  • gCentro Hospitalar de S. João, Porto, Portugal
  • hDepartment of Genetics, University of Alabama at Birmingham, Birmingham, AL 35294, United States
  • iDepartment of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, United States
  • jDepartment of Environmental Health, Center for Free Radical Biology, Center for Aging and UAB Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham Veterans Affairs Medical Center, Birmingham, AL 35294, United States

Abstract

Mitochondria are central organelles for cellular metabolism. In cancer cells, mitochondrial oxidative phosphorylation (OXPHOS) dysfunction has been shown to promote migration, invasion, metastization and apoptosis resistance. With the purpose of analysing the effects of OXPHOS dysfunction in cancer cells and the molecular players involved, we generated cybrid cell lines harbouring either wild-type (WT) or mutant mitochondrial DNA (mtDNA) [tRNAmut cybrids, which harbour the pathogenic A3243T mutation in the leucine transfer RNA gene (tRNAleu)]. tRNAmut cybrids exhibited lower oxygen consumption and higher glucose consumption and lactate production than WT cybrids. tRNAmut cybrids displayed increased motility and migration capacities, which were associated with altered integrin-β1 N-glycosylation, in particular with higher levels of β-1,6- N-acetylglucosamine (GlcNAc) branched N-glycans. This integrin-β1 N-glycosylation pattern was correlated with higher levels of membrane-bound integrin-β1 and also with increased binding to fibronectin. When cultured in vitro, tRNAmut cybrids presented lower growth rate thanWTcybrids, however, when injected in nude mice, tRNAmut cybrids produced larger tumours and showed higher metastatic potential than WT cybrids. We conclude that mtDNA-driven OXPHOS dysfunction correlates with increased motility and migration capacities, through a mechanism that may involve the cross talk between cancer cell mitochondria and the extracellular matrix. © The Author 2014. Published by Oxford University Press.

Indexed keywords

EMTREE drug terms:beta 1,6 n acetylglucosaminebeta1 integrincollagen type 1collagen type 4fibronectinglucoseglycanlactic acidleucine transfer RNAmitochondrial DNAmitochondrial proteinn acetylglucosamineoxygenphenforminunclassified drugvery late activation antigen 5beta1 integrinleucine transfer RNA
EMTREE medical terms:animal experimentanimal modelanimal tissueapoptosisArticlecancer cellcancer growthcarcinogenesiscarcinogenicitycell adhesioncell growthcell migrationcell motilitycontrolled studycybriddisorders of mitochondrial functionsextracellular matrixhumanhuman cellin vitro studylung metastasismetastasis potentialmousenonhumanoxidative phosphorylationpoint mutationpriority journalprotein bindingprotein expressionprotein glycosylationprotein modificationRNA genetumor microenvironmentWestern blottingwild typeanimalcell motionchemistrygeneticsglycosylationmetabolismmitochondrionneoplasmnude mouseoxygen consumptiontumor cell line
Species Index:Mus musculus
MeSH:AnimalsAntigens, CD29Cell Line, TumorCell MovementGlycosylationHumansMiceMice, NudeMitochondriaNeoplasmsOxidative PhosphorylationOxygen ConsumptionRNA, Transfer, Leu

Chemicals and CAS Registry Numbers:

fibronectin, 86088-83-7; glucose, 50-99-7, 84778-64-3; lactic acid, 113-21-3, 50-21-5; n acetylglucosamine, 7512-17-6; oxygen, 7782-44-7; phenformin, 114-86-3, 834-28-6;

Antigens, CD29; RNA, Transfer, Leu

Funding details

Funding sponsor Funding number Acronym
Ministry of Science, Technology and Space
Fundação para a Ciência e a Tecnologia
See opportunities		SFRH/BD/90124/2012
Fundação para a Ciência e a Tecnologia
See opportunities
1I01BX001716

  • 1

    This work was supported by Fundação para a Ciência e Tecnolo-gia through PhD grant SFRH/BD/90124/2012 (J.B.N), Program Ciên-cia 2007 (V.M.) and Program Ciência 2008 (J.L.). Further funding was obtained from the project ‘Microenvironment, metabolism and cancer’ based at IPATIMUP and partially supported by Progra-ma Operacional Regional do Norte (ON. 2—O Novo Norte), under the Quadro de Referência Estratégico Nacional (QREN) and through the Fundo Europeu de Desenvolvimento Regional (FEDER). IPATIMUP is an Associate Laboratory of the Portuguese Ministry of Science, Technology and Higher Education that is partially supported by the FCT. Research in KKS Laboratory is supported by Veterans Administration grant 1I01BX001716.

  • ISSN: 09646906
  • CODEN: HMGEE
  • Source Type: Journal
  • Original language: English
  • DOI: 10.1093/hmg/ddu612
  • PubMed ID: 25504047
  • Document Type: Article
  • Publisher: Oxford University Press

  Lima, J.; IPATIMUP, Rua Dr Roberto Frias s/n, Porto, Portugal;
© Copyright 2018 Elsevier B.V., All rights reserved.

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