title: OXPHOS dysfunction regulates integrin-β1 modifications and enhances cell motility and migration.
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 than WT cybrids, 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.
authors.affiliation: Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal, Medical Faculty and.
authors.forename: Joana B
authors.initials: JB
authors.lastname: Nunes
authors.affiliation: Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal.
authors.forename: Joana
authors.initials: J
authors.lastname: Peixoto
authors.affiliation: Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal, Medical Faculty and.
authors.forename: Paula
authors.initials: P
authors.lastname: Soares
authors.affiliation: Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal, Medical Faculty and.
authors.forename: Valdemar
authors.initials: V
authors.lastname: Maximo
authors.affiliation: Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal.
authors.forename: Sandra
authors.initials: S
authors.lastname: Carvalho
authors.affiliation: Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal.
authors.forename: Salome S
authors.initials: SS
authors.lastname: Pinho
authors.affiliation: Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal.
authors.forename: Andre F
authors.initials: AF
authors.lastname: Vieira
authors.affiliation: Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal, Medical Faculty and.
authors.forename: Joana
authors.initials: J
authors.lastname: Paredes
authors.affiliation: Center for Neuroscience and Cell Biology (CNC) and Faculty of Medicine, University of Coimbra-Pólo III, 3000-354 Coimbra, Portugal, Institute for Interdisciplinary Research (IIIUC), University of Coimbra, 3030-789 Coimbra, Portugal.
authors.forename: Ana C
authors.initials: AC
authors.lastname: Rego
authors.affiliation: Center for Neuroscience and Cell Biology (CNC) and Institute for Interdisciplinary Research (IIIUC), University of Coimbra, 3030-789 Coimbra, Portugal.
authors.forename: Ildete L
authors.initials: IL
authors.lastname: Ferreira
authors.affiliation: b.IMAGE-Bioimaging Centre for Biomaterials and Regenerative Therapies, Institute of Biomedical Engineering (INEB), University of Porto, Porto, Portugal.
authors.forename: Maria
authors.initials: M
authors.lastname: Gomez-Lazaro
authors.affiliation: Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal, Medical Faculty and Centro Hospitalar de S. João, Porto, Portugal.
authors.forename: Manuel
authors.initials: M
authors.lastname: Sobrinho-Simoes
authors.affiliation: Department of Genetics, Department of Pathology and Department of Environmental Health, Center for Free Radical Biology, Center for Aging and UAB Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, Alabama and Birmingham Veterans Affairs Medical Center, Birmingham, AL 35294, USA.
authors.forename: Keshav K
authors.initials: KK
authors.lastname: Singh
authors.affiliation: Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal, Medical Faculty and jlima@ipatimup.pt.
authors.forename: Jorge
authors.initials: J
authors.lastname: Lima
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement; D006031:Glycosylation; D006801:Humans; D019012:Integrin beta1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D008928:Mitochondria / Q000378:metabolism*; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism*; D010085:Oxidative Phosphorylation; D010101:Oxygen Consumption; D012356:RNA, Transfer, Leu / Q000235:genetics / Q000378:metabolism
chemical_list: D019012:Integrin beta1; D012356:RNA, Transfer, Leu