title: Enhanced tumorigenicity by mitochondrial DNA mild mutations.
abstract: To understand how mitochondria are involved in malignant transformation we have generated a collection of transmitochondrial cybrid cell lines on the same nuclear background (143B) but with mutant mitochondrial DNA (mtDNA) variants with different degrees of pathogenicity. These include the severe mutation in the tRNALys gene, m.8363G>A, and the three milder yet prevalent Leber's hereditary optic neuropathy (LHON) mutations in the MT-ND1 (m.3460G>A), MT-ND4 (m.11778G>A) and MT-ND6 (m.14484T>C) mitochondrial genes. We found that 143B ρ0 cells devoid of mtDNA and cybrids harboring wild type mtDNA or that causing severe mitochondrial dysfunction do not produce tumors when injected in nude mice. By contrast cybrids containing mild mutant mtDNAs exhibit different tumorigenic capacities, depending on OXPHOS dysfunction.The differences in tumorigenicity correlate with an enhanced resistance to apoptosis and high levels of NOX expression. However, the final capacity of the different cybrid cell lines to generate tumors is most likely a consequence of a complex array of pro-oncogenic and anti-oncogenic factors associated with mitochondrial dysfunction.Our results demonstrate the essential role of mtDNA in tumorigenesis and explain the numerous and varied mtDNA mutations found in human tumors, most of which give rise to mild mitochondrial dysfunction.
authors.affiliation: Instituto de Investigaciones Biomédicas "Alberto Sols", Consejo Superior de Investigaciones Científicas (CSIC), Universidad Autónoma de Madrid (UAM), Madrid, Spain.|Departamento de Bioquímica and Centro de Investigación Biomédica en Red en Enfermedades Raras (CIBERER), Facultad de Medicina, UAM, Madrid, Spain.|Instituto de Investigación Sanitaria Hospital 12 de Octubre (i+12), Madrid, Spain.
authors.forename: Alberto
authors.initials: A
authors.lastname: Cruz-Bermúdez
authors.affiliation: Instituto de Investigaciones Biomédicas "Alberto Sols", Consejo Superior de Investigaciones Científicas (CSIC), Universidad Autónoma de Madrid (UAM), Madrid, Spain.
authors.forename: Carmen G
authors.initials: CG
authors.lastname: Vallejo
authors.affiliation: Instituto de Investigaciones Biomédicas "Alberto Sols", Consejo Superior de Investigaciones Científicas (CSIC), Universidad Autónoma de Madrid (UAM), Madrid, Spain.|Departamento de Bioquímica and Centro de Investigación Biomédica en Red en Enfermedades Raras (CIBERER), Facultad de Medicina, UAM, Madrid, Spain.
authors.forename: Ramiro J
authors.initials: RJ
authors.lastname: Vicente-Blanco
authors.affiliation: Instituto de Investigaciones Biomédicas "Alberto Sols", Consejo Superior de Investigaciones Científicas (CSIC), Universidad Autónoma de Madrid (UAM), Madrid, Spain.|Departamento de Bioquímica and Centro de Investigación Biomédica en Red en Enfermedades Raras (CIBERER), Facultad de Medicina, UAM, Madrid, Spain.|Instituto de Investigación Sanitaria Hospital 12 de Octubre (i+12), Madrid, Spain.
authors.forename: María Esther
authors.initials: ME
authors.lastname: Gallardo
authors.affiliation: Instituto de Investigaciones Biomédicas "Alberto Sols", Consejo Superior de Investigaciones Científicas (CSIC), Universidad Autónoma de Madrid (UAM), Madrid, Spain.|Departamento de Bioquímica and Centro de Investigación Biomédica en Red en Enfermedades Raras (CIBERER), Facultad de Medicina, UAM, Madrid, Spain.|Instituto de Investigación Sanitaria Hospital 12 de Octubre (i+12), Madrid, Spain.
authors.forename: Miguel Ángel
authors.initials: MÁ
authors.lastname: Fernández-Moreno
authors.affiliation: Instituto de Investigaciones Biomédicas "Alberto Sols", Consejo Superior de Investigaciones Científicas (CSIC), Universidad Autónoma de Madrid (UAM), Madrid, Spain.|Instituto de Investigación Hospital Universitario La Paz (IdiPAZ), Madrid, Spain.
authors.forename: Miguel
authors.initials: M
authors.lastname: Quintanilla
authors.affiliation: Instituto de Investigaciones Biomédicas "Alberto Sols", Consejo Superior de Investigaciones Científicas (CSIC), Universidad Autónoma de Madrid (UAM), Madrid, Spain.|Departamento de Bioquímica and Centro de Investigación Biomédica en Red en Enfermedades Raras (CIBERER), Facultad de Medicina, UAM, Madrid, Spain.|Instituto de Investigación Sanitaria Hospital 12 de Octubre (i+12), Madrid, Spain.
authors.forename: Rafael
authors.initials: R
authors.lastname: Garesse
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000235:genetics*; D045744:Cell Line, Tumor; D004272:DNA, Mitochondrial / Q000235:genetics* / Q000378:metabolism; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D010101:Oxygen Consumption; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D004272:DNA, Mitochondrial; D017382:Reactive Oxygen Species
keywords: LHON; cancer; mitochondria; mtDNA mutations; retrograde signaling