title: Different mtDNA mutations modify tumor progression in dependence of the degree of respiratory complex I impairment.
abstract: Mitochondrial DNA mutations are currently investigated as modifying factors impinging on tumor growth and aggressiveness, having been found in virtually all cancer types and most commonly affecting genes encoding mitochondrial complex I (CI) subunits. However, it is still unclear whether they exert a pro- or anti-tumorigenic effect. We here analyzed the impact of three homoplasmic mtDNA mutations (m.3460G>A/MT-ND1, m.3571insC/MT-ND1 and m.3243A>G/MT-TL1) on osteosarcoma progression, chosen since they induce different degrees of oxidative phosphorylation impairment. In fact, the m.3460G>A/MT-ND1 mutation caused only a reduction in CI activity, whereas the m.3571insC/MT-ND1 and the m.3243A>G/MT-TL1 mutations induced a severe structural and functional CI alteration. As a consequence, this severe CI dysfunction determined an energetic defect associated with a compensatory increase in glycolytic metabolism and AMP-activated protein kinase activation. Osteosarcoma cells carrying such marked CI impairment displayed a reduced tumorigenic potential both in vitro and in vivo, when compared with cells with mild CI dysfunction, suggesting that mtDNA mutations may display diverse impact on tumorigenic potential depending on the type and severity of the resulting oxidative phosphorylation dysfunction. The modulation of tumor growth was independent from reactive oxygen species production but correlated with hypoxia-inducible factor 1α stabilization, indicating that structural and functional integrity of CI and oxidative phosphorylation are required for hypoxic adaptation and tumor progression.
authors.affiliation: Dipartimento di Farmacia e Biotecnologie (FABIT).
authors.forename: Luisa
authors.initials: L
authors.lastname: Iommarini
authors.forename: Ivana
authors.initials: I
authors.lastname: Kurelac
authors.forename: Mariantonietta
authors.initials: M
authors.lastname: Capristo
authors.forename: Maria Antonietta
authors.initials: MA
authors.lastname: Calvaruso
authors.forename: Valentina
authors.initials: V
authors.lastname: Giorgio
authors.forename: Christian
authors.initials: C
authors.lastname: Bergamini
authors.forename: Anna
authors.initials: A
authors.lastname: Ghelli
authors.forename: Patrizia
authors.initials: P
authors.lastname: Nanni
authors.forename: Carla
authors.initials: C
authors.lastname: De Giovanni
authors.forename: Valerio
authors.initials: V
authors.lastname: Carelli
authors.forename: Romana
authors.initials: R
authors.lastname: Fato
authors.forename: Pier Luigi
authors.initials: PL
authors.lastname: Lollini
authors.forename: Michela
authors.initials: M
authors.lastname: Rugolo
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Gasparre
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Porcelli
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D045744:Cell Line, Tumor; D004272:DNA, Mitochondrial / Q000235:genetics*; D018450:Disease Progression; D042967:Electron Transport Complex I / Q000235:genetics* / Q000378:metabolism; D004734:Energy Metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D016254:Mutagenesis, Insertional; D009245:NADH Dehydrogenase / Q000235:genetics / Q000378:metabolism*; D012516:Osteosarcoma / Q000235:genetics* / Q000473:pathology; D010085:Oxidative Phosphorylation; D017354:Point Mutation; D012343:RNA, Transfer / Q000235:genetics*; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D055372:AMP-Activated Protein Kinases; D004272:DNA, Mitochondrial; D042967:Electron Transport Complex I; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D024101:Mitochondrial Proteins; D009245:NADH Dehydrogenase; D012343:RNA, Transfer; D017382:Reactive Oxygen Species; C507225:MT-ND6 protein, human; C515075:NADH dehydrogenase subunit 1, human