Different mtDNA mutations modify tumor progression in dependence of the degree of respiratory complex I impairment

Luisa Iommarini, Ivana Kurelac, Mariantonietta Capristo, Maria Antonietta Calvaruso, Valentina Giorgio, Christian Bergamini, Anna Ghelli, Patrizia Nanni, Carla De giovanni, Valerio Carelli, Romana Fato, Pier Luigi Lollini, Michela Rugolo, Giuseppe Gasparre, Anna Maria Porcelli

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Article numberddt533
Pages (from-to)1453-1466
Number of pages14
JournalHuman Molecular Genetics
Volume23
Issue number6
DOIs
Publication statusPublished - Mar 2014

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Molecular Biology

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