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Integrated approach reveals role of mitochondrial germ-line mutation F18L in respiratory chain, oxidative alterations, drug sensitivity, and patient prognosis in glioblastoma

Research output: Contribution to journalArticlepeer-review

  • Kathleen Keatley
  • Samuel Stromei-Cleroux
  • Tammy Wiltshire
  • Nina Katja Maria Rajala
  • Gary David Burton
  • William V. Holt
  • D. Timothy J. Littlewood
  • Andrew G. Briscoe
  • Josephine Jung
  • Keyoumars Ashkan
  • Simon J. Heales
  • Geoff Pilkington
  • Brigitte Meunier
  • Professor John McGeehan
  • Iain Hargreaves
  • Dr Rhiannon Lloyd
Glioblastoma is the most common and malignant primary brain tumour in adults, with a dismal prognosis. This is partly due to considerable inter- and intra-tumour heterogeneity. Changes in the cellular energy-producing mitochondrial respiratory chain complex (MRC) activities are a hallmark of glioblastoma relative to the normal brain, and associate with differential survival outcomes. Targeting MRC complexes with drugs can also facilitate anti-glioblastoma activity. Whether mutations in the mitochondrial DNA (mtDNA) that encodes several components of the MRC contribute to these phenomena, remains underexplored. We identified a germ-line mtDNA mutation (T14798C), enriched in glioblastoma relative to healthy controls, that causes an amino acid substitution F18L within the core mtDNA-encoded cytochrome b subunit of MRC complex III. F18L is predicted to alter corresponding complex III activity, and sensitivity to complex III-targeting drugs. This could in turn alter reactive oxygen species (ROS) production, cell behaviour and, consequently, patient outcomes. Here we show that, despite a heterogeneous mitochondrial background in adult glioblastoma patient biopsy-derived cell cultures, the F18L substitution associates with alterations in individual MRC complex activities, in particular a 75% increase in MRC complex II-III activity, and a 34% reduction in CoQ10,the natural substrate for MRC complex III, levels. Downstream characterisation of an F18L-carrier revealed an 87% increase in intra-cellular ROS, an altered cellular distribution of mitochondrial-specific ROS, and a 64% increased sensitivity to clomipramine, a repurposed MRC complex III-targeting drug. In patients, F18L-carriers that received the current standard of care treatment had a poorer prognosis than non-carriers (373 days vs. 415 days, respectively). Single germ-line mitochondrial mutations could predispose individuals to differential prognoses, and sensitivity to mitochondrial targeted drugs. Thus, F18L, which is present in blood could serve as a useful non-invasive biomarker for the stratification of patients into prognostically relevant groups, one of which requires a lower dose of clomipramine to achieve clinical effect, thus minimising side-effects.
Original languageEnglish
Article number3364
JournalInternational Journal of Molecular Sciences
Issue number13
Publication statusPublished - 9 Jul 2019


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