Identification and functional prediction of mitochondrial complex III and IV mutations associated with glioblastoma

Background: Glioblastoma (GBM) is the most common primary brain tumor in adults, with a dismal prognosis. Treatment is hampered by GBM's unique biology, including differential cell response to therapy. Although several mitochondrial abnormalities have been identified, how mitochondrial DNA (mtDNA) mutations contribute to GBM biology and therapeutic response remains poorly described. We sought to determine the spectrum of functional complex III and IV mtDNA mutations in GBM. Methods: The complete mitochondrial genomes of 10 GBM cell lines were obtained using next-generation sequencing and combined with another set obtained from 32 GBM tissues. Three-dimensional structural mapping and analysis of all the nonsynonymous mutations identified in complex III and IV proteins was then performed to investigate functional importance. Results: Over 200 mutations were identified in the mtDNAs, including a significant proportion with very low mutational loads. Twenty-five were nonsynonymous mutations in complex III and IV, 9 of which were predicted to be functional and affect mitochondrial respiratory chain activity. Most of the functional candidates were GBM specific and not found in the general population, and 2 were present in the germ-line. Patient-specific maps reveal that 43% of tumors carry at least one functional candidate. Conclusions: We reveal that the spectrum of GBM-associated mtDNA mutations is wider than previously thought, as well as novel structural-functional links between specific mtDNA mutations, abnormal mitochondria, and the biology of GBM. These results could provide tangible new prognostic indicators as well as targets with which to guide the development of patient-specific mitochondrially mediated chemotherapeutic approaches.

Citation

Rhiannon E. Lloyd, Kathleen Keatley, D. Timothy J. Littlewood, Brigitte Meunier, William V. Holt, Qian An, Samantha C. Higgins, Stavros Polyzoidis, Katie F. Stephenson, Keyoumars Ashkan, Helen L. Fillmore, Geoffrey J. Pilkington, John E. McGeehan, Identification and functional prediction of mitochondrial complex III and IV mutations associated with glioblastoma, Neuro-Oncology, Volume 17, Issue 7, July 2015, Pages 942–952

Type

Journal Article

Item Description

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
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ISSN

1522-8517

EISSN

1523-5866