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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

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 gliobla...

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Autores principales: Keatley, Kathleen, Stromei-Cleroux, Samuel, Wiltshire, Tammy, Rajala, Nina, Burton, Gary, Holt, William V., Littlewood, D. Timothy J., Briscoe, Andrew G., Jung, Josephine, Ashkan, Keyoumars, Heales, Simon J., Pilkington, Geoffrey J., Meunier, Brigitte, McGeehan, John E., Hargreaves, Iain P., McGeehan, Rhiannon E.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6651022/
https://www.ncbi.nlm.nih.gov/pubmed/31323957
http://dx.doi.org/10.3390/ijms20133364
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author Keatley, Kathleen
Stromei-Cleroux, Samuel
Wiltshire, Tammy
Rajala, Nina
Burton, Gary
Holt, William V.
Littlewood, D. Timothy J.
Briscoe, Andrew G.
Jung, Josephine
Ashkan, Keyoumars
Heales, Simon J.
Pilkington, Geoffrey J.
Meunier, Brigitte
McGeehan, John E.
Hargreaves, Iain P.
McGeehan, Rhiannon E.
author_facet Keatley, Kathleen
Stromei-Cleroux, Samuel
Wiltshire, Tammy
Rajala, Nina
Burton, Gary
Holt, William V.
Littlewood, D. Timothy J.
Briscoe, Andrew G.
Jung, Josephine
Ashkan, Keyoumars
Heales, Simon J.
Pilkington, Geoffrey J.
Meunier, Brigitte
McGeehan, John E.
Hargreaves, Iain P.
McGeehan, Rhiannon E.
author_sort Keatley, Kathleen
collection PubMed
description 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 encode several components of the MRC contribute to these phenomena remains underexplored. We identified a germ-line mtDNA mutation (m. 14798T > C), 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.
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spelling pubmed-66510222019-08-07 Integrated Approach Reveals Role of Mitochondrial Germ-Line Mutation F18L in Respiratory Chain, Oxidative Alterations, Drug Sensitivity, and Patient Prognosis in Glioblastoma Keatley, Kathleen Stromei-Cleroux, Samuel Wiltshire, Tammy Rajala, Nina Burton, Gary Holt, William V. Littlewood, D. Timothy J. Briscoe, Andrew G. Jung, Josephine Ashkan, Keyoumars Heales, Simon J. Pilkington, Geoffrey J. Meunier, Brigitte McGeehan, John E. Hargreaves, Iain P. McGeehan, Rhiannon E. Int J Mol Sci Article 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 encode several components of the MRC contribute to these phenomena remains underexplored. We identified a germ-line mtDNA mutation (m. 14798T > C), 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. MDPI 2019-07-09 /pmc/articles/PMC6651022/ /pubmed/31323957 http://dx.doi.org/10.3390/ijms20133364 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Keatley, Kathleen
Stromei-Cleroux, Samuel
Wiltshire, Tammy
Rajala, Nina
Burton, Gary
Holt, William V.
Littlewood, D. Timothy J.
Briscoe, Andrew G.
Jung, Josephine
Ashkan, Keyoumars
Heales, Simon J.
Pilkington, Geoffrey J.
Meunier, Brigitte
McGeehan, John E.
Hargreaves, Iain P.
McGeehan, Rhiannon E.
Integrated Approach Reveals Role of Mitochondrial Germ-Line Mutation F18L in Respiratory Chain, Oxidative Alterations, Drug Sensitivity, and Patient Prognosis in Glioblastoma
title Integrated Approach Reveals Role of Mitochondrial Germ-Line Mutation F18L in Respiratory Chain, Oxidative Alterations, Drug Sensitivity, and Patient Prognosis in Glioblastoma
title_full Integrated Approach Reveals Role of Mitochondrial Germ-Line Mutation F18L in Respiratory Chain, Oxidative Alterations, Drug Sensitivity, and Patient Prognosis in Glioblastoma
title_fullStr Integrated Approach Reveals Role of Mitochondrial Germ-Line Mutation F18L in Respiratory Chain, Oxidative Alterations, Drug Sensitivity, and Patient Prognosis in Glioblastoma
title_full_unstemmed Integrated Approach Reveals Role of Mitochondrial Germ-Line Mutation F18L in Respiratory Chain, Oxidative Alterations, Drug Sensitivity, and Patient Prognosis in Glioblastoma
title_short Integrated Approach Reveals Role of Mitochondrial Germ-Line Mutation F18L in Respiratory Chain, Oxidative Alterations, Drug Sensitivity, and Patient Prognosis in Glioblastoma
title_sort integrated approach reveals role of mitochondrial germ-line mutation f18l in respiratory chain, oxidative alterations, drug sensitivity, and patient prognosis in glioblastoma
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6651022/
https://www.ncbi.nlm.nih.gov/pubmed/31323957
http://dx.doi.org/10.3390/ijms20133364
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