MtDNA mutations are one of the hallmarks of ageing and age-related diseases. It is well established that somatic point mutations accumulate in mtDNA of multiple organs and tissues with increasing age and heteroplasmy is universal in mammals. However, the origin of these mutations remains controversial. The long-lasting hypothesis stating that mtDNA mutations emanate from oxidative damage via a self-perpetuating mechanism has been extensively challenged in recent years. Contrary to this initial ascertainment, mtDNA appears to be well protected from action of reactive oxygen species (ROS) through robust protein coating and endomitochondrial microcompartmentalization. Extensive development of scrupulous high-throughput DNA sequencing methods suggests that an imperfect replication process, rather than oxidative lesions are the main sources of mtDNA point mutations, indicating that mtDNA polymerase γ (POLG) might be responsible for the majority of mtDNA mutagenic events. Here, we summarize the recent knowledge in prevention and defence of mtDNA oxidative lesions and discuss the plausible mechanisms of mtDNA point mutation generation and fixation.
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July 2017
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This issue explores the molecular and cellular mechanisms which underpin the process of ageing. Guest Edited by Professor Tom Kirkwood, CBE and Dr Viktor Korolchuk of the Newcastle University Institute for Ageing and Health, the issue includes reviews on mechanisms involved in ageing include genome instability and redox stress as well as insights from systems biology and approaches for extending the human healthspan. - PDF Icon PDF LinkTable of Contents
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Review Article|
July 11 2017
Origins of mtDNA mutations in ageing
Karolina Szczepanowska;
Karolina Szczepanowska
1Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD) and Institute for Mitochondrial Diseases and Aging, Medical Faculty, University of Cologne, Cologne D-50931, Germany
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Aleksandra Trifunovic
1Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD) and Institute for Mitochondrial Diseases and Aging, Medical Faculty, University of Cologne, Cologne D-50931, Germany
2Center for Molecular Medicine Cologne (CMMC), Cologne D-50931, Germany
Correspondence: Aleksandra Trifunovic (aleksandra.trifunovic@uk-koeln.de)
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Publisher: Portland Press Ltd
Received:
February 16 2017
Revision Received:
May 24 2017
Accepted:
May 26 2017
Online ISSN: 1744-1358
Print ISSN: 0071-1365
© 2017 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society
2017
Essays Biochem (2017) 61 (3): 325–337.
Article history
Received:
February 16 2017
Revision Received:
May 24 2017
Accepted:
May 26 2017
Citation
Thomas B.L. Kirkwood, Viktor I. Korolchuk, Karolina Szczepanowska, Aleksandra Trifunovic; Origins of mtDNA mutations in ageing. Essays Biochem 11 July 2017; 61 (3): 325–337. doi: https://doi.org/10.1042/EBC20160090
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