mtDNA is a multicopy genome. When mutations exist, they can affect a varying proportion of the mtDNA present within every cell (heteroplasmy). Heteroplasmic mtDNA mutations can be maternally inherited, but the proportion of mutated alleles differs markedly between offspring within one generation. This led to the genetic bottleneck hypothesis, explaining the rapid changes in allele frequency seen during transmission from one generation to the next. Although a physical reduction in mtDNA has been demonstrated in several species, a comprehensive understanding of the molecular mechanisms is yet to be revealed. Several questions remain, including the role of selection for and against specific alleles, whether all bottlenecks are the same, and precisely how the bottleneck is controlled during development. Although originally thought to be limited to the germline, there is evidence that bottlenecks exist in other cell types during development, perhaps explaining why different tissues in the same organism contain different levels of mutated mtDNA. Moreover, tissue-specific bottlenecks may occur throughout life in response to environmental influences, adding further complexity to the situation. Here we review key recent findings, and suggest ways forward that will hopefully advance our understanding of the role of mtDNA in human disease.
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July 2018
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Cover Image
Cover Image
Mitochondria are unique organelles under the dual genetic control executed by nuclear DNA and their own genome, mitochondrial DNA. Every cell contains a population of mitochondria and multiple copies of mtDNA, carrying wild type or mutated variants (heteroplasmy). The genetic variability together with the complex regulation of multiple metabolic pathways operating in mitochondria are responsible for phenotypic variability, schematically represented in the cover image. In this issue of Essays in Biochemistry, we illustrate the biological pathways operating in mitochondria and the pathomechanisms leading to disease. We also provide an overview of the current advances in the approach to diagnosis, design of new therapies, and development of clinical trials. Image kindly provided by Caterina Garone (MRC Mitochondrial Biology Unit).
Review Article|
June 07 2018
The mitochondrial DNA genetic bottleneck: inheritance and beyond
Haixin Zhang;
Haixin Zhang
1Department of Clinical Neurosciences, University of Cambridge, Cambridge CB2 0XY, U.K.
2MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge CB2 0XY, U.K.
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Stephen P. Burr;
Stephen P. Burr
1Department of Clinical Neurosciences, University of Cambridge, Cambridge CB2 0XY, U.K.
2MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge CB2 0XY, U.K.
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Patrick F. Chinnery
1Department of Clinical Neurosciences, University of Cambridge, Cambridge CB2 0XY, U.K.
2MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge CB2 0XY, U.K.
Correspondence: Patrick F. Chinnery (pfc25@cam.ac.uk)
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Publisher: Portland Press Ltd
Received:
May 04 2018
Revision Received:
May 21 2018
Accepted:
May 23 2018
Online ISSN: 1744-1358
Print ISSN: 0071-1365
© 2018 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society
2018
Essays Biochem (2018) 62 (3): 225–234.
Article history
Received:
May 04 2018
Revision Received:
May 21 2018
Accepted:
May 23 2018
Citation
Caterina Garone, Michal Minczuk, Haixin Zhang, Stephen P. Burr, Patrick F. Chinnery; The mitochondrial DNA genetic bottleneck: inheritance and beyond. Essays Biochem 20 July 2018; 62 (3): 225–234. doi: https://doi.org/10.1042/EBC20170096
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