Context-dependant role of mitochondrial fusion-fission in clonal expansion of mtDNA mutations

The accumulation of mutant mitochondrial DNA (mtDNA) molecules in aged cells has been associated with mitochondrial dysfunction, age-related diseases and the ageing process itself. This accumulation has been shown to often occur clonally, where mutant mtDNA grow in number and overpopulate the wild-t...

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Main Authors: Tam, Zhi Yang, Gruber, Jan, Halliwell, Barry, Gunawan, Rudiyanto
Other Authors: Morozov, Alexandre V
Format: Article
Language:English
Published: 2015
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Online Access:https://hdl.handle.net/10356/79467
http://hdl.handle.net/10220/26112
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Institution: Nanyang Technological University
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spelling sg-ntu-dr.10356-794672022-02-16T16:29:20Z Context-dependant role of mitochondrial fusion-fission in clonal expansion of mtDNA mutations Tam, Zhi Yang Gruber, Jan Halliwell, Barry Gunawan, Rudiyanto Morozov, Alexandre V Lee Kong Chian School of Medicine (LKCMedicine) DRNTU::Science::Biological sciences::Genetics The accumulation of mutant mitochondrial DNA (mtDNA) molecules in aged cells has been associated with mitochondrial dysfunction, age-related diseases and the ageing process itself. This accumulation has been shown to often occur clonally, where mutant mtDNA grow in number and overpopulate the wild-type mtDNA. However, the cell possesses quality control (QC) mechanisms that maintain mitochondrial function, in which dysfunctional mitochondria are isolated and removed by selective fusion and mitochondrial autophagy (mitophagy), respectively. The aim of this study is to elucidate the circumstances related to mitochondrial QC that allow the expansion of mutant mtDNA molecules. For the purpose of the study, we have developed a mathematical model of mitochondrial QC process by extending our previous validated model of mitochondrial turnover and fusion-fission. A global sensitivity analysis of the model suggested that the selectivity of mitophagy and fusion is the most critical QC parameter for clearing de novo mutant mtDNA molecules. We further simulated several scenarios involving perturbations of key QC parameters to gain a better understanding of their dynamic and synergistic interactions. Our model simulations showed that a higher frequency of mitochondrial fusion-fission can provide a faster clearance of mutant mtDNA, but only when mutant–rich mitochondria that are transiently created are efficiently prevented from re-fusing with other mitochondria and selectively removed. Otherwise, faster fusion-fission quickens the accumulation of mutant mtDNA. Finally, we used the insights gained from model simulations and analysis to propose a possible circumstance involving deterioration of mitochondrial QC that permits mutant mtDNA to expand with age. Published version 2015-06-29T02:38:54Z 2019-12-06T13:26:03Z 2015-06-29T02:38:54Z 2019-12-06T13:26:03Z 2015 2015 Journal Article Tam, Z. Y., Gruber, J., Halliwell, B., & Gunawan, R. (2015). Context-dependent role of mitochondrial fusion-fission in clonal expansion of mtDNA mutations. PLOS computational biology, 11(5), e1004183-. 1553-7358 https://hdl.handle.net/10356/79467 http://hdl.handle.net/10220/26112 10.1371/journal.pcbi.1004183 25996936 en PLOS computational biology © 2015 Tam et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. application/pdf
institution Nanyang Technological University
building NTU Library
continent Asia
country Singapore
Singapore
content_provider NTU Library
collection DR-NTU
language English
topic DRNTU::Science::Biological sciences::Genetics
spellingShingle DRNTU::Science::Biological sciences::Genetics
Tam, Zhi Yang
Gruber, Jan
Halliwell, Barry
Gunawan, Rudiyanto
Context-dependant role of mitochondrial fusion-fission in clonal expansion of mtDNA mutations
description The accumulation of mutant mitochondrial DNA (mtDNA) molecules in aged cells has been associated with mitochondrial dysfunction, age-related diseases and the ageing process itself. This accumulation has been shown to often occur clonally, where mutant mtDNA grow in number and overpopulate the wild-type mtDNA. However, the cell possesses quality control (QC) mechanisms that maintain mitochondrial function, in which dysfunctional mitochondria are isolated and removed by selective fusion and mitochondrial autophagy (mitophagy), respectively. The aim of this study is to elucidate the circumstances related to mitochondrial QC that allow the expansion of mutant mtDNA molecules. For the purpose of the study, we have developed a mathematical model of mitochondrial QC process by extending our previous validated model of mitochondrial turnover and fusion-fission. A global sensitivity analysis of the model suggested that the selectivity of mitophagy and fusion is the most critical QC parameter for clearing de novo mutant mtDNA molecules. We further simulated several scenarios involving perturbations of key QC parameters to gain a better understanding of their dynamic and synergistic interactions. Our model simulations showed that a higher frequency of mitochondrial fusion-fission can provide a faster clearance of mutant mtDNA, but only when mutant–rich mitochondria that are transiently created are efficiently prevented from re-fusing with other mitochondria and selectively removed. Otherwise, faster fusion-fission quickens the accumulation of mutant mtDNA. Finally, we used the insights gained from model simulations and analysis to propose a possible circumstance involving deterioration of mitochondrial QC that permits mutant mtDNA to expand with age.
author2 Morozov, Alexandre V
author_facet Morozov, Alexandre V
Tam, Zhi Yang
Gruber, Jan
Halliwell, Barry
Gunawan, Rudiyanto
format Article
author Tam, Zhi Yang
Gruber, Jan
Halliwell, Barry
Gunawan, Rudiyanto
author_sort Tam, Zhi Yang
title Context-dependant role of mitochondrial fusion-fission in clonal expansion of mtDNA mutations
title_short Context-dependant role of mitochondrial fusion-fission in clonal expansion of mtDNA mutations
title_full Context-dependant role of mitochondrial fusion-fission in clonal expansion of mtDNA mutations
title_fullStr Context-dependant role of mitochondrial fusion-fission in clonal expansion of mtDNA mutations
title_full_unstemmed Context-dependant role of mitochondrial fusion-fission in clonal expansion of mtDNA mutations
title_sort context-dependant role of mitochondrial fusion-fission in clonal expansion of mtdna mutations
publishDate 2015
url https://hdl.handle.net/10356/79467
http://hdl.handle.net/10220/26112
_version_ 1725985679267069952