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The Effect of Mitochondrial DNA Half-Life on Deletion Mutation Proliferation in Long Lived Cells

The Effect of Mitochondrial DNA Half-Life on Deletion Mutation Proliferation in Long Lived Cells The proliferation of mitochondrial DNA (mtDNA) with deletion mutations has been linked to aging and age related neurodegenerative conditions. In this study we model the effect of mtDNA half-life on mtDNA competition and selection. It has been proposed that mutation deletions (mtDNAdel\documentclass[12pt]{minimal}\usepackage{amsmath}\usepackage{wasysym}\usepackage{amsfonts}\usepackage{amssymb}\usepackage{amsbsy}\usepackage{mathrsfs}\usepackage{upgreek}\setlength{\oddsidemargin}{-69pt}\begin{document}$$\text {mtDNA}_{del}$$\end{document}) have a replicative advantage over wild-type (mtDNAwild\documentclass[12pt]{minimal}\usepackage{amsmath}\usepackage{wasysym}\usepackage{amsfonts}\usepackage{amssymb}\usepackage{amsbsy}\usepackage{mathrsfs}\usepackage{upgreek}\setlength{\oddsidemargin}{-69pt}\begin{document}$$\text {mtDNA}_{wild}$$\end{document}) and that this is detrimental to the host cell, especially in post-mitotic cells. An individual cell can be viewed as forming a closed ecosystem containing a large population of independently replicating mtDNA. Within this enclosed environment a selfishly replicating mtDNAdel\documentclass[12pt]{minimal}\usepackage{amsmath}\usepackage{wasysym}\usepackage{amsfonts}\usepackage{amssymb}\usepackage{amsbsy}\usepackage{mathrsfs}\usepackage{upgreek}\setlength{\oddsidemargin}{-69pt}\begin{document}$$\text {mtDNA}_{del}$$\end{document} would compete with the mtDNAwild\documentclass[12pt]{minimal}\usepackage{amsmath}\usepackage{wasysym}\usepackage{amsfonts}\usepackage{amssymb}\usepackage{amsbsy}\usepackage{mathrsfs}\usepackage{upgreek}\setlength{\oddsidemargin}{-69pt}\begin{document}$$\text {mtDNA}_{wild}$$\end{document} for space and resources to the detriment of the host cell. In this paper, we use a computer simulation to model cell survival in an environment where mtDNAwild\documentclass[12pt]{minimal}\usepackage{amsmath}\usepackage{wasysym}\usepackage{amsfonts}\usepackage{amssymb}\usepackage{amsbsy}\usepackage{mathrsfs}\usepackage{upgreek}\setlength{\oddsidemargin}{-69pt}\begin{document}$$\text {mtDNA}_{wild}$$\end{document} compete with mtDNAdel\documentclass[12pt]{minimal}\usepackage{amsmath}\usepackage{wasysym}\usepackage{amsfonts}\usepackage{amssymb}\usepackage{amsbsy}\usepackage{mathrsfs}\usepackage{upgreek}\setlength{\oddsidemargin}{-69pt}\begin{document}$$\text {mtDNA}_{del}$$\end{document} such that the cell expires upon mtDNAwild\documentclass[12pt]{minimal}\usepackage{amsmath}\usepackage{wasysym}\usepackage{amsfonts}\usepackage{amssymb}\usepackage{amsbsy}\usepackage{mathrsfs}\usepackage{upgreek}\setlength{\oddsidemargin}{-69pt}\begin{document}$$\text {mtDNA}_{wild}$$\end{document} extinction. We focus on the survival time for long lived post-mitotic cells, such as neurons. We confirm previous observations that mtDNAdel\documentclass[12pt]{minimal}\usepackage{amsmath}\usepackage{wasysym}\usepackage{amsfonts}\usepackage{amssymb}\usepackage{amsbsy}\usepackage{mathrsfs}\usepackage{upgreek}\setlength{\oddsidemargin}{-69pt}\begin{document}$$\text {mtDNA}_{del}$$\end{document} do have a replicative advantage over mtDNAwild\documentclass[12pt]{minimal}\usepackage{amsmath}\usepackage{wasysym}\usepackage{amsfonts}\usepackage{amssymb}\usepackage{amsbsy}\usepackage{mathrsfs}\usepackage{upgreek}\setlength{\oddsidemargin}{-69pt}\begin{document}$$\text {mtDNA}_{wild}$$\end{document}. As expected, cell survival times diminished with increased mutation probabilities, however, the relationship between survival time and mutation rate was non-linear, that is, a ten-fold increase in mutation probability only halved the survival time. The results of our model also showed that a modest increase in half-life had a profound affect on extending cell survival time, thereby, mitigating the replicative advantage of mtDNAdel\documentclass[12pt]{minimal}\usepackage{amsmath}\usepackage{wasysym}\usepackage{amsfonts}\usepackage{amssymb}\usepackage{amsbsy}\usepackage{mathrsfs}\usepackage{upgreek}\setlength{\oddsidemargin}{-69pt}\begin{document}$$\text {mtDNA}_{del}$$\end{document}. Given the relevance of mitochondrial dysfunction to various neurodegenerative conditions, we propose that therapies to increase mtDNA half-life could significantly delay their onset. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Acta Biotheoretica Springer Journals

The Effect of Mitochondrial DNA Half-Life on Deletion Mutation Proliferation in Long Lived Cells

Acta Biotheoretica , Volume 69 (4) – Dec 1, 2021

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Publisher
Springer Journals
Copyright
Copyright © Springer Nature B.V. 2021
ISSN
0001-5342
eISSN
1572-8358
DOI
10.1007/s10441-021-09417-z
Publisher site
See Article on Publisher Site

Abstract

The proliferation of mitochondrial DNA (mtDNA) with deletion mutations has been linked to aging and age related neurodegenerative conditions. In this study we model the effect of mtDNA half-life on mtDNA competition and selection. It has been proposed that mutation deletions (mtDNAdel\documentclass[12pt]{minimal}\usepackage{amsmath}\usepackage{wasysym}\usepackage{amsfonts}\usepackage{amssymb}\usepackage{amsbsy}\usepackage{mathrsfs}\usepackage{upgreek}\setlength{\oddsidemargin}{-69pt}\begin{document}$$\text {mtDNA}_{del}$$\end{document}) have a replicative advantage over wild-type (mtDNAwild\documentclass[12pt]{minimal}\usepackage{amsmath}\usepackage{wasysym}\usepackage{amsfonts}\usepackage{amssymb}\usepackage{amsbsy}\usepackage{mathrsfs}\usepackage{upgreek}\setlength{\oddsidemargin}{-69pt}\begin{document}$$\text {mtDNA}_{wild}$$\end{document}) and that this is detrimental to the host cell, especially in post-mitotic cells. An individual cell can be viewed as forming a closed ecosystem containing a large population of independently replicating mtDNA. Within this enclosed environment a selfishly replicating mtDNAdel\documentclass[12pt]{minimal}\usepackage{amsmath}\usepackage{wasysym}\usepackage{amsfonts}\usepackage{amssymb}\usepackage{amsbsy}\usepackage{mathrsfs}\usepackage{upgreek}\setlength{\oddsidemargin}{-69pt}\begin{document}$$\text {mtDNA}_{del}$$\end{document} would compete with the mtDNAwild\documentclass[12pt]{minimal}\usepackage{amsmath}\usepackage{wasysym}\usepackage{amsfonts}\usepackage{amssymb}\usepackage{amsbsy}\usepackage{mathrsfs}\usepackage{upgreek}\setlength{\oddsidemargin}{-69pt}\begin{document}$$\text {mtDNA}_{wild}$$\end{document} for space and resources to the detriment of the host cell. In this paper, we use a computer simulation to model cell survival in an environment where mtDNAwild\documentclass[12pt]{minimal}\usepackage{amsmath}\usepackage{wasysym}\usepackage{amsfonts}\usepackage{amssymb}\usepackage{amsbsy}\usepackage{mathrsfs}\usepackage{upgreek}\setlength{\oddsidemargin}{-69pt}\begin{document}$$\text {mtDNA}_{wild}$$\end{document} compete with mtDNAdel\documentclass[12pt]{minimal}\usepackage{amsmath}\usepackage{wasysym}\usepackage{amsfonts}\usepackage{amssymb}\usepackage{amsbsy}\usepackage{mathrsfs}\usepackage{upgreek}\setlength{\oddsidemargin}{-69pt}\begin{document}$$\text {mtDNA}_{del}$$\end{document} such that the cell expires upon mtDNAwild\documentclass[12pt]{minimal}\usepackage{amsmath}\usepackage{wasysym}\usepackage{amsfonts}\usepackage{amssymb}\usepackage{amsbsy}\usepackage{mathrsfs}\usepackage{upgreek}\setlength{\oddsidemargin}{-69pt}\begin{document}$$\text {mtDNA}_{wild}$$\end{document} extinction. We focus on the survival time for long lived post-mitotic cells, such as neurons. We confirm previous observations that mtDNAdel\documentclass[12pt]{minimal}\usepackage{amsmath}\usepackage{wasysym}\usepackage{amsfonts}\usepackage{amssymb}\usepackage{amsbsy}\usepackage{mathrsfs}\usepackage{upgreek}\setlength{\oddsidemargin}{-69pt}\begin{document}$$\text {mtDNA}_{del}$$\end{document} do have a replicative advantage over mtDNAwild\documentclass[12pt]{minimal}\usepackage{amsmath}\usepackage{wasysym}\usepackage{amsfonts}\usepackage{amssymb}\usepackage{amsbsy}\usepackage{mathrsfs}\usepackage{upgreek}\setlength{\oddsidemargin}{-69pt}\begin{document}$$\text {mtDNA}_{wild}$$\end{document}. As expected, cell survival times diminished with increased mutation probabilities, however, the relationship between survival time and mutation rate was non-linear, that is, a ten-fold increase in mutation probability only halved the survival time. The results of our model also showed that a modest increase in half-life had a profound affect on extending cell survival time, thereby, mitigating the replicative advantage of mtDNAdel\documentclass[12pt]{minimal}\usepackage{amsmath}\usepackage{wasysym}\usepackage{amsfonts}\usepackage{amssymb}\usepackage{amsbsy}\usepackage{mathrsfs}\usepackage{upgreek}\setlength{\oddsidemargin}{-69pt}\begin{document}$$\text {mtDNA}_{del}$$\end{document}. Given the relevance of mitochondrial dysfunction to various neurodegenerative conditions, we propose that therapies to increase mtDNA half-life could significantly delay their onset.

Journal

Acta BiotheoreticaSpringer Journals

Published: Dec 1, 2021

Keywords: Mitochondrial DNA; Mitochondrial mutation; Aging; Computer simulation; Half-life; Neurodegenerative diseases

References