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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

Holt, Alan G.; Davies, Adrian M.
Acta Biotheoretica , Volume 69 (4) – Dec 1, 2021
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Springer Journals
Copyright
Copyright © Springer Nature B.V. 2021
ISSN
0001-5342
eISSN
1572-8358
DOI
10.1007/s10441-021-09417-z
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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 Biotheoretica – Springer Journals

Published: Dec 1, 2021

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

References

  • Mitochondrial biology
    Agaronyan, K; Morozov, YI; Anikin, M; Temiakov, D
  • The Maintenance of Mitochondrial DNA Integrity-Critical Analysis and Update
    Alexeyev, M; Shokolenko, I; Wilson, G; LeDoux, S
  • Ultra-Deep Sequencing of Mouse Mitochondrial DNA: Mutational Patterns and Their Origins
    Ameur, A; Stewart, JB; Freyer, C; Hagström, E; Ingman, M; Larsson, NG; Gyllensten, U
  • Oxidative damage diminishes mitochondrial DNA polymerase replication fidelity
    Anderson, AP; Luo, X; Russell, W; Yin, YW
  • High levels of mitochondrial DNA deletions in substantia nigra neurons in aging and Parkinson disease
    Bender, A; Krishnan, KJ; Morris, CM; Taylor, GA; Reeve, AK; Perry, RH; Jaros, E; Hersheson, JS; Betts, J; Klopstock, T; Taylor, RW; Turnbull, DM
  • Why mitochondrial genes are most often found in nuclei
    Berg, OG; Kurland, CG
  • Mitochondrial genomes are retained by selective constraints on protein targeting
    Björkholm, P; Harish, A; Hagström, E; Ernst, AM; Andersson, SGE
  • SnapShot: Mitochondrial Nucleoid
    Bonekamp, NA; Larsson, NG
  • The cellular production of hydrogen peroxide
    Boveris, A; Oshino, N; Chance, B
  • Quality matters: how does mitochondrial network dynamics and quality control impact on mtDNA integrity?
    Busch, KB; Kowald, A; Spelbrink, JN
  • Chen JZ (2013) Simultaneous Quantification of Mitochondrial DNA Damage and Copy Number in Circulating Blood: A Sensitive Approach to Systemic Oxidative Stress
    Chan, SW; Chevalier, S; Aprikian, A
  • The emergence of longevous populations
    Colchero, F; Rau, R; Jones, OR; Barthold, JA; Conde, DA; Lenart, A; Nemeth, L; Scheuerlein, A; Schoeley, J; Torres, C; Zarulli, V; Altmann, J; Brockman, DK; Bronikowski, AM; Fedigan, LM; Pusey, AE; Stoinski, TS; Strier, KB; Baudisch, A; Alberts, SC; Vaupel, JW
  • A synopsis on aging–Theories, mechanisms and future prospects
    da Costa, JP; Vitorino, R; Silva, GM; Vogel, C; Duarte, AC; Rocha-Santos, T
  • Why antioxidant therapies have failed in clinical trials
    Davies, AM; Holt, AG
  • Tissue-specific mtDNA abundance from exome data and its correlation with mitochondrial transcription, mass and respiratory activity
    D’Erchia, AM; Atlante, A; Gadaleta, G; Pavesi, G; Chiara, M; De Virgilio, C; Manzari, C; Mastropasqua, F; Prazzoli, GM; Picardi, E; Gissi, C; Horner, D; Reyes, A; Sbisà, E; Tullo, A; Pesole, G
  • Defective mitochondrial DNA homeostasis in the substantia nigra in Parkinson disease
    Dölle, C; Flønes, I; Nido, GS; Miletic, H; Osuagwu, N; Kristoffersen, S; Lilleng, PK; Larsen, JP; Tysnes, OB; Haugarvoll, K; Bindoff, LA; Tzoulis, C
  • Recent Advances in Detecting Mitochondrial DNA Heteroplasmic Variations
    Duan, Mengqin; Jing, Tu; Zuhong, Lu
  • Mitochondrial DNA replication in mammalian cells: overview of the pathway
    Falkenberg, M
  • Brain aging and neurodegeneration: from a mitochondrial point of view
    Grimm, A; Eckert, A
  • Mitochondrial DNA Deletions/Rearrangements in Parkinson Disease and Related Neurodegenerative Disorders
    Gu, G; Reyes, PF; Golden, GT; Woltjer, RL; Hulette, C; Montine, TJ; Zhang, J
  • White matter changes with normal aging
    Guttmann, CR; Jolesz, FA; Kikinis, R; Killiany, RJ; Moss, MB; Sandor, T; Albert, MS
  • Aging: a theory based on free radical and radiation chemistry
    Harman, D
  • The free radical theory of aging
    Harman, D
  • Age-associated oxygen damage and mutations in mitochondrial DNA in human hearts
    Hayakawa, M; Hattori, K; Sugiyama, S; Ozawa, T
  • Deletions of muscle mitochondrial DNA in patients with mitochondrial myopathies
    Holt, HAEIJ; Morgan-Hughs, JA
  • The road to rack and ruin: selecting deleterious mitochondrial DNA variants
    Holt, IJ; Speijer, D; Kirkwood, TBL
  • The role of mitochondria in aging
    Jang, JY; Blum, A; Liu, J; Finkel, T
  • Regulation of mitochondrial biogenesis
    Jornayvaz, FR; Shulman, GI
  • Intrinsic and extrinsic uncoupling of oxidative phosphorylation
    Kadenbach, B
  • Rapid and random turnover of mitochondrial DNA in rat hepatocytes of primary culture
    Kai, Y; Takamatsu, C; Tokuda, K; Okamoto, M; Irita, K; Takahashi, S
  • Stewart JB (2015) Mitochondrial DNA: Radically free of free-radical driven mutations
    Kauppila, JHK
  • Mammalian Mitochondria and Aging: An Update
    Kauppila, TES; Kauppila, JHK; Larsson, NG
  • Cell-by-cell scanning of whole mitochondrial genomes in aged human heart reveals a significant fraction of myocytes with clonally expanded deletions
    Khrapko, K; Bodyak, N; Thilly, WG; van Orsouw, NJ; Zhang, X; Coller, HA; Perls, TT; Upton, M; Vijg, J; Wei, JY
  • Mitochondrial DNA synthesis studied autoradiographically in various cell types in vivo
    Korr, H; Kurz, C; Seidler, TO; Sommer, D; Schmitz, C
  • A network theory of ageing: the interactions of defective mitochondria, aberrant proteins, free radicals and scavengers in the ageing process
    Kowald, A; Kirkwood, TB
  • Resolving the Enigma of the Clonal Expansion of mtDNA Deletions
    Kowald, A; Kirkwood, T
  • Mitochondrial mutations and ageing: can mitochondrial deletion mutants accumulate via a size based replication advantage?
    Kowald, A; Dawson, M; Kirkwood, TBL
  • In vivo assessment of muscle mitochondrial function in healthy, young males in relation to parameters of aerobic fitness
    Lagerwaard, B; Keijer, J; McCully, KK; de Boer, VCJ; Nieuwenhuizen, AG
  • Ultrasensitive deletion detection links mitochondrial DNA replication, disease, and aging
    Lujan, SA; Longley, MJ; Humble, MH; Lavender, CA; Burkholder, A; Blakely, EL; Alston, CL; Gorman, GS; Turnbull, DM; McFarland, R; Taylor, RW; Kunkel, TA; Copeland, WC
  • The turnover of mitochondria in a variety of tissues of young adult and aged rats
    Menzies, RA; Gold, PH
  • Inter-mitochondrial complementation: Mitochondria-specific system preventing mice from expression of disease phenotypes by mutant mtDNA
    Nakada, K; Inoue, K; Ono, T; Isobe, K; Ogura, A; Goto, YI; Nonaka, I; Hayashi, JI
  • Mitochondrial functional complementation in mitochondrial DNA-based diseases
    Nakada, K; Sato, A; Hayashi, JI
  • Ultradeep mapping of neuronal mitochondrial deletions in Parkinson’s disease
    Nido, GS; Dölle, C; Flønes, I; Tuppen, HA; Alves, G; Tysnes, OB; Haugarvoll, K; Tzoulis, C
  • Mitochondrial DNA damage and reactive oxygen species in neurodegenerative disease
    Nissanka, N; Moraes, CT
  • Mitochondrial DNA deletions in Alzheimer’s brains: A review
    Phillips, NR; Simpkins, JW; Roby, RK
  • Is mitochondrial DNA turnover slower than commonly assumed?
    Poovathingal, SK; Gruber, J; Lakshmanan, L; Halliwell, B; Gunawan, R
  • Why have organelles retained genomes?
    Race, HL; Herrmann, RG; Martin, W
  • Mitochondrial DNA copy numbers in pyramidal neurons are decreased and mitochondrial biogenesis transcriptome signaling is disrupted in Alzheimer’s disease hippocampi
    Rice, AC; Keeney, PM; Algarzae, NK; Ladd, AC; Thomas, RR; Bennett, JP
  • Mitochondrial DNA molecules and virtual number of mitochondria per cell in mammalian cells
    Robin, ED; Wong, R
  • The Alterations in Mitochondrial DNA Copy Number and Nuclear-Encoded Mitochondrial Genes in Rat Brain Structures after Cocaine Self-Administration
    Sadakierska-Chudy, A; Kotarska, A; Frankowska, M; Jastrzębska, J; Wydra, K; Miszkiel, J; Przegaliński, E; Filip, M
  • Mitochondrial DNA Oxidative Damage and Repair in Aging and Alzheimer’s Disease
    Santos, RX; Correia, SC; Zhu, X; Smith, MA; Moreira, PI; Castellani, RJ; Nunomura, A; Perry, G
  • The mitochondrial free radical theory of aging: a critical view
    Sanz, A; Stefanatos, RKA
  • The Mitochondrial Basis of Aging
    Sun, N; Youle, RJ; Finkel, T
  • Origins of mtDNA mutations in ageing
    Szczepanowska, K; Trifunovic, A
  • The mitochondrial genome: structure, transcription, translation and replication
    Taanman, JW
  • DNA deletions and clonal mutations drive premature aging in mitochondrial mutator mice
    Vermulst, M; Wanagat, J; Kujoth, GC; Bielas, JH; Rabinovitch, PS; Prolla, TA; Loeb, LA
  • Mitochondrial genetics: a paradigm for aging and degenerative diseases?
    Wallace, A
  • Diseases of the mitochondrial DNA
    Wallace, A
  • Mitochondrial DNA mutation associated with Leber’s hereditary optic neuropathy
    Wallace, A; Singh, G; Lott, MT; Hodge, JA; Schurr, TG; Lezza, AM; Elsas, LJ; Nikoskelainen, EK
  • Intimate Relations-Mitochondria and Ageing
    Webb, M; Sideris, DP
  • Oxidative damage and mutation to mitochondrial DNA and age-dependent decline of mitochondrial respiratory function
    Wei, YH; Lu, CY; Lee, HC; Pang, CY; Ma, YS
  • Bioenergetic role of mitochondrial fusion and fission
    Westermann, B
  • Mitochondrial DNA damage is more extensive and persists longer than nuclear DNA damage in human cells following oxidative stress
    Yakes, FM; Van Houten, B