10.1371/journal.pone.0076230PLOS ONE8101-1

A Ameur

A Herbst

A Hori

A Malena

AC Poole

AK Reeve

B Huang

Barry Halliwell

CD Saunter

CW Birky

D Narendra

Dov Joseph Stekel

DT Gillespie

ED Robin

F Malka

FJ Iborra

G Twig

H Chen

H Korr

HT Jacobs

J Wanagat

Jan Gruber

JL Elson

K Nakada

KB Busch

LC Greaves

M D’Aurelio

M Matsumoto

M Satoh

ML Collins

MT Figge

MT Ryan

N Sondheimer

NG Larsson

PA Parone

PF Chinnery

PK Mouli

RA Capaldi

RP Huemer

Rudiyanto Gunawan

RW Gilkerson

S Miwa

S-i Arimura

SA Detmer

SB Berman

SE Durham

SK Poovathingal

T Ono

W Johnston

X Liu

Y Kraytsberg

Zhi Yang Tam

PLoS ONE

PubMed

Crossref

Mathematical Modeling of the Role of Mitochondrial Fusion and Fission in Mitochondrial DNA Maintenance

<div><p>Accumulation of mitochondrial DNA (mtDNA) mutations has been implicated in a wide range of human pathologies, including neurodegenerative diseases, sarcopenia, and the aging process itself. In cells, mtDNA molecules are constantly turned over (i.e. replicated and degraded) and are also exchanged among mitochondria during the fusion and fission of these organelles. While the expansion of a mutant mtDNA population is believed to occur by random segregation of these molecules during turnover, the role of mitochondrial fusion-fission in this context is currently not well understood. In this study, an <i>in silico</i> modeling approach is taken to investigate the effects of mitochondrial fusion and fission dynamics on mutant mtDNA accumulation. Here we report model simulations suggesting that when mitochondrial fusion-fission rate is low, the slow mtDNA mixing can lead to an uneven distribution of mutant mtDNA among mitochondria in between two mitochondrial autophagic events leading to more stochasticity in the outcomes from a single random autophagic event. Consequently, slower mitochondrial fusion-fission results in higher variability in the mtDNA mutation burden among cells in a tissue over time, and mtDNA mutations have a higher propensity to clonally expand due to the increased stochasticity. When these mutations affect cellular energetics, nuclear retrograde signalling can upregulate mtDNA replication, which is expected to slow clonal expansion of these mutant mtDNA. However, our simulations suggest that the protective ability of retrograde signalling depends on the efficiency of fusion-fission process. Our results thus shed light on the interplay between mitochondrial fusion-fission and mtDNA turnover and may explain the mechanism underlying the experimentally observed increase in the accumulation of mtDNA mutations when either mitochondrial fusion or fission is inhibited.</p></div

Zhi Yang Tam (469773)

Jan Gruber (170653)

Barry Halliwell (120788)

Rudiyanto Gunawan (170659)

The Francis Crick Institute

Accumulation of mitochondrial DNA (mtDNA) mutations has been implicated in a wide range of human pathologies, including neurodegenerative diseases, sarcopenia, and the aging process itself. In cells, mtDNA molecules are constantly turned over (i.e. replicated and degraded) and are also exchanged among mitochondria during the fusion and fission of these organelles. While the expansion of a mutant mtDNA population is believed to occur by random segregation of these molecules during turnover, the role of mitochondrial fusion-fission in this context is currently not well understood. In this study, an in silico modeling approach is taken to investigate the effects of mitochondrial fusion and fission dynamics on mutant mtDNA accumulation. Here we report model simulations suggesting that when mitochondrial fusion-fission rate is low, the slow mtDNA mixing can lead to an uneven distribution of mutant mtDNA among mitochondria in between two mitochondrial autophagic events leading to more stochasticity in the outcomes from a single random autophagic event. Consequently, slower mitochondrial fusion-fission results in higher variability in the mtDNA mutation burden among cells in a tissue over time, and mtDNA mutations have a higher propensity to clonally expand due to the increased stochasticity. When these mutations affect cellular energetics, nuclear retrograde signalling can upregulate mtDNA replication, which is expected to slow clonal expansion of these mutant mtDNA. However, our simulations suggest that the protective ability of retrograde signalling depends on the efficiency of fusion-fission process. Our results thus shed light on the interplay between mitochondrial fusion-fission and mtDNA turnover and may explain the mechanism underlying the experimentally observed increase in the accumulation of mtDNA mutations when either mitochondrial fusion or fission is inhibited.ISSN:1932-620

Tam, Zhi Yang

Gruber, Jan

Halliwell, Barry

Gunawan, Rudiyanto

Repository for Publications and Research Data

Accumulation of mitochondrial DNA (mtDNA) mutations has been implicated in a wide range of human pathologies, including neurodegenerative diseases, sarcopenia, and the aging process itself. In cells, mtDNA molecules are constantly turned over (i.e. replicated and degraded) and are also exchanged among mitochondria during the fusion and fission of these organelles. While the expansion of a mutant mtDNA population is believed to occur by random segregation of these molecules during turnover, the role of mitochondrial fusion-fission in this context is currently not well understood. In this study, an in silico modeling approach is taken to investigate the effects of mitochondrial fusion and fission dynamics on mutant mtDNA accumulation. Here we report model simulations suggesting that when mitochondrial fusion-fission rate is low, the slow mtDNA mixing can lead to an uneven distribution of mutant mtDNA among mitochondria in between two mitochondrial autophagic events leading to more stochasticity in the outcomes from a single random autophagic event. Consequently, slower mitochondrial fusion-fission results in higher variability in the mtDNA mutation burden among cells in a tissue over time, and mtDNA mutations have a higher propensity to clonally expand due to the increased stochasticity. When these mutations affect cellular energetics, nuclear retrograde signalling can upregulate mtDNA replication, which is expected to slow clonal expansion of these mutant mtDNA. However, our simulations suggest that the protective ability of retrograde signalling depends on the efficiency of fusion-fission process. Our results thus shed light on the interplay between mitochondrial fusion-fission and mtDNA turnover and may explain the mechanism underlying the experimentally observed increase in the accumulation of mtDNA mutations when either mitochondrial fusion or fission is inhibited

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Mathematical modeling of the role of mitochondrial fusion and fission in mitochondrial DNA maintenance.

Tam Zhi Yang

Gruber Jan

Halliwell Barry

Gunawan Rudiyanto

Public Library of Science (PLOS)

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Mathematical Modeling of the Role of Mitochondrial Fusion and Fission in Mitochondrial DNA Maintenance

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The Francis Crick Institute

Repository for Publications and Research Data

Directory of Open Access Journals

Public Library of Science (PLOS)