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

Zhi Yang Tam,Barry Halliwell,Jan Gruber,Rudiyanto Gunawan,Dov Joseph Stekel

doi:10.1371/journal.pone.0076230

Abstract

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.

Highlights

Mitochondria are the powerhouses of eukaryotic cells, whose main function is to produce ATP [1]
Imperfect mixing of mitochondrial DNA (mtDNA) nucleoids can give rise to additional variability in the outcome of mitophagy events, and in this case, higher inter-mitochondrial mtDNA heterogeneity of mitochondria population contributes toward an increase in the intercellular mtDNA heterogeneity
Our model simulations suggest an intuitive and novel mechanism that explains the increase in mutant mtDNA accumulation when mitochondrial fusion-fission is perturbed

Summary

Introduction

Mitochondria are the powerhouses of eukaryotic cells, whose main function is to produce ATP [1]. Mitochondrial DNA mutations can lead to the loss of mitochondrial function when the level of mutations exceeds a critical threshold [4,5]. While the mechanism underlying accumulation of mutant mtDNA is not precisely understood, the consensus is that such mutations expand over time due to random segregation during mtDNA turnover [7]. Consistent with this hypothesis, the proportion of cells with heteroplasmic mtDNA has been reported to significantly increase with age [8]. Understanding how mtDNA mutations propagate and clonally expand in cells is critical in elucidating the pathogenesis of mitochondrial diseases as well as the ageing process

Methods

Results

Conclusion