Title: Mitochondrial network fragmentation modulates mutant mtDNA accumulation independently of absolute fission-fusion rates,
Abstract: Mitochondrial DNA (mtDNA) mutations cause severe congenital diseases but may
also be associated with healthy aging. MtDNA is stochastically replicated and
degraded, and exists within organelles which undergo dynamic fusion and
fission. The role of the resulting mitochondrial networks in determining the
time evolution of the cellular proportion of mutated mtDNA molecules
(heteroplasmy), and cell-to-cell variability in heteroplasmy (heteroplasmy
variance), remains incompletely understood. Heteroplasmy variance is
particularly important since it modulates the number of pathological cells in a
tissue. Here, we provide the first wide-reaching mathematical treatment which
bridges mitochondrial network and genetic states. We show that, for a range of
models, the rate of increase in heteroplasmy variance, and the rate of
\textit{de novo} mutation, is proportionately modulated by the fraction of
unfused mitochondria, independently of the absolute fission-fusion rate. In the
context of selective fusion, we show that intermediate fusion/fission ratios
are optimal for the clearance of mtDNA mutants. Our findings imply that
modulating network state, mitophagy rate and copy number to slow down
heteroplasmy dynamics when mean heteroplasmy is low, could have therapeutic
advantages for mitochondrial disease and healthy aging.