  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 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 theoretical framework which bridges mitochondrial network
and genetic states. We show that, under a range of conditions, the (genetic)
rate of increase in heteroplasmy variance and de novo mutation are
proportionally modulated by the (physical) 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.
