Mitochondrial network state scales mtDNA genetic dynamics

TL;DR

This paper develops a theoretical framework linking mitochondrial network dynamics to mtDNA genetic variation, revealing how network state influences mutation accumulation and heteroplasmy variance, with implications for disease and aging.

Contribution

It introduces the first comprehensive model connecting mitochondrial network states with mtDNA genetic dynamics, highlighting the impact of network modulation on heteroplasmy evolution.

Findings

Heteroplasmy variance increase rate is proportional to the fraction of unfused mitochondria.

Intermediate fusion/fission ratios optimize mutant clearance.

Modulating network state can slow heteroplasmy dynamics, offering therapeutic potential.

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 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.