Survival of the densest accounts for the expansion of mitochondrial mutations in ageing

TL;DR

This paper introduces a spatial model explaining the expansion of mitochondrial mutations in aging, emphasizing density and noise effects over replicative advantage, aligning with experimental observations.

Contribution

It proposes the 'survival of the densest' mechanism as an alternative to replicative advantage for mutation expansion in aging.

Findings

Wave speed decreases with copy number, matching experimental data.

Mutants can expand even when preferentially eliminated.

The model predicts mutation wave dynamics without replicative advantage.

Abstract

The expansion of deleted mitochondrial DNA (mtDNA) molecules has been linked to ageing, particularly in skeletal muscle fibres; its mechanism has remained unclear for three decades. Previous accounts assigned a replicative advantage to the deletions, but there is evidence that cells can, instead, selectively remove defective mtDNA. We present a spatial model that, without a replicative advantage, but instead through a combination of enhanced density for mutants and noise, produces a wave of expanding mutations with wave speed consistent with experimental data, unlike a standard model based on replicative advantage. We provide a formula that predicts that the wave speed drops with copy number, in agreement with experimental data. Crucially, our model yields travelling waves of mutants even if mutants are preferentially eliminated. Justified by this exemplar of how noise, density and spatial structure affect muscle ageing, we introduce the mechanism of stochastic survival of the densest, an alternative to replicative advantage, that may underpin other phenomena, like the evolution of altruism.