The bottleneck for maternal transmission of mtDNA is linked to purifying selection by autophagy

Nov 12, 2025Science advances

Maternal inheritance of mitochondrial DNA is limited by cell cleanup processes that remove damaged parts

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Abstract

Tightening the mtDNA bottleneck increases heteroplasmic variance between individuals.

Mammalian mitochondrial DNA is inherited exclusively from the mother and has a high mutation rate.
The mtDNA bottleneck drives random transmission of maternal variants.
Tighter mtDNA bottlenecks lead to lower mutational burdens and altered ratios of nonsynonymous to synonymous mutations.
Reduced autophagy results in weaker purifying selection, increasing mutational burden and affecting mutation ratios.
The size of the mtDNA bottleneck may influence the effectiveness of purifying selection on mitochondrial mutations.

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Mammalian mitochondrial DNA (mtDNA) inheritance differs fundamentally from nuclear inheritance owing to exclusive maternal transmission, high mutation rate, and lack of recombination. Two key mechanisms shape this inheritance: the bottleneck, which drives stochastic transmission of maternal mtDNA variants, and purifying selection, which actively removes mutant mtDNA. Whether these mechanisms interact has been unresolved. To address this question, we generated a series of mouse models with random mtDNA mutations alongside alleles altering mtDNA copy number or decreasing autophagy. We demonstrate that tightening the mtDNA bottleneck increases heteroplasmic variance between individuals, causing lower mutational burden and nonsynonymous-to-synonymous ratios. In contrast, reduced autophagy weakens purifying selection, leading to decreased interoffspring heteroplasmic variance and increased mutational burden with higher nonsynonymous-to-synonymous ratios. These findings provide experimental evidence that the mtDNA bottleneck size modulates the efficacy of purifying selection. Our findings yield fundamental insights into the processes governing mammalian mtDNA transmission with direct implications for the origin and propagation of mtDNA mutations causing human disease.

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The bottleneck for maternal transmission of mtDNA is linked to purifying selection by autophagy

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