Mammalian cells prevent the gradual buildup of harmful mutations in mitochondrial DNA (mtDNA) – the vital genome powering every cell – through a surprisingly effective process: natural selection at the microscopic level. Researchers at the Karolinska Institutet have discovered how this works, revealing a connection between the number of mtDNA copies passed from mother to offspring and the effectiveness of weeding out defective molecules. The study, published in Science Advances, explains why mtDNA inheritance remains stable despite its rapid mutation rate and exclusive maternal transmission.
The Problem of Maternal Inheritance
Unlike nuclear DNA, which benefits from recombination and dual-parent inheritance, mtDNA is passed down solely from the mother. This makes it uniquely vulnerable to the irreversible accumulation of mutations over generations. Without a mechanism to correct errors, mtDNA could eventually suffer a “mutational meltdown,” threatening species survival. Evolution, however, has equipped cells with two protective measures: a genetic bottleneck and purifying selection.
The Two-Step Defense System
The genetic bottleneck is a stochastic process where only a subset of all mtDNA copies in the mother is transmitted to her offspring. This random sampling creates genetic variation between individuals. Purifying selection then actively eliminates mutated mtDNA molecules as the egg develops. Until now, the connection between these two processes and the molecular mechanisms of purifying selection were unknown.
Smaller Bottlenecks, Healthier mtDNA
Using mouse models, researchers found that fewer mtDNA copies passed from mother to offspring actually resulted in lower mutation burdens in the next generation. A smaller genetic bottleneck allows purifying selection to work more effectively, removing defective mtDNA. Conversely, disrupting the cell’s ability to recycle damaged mitochondria through impaired autophagy weakened this filtering process. Harmful mutations accumulated, and mtDNA quality declined.
Autophagy: The Cellular Recycler
Autophagy – the process where cells break down and recycle damaged components – plays a critical role in mtDNA quality control. When autophagy is impaired, defective mtDNA accumulates because the cell cannot efficiently remove it. This highlights the importance of cellular “housekeeping” in maintaining mtDNA integrity.
Evolutionary Stability and Disease Implications
“Our results show that the size of the mitochondrial bottleneck determines how effectively mutated mitochondrial DNA can be removed during maternal transmission,” explains Nils-Göran Larsson, Professor at the Department of Medical Biochemistry and Biophysics at Karolinska Institutet. “This provides a mechanistic explanation for how mitochondrial inheritance remains stable over evolutionary time.”
Understanding this process has major biomedical implications. Mutations in mtDNA are linked to a wide range of diseases, including mitochondrial disorders, cancer, neurodegeneration, diabetes, and aging. By uncovering the link between mitochondrial turnover, bottleneck size, and selection, researchers now have a clearer view of how cells maintain healthy mitochondria – and where this process might fail in disease.
Therapeutic Potential
“By uncovering the link between mitochondrial turnover, bottleneck size, and selection, we now have a clearer view of how cells can maintain healthy mitochondria—and where this process might fail in disease,” says Laura Kremer, first author and currently researcher at the University of Göttingen. The findings establish a framework for studying how mtDNA quality control could be enhanced therapeutically, offering new perspectives for conditions driven by mitochondrial genome instability. The research suggests that manipulating the bottleneck size or enhancing autophagy could be potential strategies for preventing or treating diseases linked to mtDNA mutations
