Local mitochondrial physiology defined by mtDNA quality guides purifying selection

Thoma, Felix; Hagen, Johannes; Rathberger, Romina; Padovani, Francesco; Hörl, David; Schmoller, Kurt M.; Osman, Christof; Peñalva, Miguel A. (2026): Local mitochondrial physiology defined by mtDNA quality guides purifying selection. PLOS Genetics, 22 (1). e1011836. ISSN 1553-7404

Abstract

Mitochondria are essential organelles in our cells that convert nutrients into usable cellular energy. They contain their own DNA, and mutations in this DNA can compromise mitochondrial function and contribute to disease. In this work, we asked how cells recognize and limit the transmission of defective mitochondrial DNA. Using baker’s yeast as a model system, we developed a rapid approach that allows us to track how healthy and mutant mitochondrial DNA variants are inherited when cells divide. We found that cells preferentially retain mitochondrial DNA that supports normal mitochondrial function, even under conditions where respiration is not required. By combining cell sorting, growth measurements, microscopy, and simulations, we show that this selective process is influenced not only by the initial abundance of each mitochondrial genome, but also by localized physiological differences within the mitochondrial network. Regions containing mutant mitochondrial DNA exhibit reduced membrane potential and lower ATP availability, making them distinguishable from regions harboring intact genomes. When we impaired the respiratory chain, these physiological differences disappeared and selective quality control broke down. Our findings suggest that cells rely on local mitochondrial signals to preserve functional mitochondrial DNA, offering insight into how healthy mitochondria are maintained across generations.

• Doc-Type: Article (LMU)
• Organisational unit (Faculties): 19 Biology > Department Biology I; 19 Biology > Department Biology II
• DFG subject classification of scientific disciplines: Natural sciences
• DFG: Funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) - 513597632
• DFG: Funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) - 491502892