Der Einfluss der mtDNA-Menge auf Zellfunktion und - dysfunktion

01.01.2027 bis 31.12.2029

Mitochondria are an essential organelle in almost all eukaryotic cells. Reminiscent of their endosymbiotic origin, they still contain their own genome. This mitochondrial DNA (mtDNA) encodes for several tRNAs, ribosomal RNAs, and proteins required for oxidative phosphorylation. Typically, cells contain multiple copies of mtDNA, and the copy number can vary dramatically from a few copies to several thousand, depending on organism, cell type and external conditions. Although multiple severe diseases as well as aging have been associated with altered mtDNA copy number, our understanding of how mtDNA copy number is regulated, and how it impacts on cell physiology and function is surprisingly limited.

In this project, we will use the budding yeast S. cerevisiae as a model to investigate how mtDNA copy number affects cell function. Building on our recent work and exploiting the powerful tools and resources available for budding yeast, we propose to apply a two-fold strategy:

First, we will genetically manipulate the concentration of nuclear encoded proteins controlling mtDNA copy number. This will enable us to alter mtDNA copy number several-fold, providing a unique opportunity to study the consequences on the spatiotemporal organization of mtDNA, on mitochondrial function, and on cell fitness. Through genetics screens, we will also identify molecular mechanisms that make cells robust to moderate mtDNA copy number changes.

Second, we will use a well-characterized collection of wild budding yeast isolates with pronounced differences in mtDNA copy number to reveal the link between natural variability of mtDNA copy number and cell function. Through genetic manipulation of mtDNA copy number, we will then identify causal relationships.

Taken together, our integrative approach, combining molecular biology, genetics, live-cell microscopy and AI-driven image analysis, as well as bioinformatics analysis of large data-sets, will enable us to obtain a detailed understanding of how mitochondrial copy number affects cell function. Given that both the function of mitochondria and key components of the nuclear encoded machinery that regulates mtDNA copy number are well conserved from yeast to humans, we anticipate that our work will guide future efforts to understand the contribution of mtDNA copy number changes to human cell function in health and disease.