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Mitochondrial DNA Regulation: The Connection between Cell Size and the Amount of Genetic Material

Featured Publication, IFE,

A recent discovery led by Dr. Anika Seel and Dr. Kurt Schmoller at the Institute for Functional Epigenetics (IFE) at Helmholtz Munich has uncovered a fascinating link between cell size and mitochondrial DNA regulation, shedding light on a previously mysterious aspect of cellular biology.

In humans and all other animals, as well as in plants and fungi, the genetic information, that is the DNA, is tightly packed in the nucleus within the cell. These life forms are known as eukaryotes, differing from simpler organisms like bacteria, which lack a nucleus. In addition to the majority of genes that are encoded by this nuclear DNA, almost all eukaryotic organisms, also contain a second essential type of DNA located in the mitochondria, a cell compartment responsible for the energy production in the cell. This mitochondrial DNA is a remnant of the ancient endosymbiotic event in which a bacterial cell was engulfed by the proto-eukaryote and eventually evolved into the mitochondria we see today. Mitochondrial DNA contains a few genes that are essential for mitochondria to fulfill their critical function in cellular metabolism, in particular production of ATP, the ‘energy currency’ of the cell (this is why the mitochondria got its fame as the ‘powerhouse of the cell’).

Mitochondrial DNA Copy Number Increases with Cell Volume

Typically, cells have multiple copies of the mitochondrial genome, and the amount of mitochondrial DNA needs to be controlled by the cell to avoid severe metabolic diseases. The nuclear DNA is doubled each cell cycle so that every new cell has the exact same amount of nuclear DNA as the original cell. However, it is still unclear how proliferating cells regulate the replication of mitochondrial DNA, so that after cell division, each daughter cell inherits the right amount. A team of researchers led by Dr. Anika Seel and Dr. Kurt Schmoller at Helmholtz Munich now found that mitochondrial DNA copy number is tightly coupled to the size of cells. Specifically, larger cells have proportionally more DNA, which allows growing cells to always maintain constant concentrations.

Using the unicellular baker’s yeast as a model, the research team and their collaborators were able to identify the molecular basis for this regulation. During evolution, mitochondria transferred most of their genes to the nuclear DNA, including all the genes that are needed for the replication of mitochondrial DNA. Because larger cells typically produce more of the proteins that are encoded by the genes of the nuclear DNA, they also produce more of those factors that are necessary for mitochondrial DNA replication. This then leads to larger cells producing more mitochondrial DNA.

“Understanding this fundamental principle of mitochondrial DNA regulation in healthy cells is an important step towards understanding diseases caused by misregulation of mitochondrial DNA”, says Kurt Schmoller. “Based on our findings, researchers can now study how this regulation fails in patients with mitochondrial diseases. In the future, this will hopefully lead the way to new therapeutic interventions”.


Original publication

Seel et. al (2023): Regulation with cell size ensures mitochondrial DNA homeostasis during cell growth. Nature Structural & Molecular Biology. DOI: 10.1038/s41594-023-01091-8

About the scientists

Dr. Anika Seel, former PhD student in the Schmoller group at Helmholtz Munich
Dr. Kurt Schmoller, group leader at the Institute of Functional Epigenetics at Helmholtz Munich


Funding information

This work was funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation)—431480687 and 459304237, by the Human Frontier Science Program (career development award to K.M.S.), by the Elitenetzwerk Bayern through the Biological Physics program (T.K.) and the Helmholtz Gesellschaft.

Dr. Kurt Schmoller

Group Leader