Scientists discover mechanism of competition between coexisting mitochondrial genomes

Research at the National Center for Cardiovascular Investigators (CNIC) has identified the mechanism of competition between different mitochondrial genomes that coexist in the same cell. The study, published today in Scientific advances, examines why the simultaneous presence of more than one variant of mitochondrial DNA (mtDNA) in a cell is rejected in most cells, which select a single variant of mtDNA whose identity depends on the tissue.

The study was coordinated by Dr. José Antonio Enríquez, head of the Functional Genetics Laboratory of the CNIC Oxidative Phosphorylation System. Mitochondrial DNA is a genetic material transmitted exclusively from the mother to the offspring. The research team found that selection between mtDNAs present in the same cell depends on their impact on cell metabolism and can be influenced by differences in gene function, drug action, or changes in diet. Together these factors determine the preference for a particular mtDNA variant.

The study is the result of more than five years of research and collaborations with various laboratories across Europe. The results show that cells can detect the presence of mitochondria with different mtDNA genomes and select the most suitable variant for the metabolic needs of the specific cell type. This explains how the selected mtDNA variant may differ between cell types.

“The study establishes that the selection of a mtDNA variant depends on the cell type and not on the tissue, as previously thought,” explained Dr. Ana Victoria Lechuga-Vieco, first author of the study. “The preference of a cell for a specific mitochondrial variant depends on the metabolic program of the cell and various nuclear genes that have subtle effects on metabolism and control of mitochondrial quality. We have shown that this mechanism is a process of functional selection” .

Mitochondria are organelles present in the cytoplasm of most eukaryotic cells. Mitochondria provide most of the energy available in the cell by generating ATP (Adenosine Triphosphate), the main source of energy in living organisms, in the respiratory chain. Mitochondria have their own DNA, which represents only 0.2% of genetic information in humans and encodes 37 genes.

“The coexistence of more than one mtDNA variant in the same cell is more common than expected in humans and may be the result of new treatments for mitochondrial diseases and new medical technologies involving mitochondrial donation. This situation is technically defined as heteroplasmia. Understanding the implications Heteroplasmia is vital to assess the safety of the procedures that cause it, “explained Dr. Enriquez.

Dr. Ana Latorre-Pellicer, co-author of the article and currently a researcher at the University of Zaragoza, says that the new study “provides the first description of the presence of the mitochondrial genome more than once at the cellular level, in addition to defining the mechanism of competition between different mitochondrial genomes within the same cell. “

The research was conducted using mice with distinct mitochondrial genomes that coexist in individual cells. This model system allowed the team to determine how cells select a mitochondrial variant to avoid the presence of more than one type of mtDNA and to study the complexity of communication between cell nuclei and mitochondria.

Furthermore, the researchers add, the study has identified molecular targets for developing tools to control mtDNA selection and cellular metabolism to prevent accidental generation of heteroplasmia through new medical procedures. These new technologies include transplantation of healthy mitochondria to prevent mitochondrial diseases, injection of mitochondria into oocytes to increase fertility, and proposed transfer of mitochondria into cellular therapies to treat various diseases, including cardiovascular, lung, and neurological diseases.

Provided by the Carlos III National Cardiovascular Research Center (FSP)