Browsing by Subject "mitochondrial Medicine - Integrative Life Sciences"

Sort by: Order: Results:

Now showing items 1-1 of 1
  • Landoni Martin, Juan Cruz (Helsingin yliopisto, 2022)
    Mitochondria are organelles crucially involved in energy metabolism (hence the “powerhouses of the cell”) and most other cellular processes. They accommodate the second essential genome of the human cell: mitochondrial DNA (mtDNA). The integrity and quantity of mitochondrial genomes, as well as the systems in charge of its maintenance, have been associated with a wide variety of rare and common human diseases, as well as ageing. The causes behind such striking diversity in presentation remain largely unknown and an outstanding question for many fields of biology and medicine. One of the most prolific models for mitochondrial dysfunction is the prematurely ageing mtDNA Mutator mouse, carrying a defective mtDNA replicase that causes the accumulation of point mutations in mtDNA. Prompted by the observation that the Mutator mouse phenotype closely mimics that of other premature ageing models (typically related to nuclear DNA damage), we investigated the cell cycle and nuclear integrity in a stem cell model and its relationship with mtDNA replication. We discovered that, in addition to mtDNA mutations, Mutator mice also present accelerated mtDNA replication and rewiring of nucleotide metabolism. We developed the state-of-the-art methodology for deoxynucleotide quantification to confirm this observation and found that deoxynucleotides are being prioritised to mitochondria in stem cells, depriving nuclear replication of building blocks and causing DNA damage in the nucleus. The data reframe the mtDNA Mutator model as a secondary nuclear DNA instability model, unifying mouse premature ageing models under the same proposed mechanism. To further explore the aforementioned hypothesis and test recent reports on the beneficial effects of boosting mtDNA, we crossed the mtDNA Mutator mice with mice overexpressing the mtDNA helicase Twinkle, which further increased mtDNA replication and amount. This resulted in an unexpected and fatal neonatal heart failure phenotype. Characterising the mechanisms behind this pathology revealed intriguing effects in mtDNA integrity and maintenance, as well as large-scale metabolic stress responses which appear to disrupt normal heart development and maturation. Altogether, the thesis provides new paradigms on the roles of mtDNA replication in physiology. On one hand, its ability to influence cellular metabolism and threaten nuclear DNA stability in progenitor/stem cells, causing premature ageing. On the other, its role in early life maturation, opening the door to novel discoveries on its relationship to heart function, adaptation to oxygen, cell death signalling, and related human diseases.