PhD Scientific Days 2023

Molecular Sciences - Posters L

Role of Autophagy in Maintaining the Integrity of the Mitochondrial and the Nuclear Genomes

Text of the abstract

Mitochondria are unique organelles, which contain their own genome (mitochondrial DNA (mtDNA)). Cells contain ten to thousand copies of mtDNA in proteins and DNA containing structures called nucleoids. Despite the crucial role of mitochondria, much remains elusive about mtDNA maintenance and replication. Autophagy is an evolutionarily conserved mechanism, which is activated upon various stresses including nutritional stress. It has been well documented that dysfunctional autophagy leads to aberrations in nuclear DNA integrity, however the mechanistic link between autophagy and DNA damage is still lacking. Previously, we have reported that, upon nitrogen starvation, yeast cells lacking autophagy cannot maintain their dNTP balance and degrade their mtDNA in a polymerase γ (POLG)-dependent fashion. Here, we show that, in parallel to the mtDNA degradation, autophagy-deficient cells also suffer from nuclear DNA damage, which can be abolished by blocking either the POLG-dependent mtDNA degradation or Porin1 (VDAC1 homologue)-dependent mtDNA escape. Moreover, we observe that deletion of certain DNA damage repair (DDR) components such as genes encoding the MRX complex or HR pathway proteins prevent both mtDNA degradation and consequent DNA damage in autophagy-deficient cells. Finally, we also show that, unlike their wt counterparts, autophagy-deficient cells cannot resolve nuclear DNA damage. Together, our findings suggest a model where inability of the autophagy-deficient cells to resolve DNA damage leads to accumulation of DNA damage, which is exacerbated by mtDNA degradation and its Porin1-dependent escape. The project is part of the The Collaborative Research Centre (CRC)/Sonderforschungsbereich (SFB) 1218, which is funded by the DFG (German Research Foundation).