Dynamic reorganization and selective segregation of mitochondria under DarT-mediated mtDNA damage

Abstract

Mitochondria are dynamic organelles that play essential roles in cell growth and survival. Processes of fission and fusion are critical for distribution, segregation and maintenance of mitochondria and their genomes (mtDNA). While recent work has revealed the significance of mitochondrial organization for mtDNA maintenance, impact of mtDNA perturbations on mitochondrial dynamics remains less understood. Here we develop a tool to induce mitochondria-specific DNA damage, using a mitochondrial-targeted base modifying bacterial toxin, DarT. Following damage, we observe dynamic reorganization of mitochondrial networks, likely driven by mitochondrial dysfunction. Changes in organization are associated with loss of mtDNA, independent of mitophagy. Unexpectedly, perturbation to exonuclease function of mtDNA replicative polymerase, Mip1, results in rapid loss of mtDNA. Our data suggest that, under damage, partitioning of defective mtDNA and organelle are de-coupled, with emphasis on mitochondrial segregation independent of its DNA. Together, our works underscores the importance of genome maintenance on mitochondrial function, that can act as a modulator of organelle organization and segregation.