Decreasing mitochondrial RNA polymerase activity reverses biased inheritance of hypersuppressive mtDNA

Abstract

<jats:p>Faithful inheritance of mitochondrial DNA (mtDNA) is crucial for cellular respiration/oxidative phosphorylation and mitochondrial membrane potential. However, how mtDNA is transmitted to progeny is not fully understood. We utilized hypersuppressive mtDNA, a class of respiratory deficient <jats:italic>Saccharomyces cerevisiae</jats:italic> mtDNA that is preferentially inherited over wild-type mtDNA (<jats:italic>rho+</jats:italic>), to uncover the factors governing mtDNA inheritance. We found that some regions of <jats:italic>rho+</jats:italic> mtDNA persisted while others were lost after a specific hypersuppressive takeover indicating that hypersuppressive preferential inheritance may partially be due to active destruction of <jats:italic>rho+</jats:italic> mtDNA. From a multicopy suppression screen, we found that overexpression of putative mitochondrial RNA exonuclease <jats:italic>PET127</jats:italic> reduced biased inheritance of a subset of hypersuppressive genomes. This suppression required <jats:italic>PET127</jats:italic> binding to the mitochondrial RNA polymerase <jats:italic>RPO41</jats:italic> but not <jats:italic>PET127</jats:italic> exonuclease activity. A temperature-sensitive allele of <jats:italic>RPO41</jats:italic> improved <jats:italic>rho+</jats:italic> mtDNA inheritance over a specific hypersuppressive mtDNA at semi-permissive temperatures revealing a previously unknown role for <jats:italic>rho+</jats:italic> transcription in promoting hypersuppressive mtDNA inheritance.</jats:p>