title: Activation of the pleiotropic drug resistance pathway can promote mitochondrial DNA retention by fusion-defective mitochondria in Saccharomyces cerevisiae.
abstract: Genetic and microscopic approaches using Saccharomyces cerevisiae have identified many proteins that play a role in mitochondrial dynamics, but it is possible that other proteins and pathways that play a role in mitochondrial division and fusion remain to be discovered. Mutants lacking mitochondrial fusion are characterized by rapid loss of mitochondrial DNA. We took advantage of a petite-negative mutant that is unable to survive mitochondrial DNA loss to select for mutations that allow cells with fusion-deficient mitochondria to maintain the mitochondrial genome on fermentable medium. Next-generation sequencing revealed that all identified suppressor mutations not associated with known mitochondrial division components were localized to PDR1 or PDR3, which encode transcription factors promoting drug resistance. Further studies revealed that at least one, if not all, of these suppressor mutations dominantly increases resistance to known substrates of the pleiotropic drug resistance pathway. Interestingly, hyperactivation of this pathway did not significantly affect mitochondrial shape, suggesting that mitochondrial division was not greatly affected. Our results reveal an intriguing genetic connection between pleiotropic drug resistance and mitochondrial dynamics.
authors.affiliation: Department of Molecular Biology and Genetic, Koç University, Sarıyer, İstanbul, 34450, Turkey.
authors.forename: Nebibe
authors.initials: N
authors.lastname: Mutlu
authors.affiliation: Department of Molecular Biology and Genetic, Koç University, Sarıyer, İstanbul, 34450, Turkey.
authors.forename: Görkem
authors.initials: G
authors.lastname: Garipler
authors.affiliation: Department of Molecular Biology and Genetic, Koç University, Sarıyer, İstanbul, 34450, Turkey.
authors.forename: Emel
authors.initials: E
authors.lastname: Akdoğan
authors.affiliation: Department of Molecular Biology and Genetic, Koç University, Sarıyer, İstanbul, 34450, Turkey cdunn@ku.edu.tr.
authors.forename: Cory D
authors.initials: CD
authors.lastname: Dunn
mesh_terms: D000483:Alleles; D004272:DNA, Mitochondrial / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics; D004352:Drug Resistance, Microbial / Q000235:genetics*; D020558:GTP Phosphohydrolases / Q000235:genetics / Q000378:metabolism; D059014:High-Throughput Nucleotide Sequencing; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008928:Mitochondria / Q000235:genetics*; D000226:Mitochondrial ADP, ATP Translocases / Q000235:genetics / Q000378:metabolism; D063154:Mitochondrial Dynamics; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D012441:Saccharomyces cerevisiae / Q000235:genetics*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism; D017422:Sequence Analysis, DNA; D014157:Transcription Factors / Q000235:genetics
chemical_list: D004272:DNA, Mitochondrial; D004268:DNA-Binding Proteins; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; C085480:PDR1 protein, S cerevisiae; C089261:PDR3 protein, S cerevisiae; C112225:PET9 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D014157:Transcription Factors; D000226:Mitochondrial ADP, ATP Translocases; C401395:FZO1 protein, S cerevisiae; D020558:GTP Phosphohydrolases
keywords: bulk segregant analysis; drug resistance; mitochondrial genome; mitochondrial shape; petite-negative