title: Mitochondrial depolarization in yeast zygotes inhibits clonal expansion of selfish mtDNA.
abstract: Non-identical copies of mitochondrial DNA (mtDNA) compete with each other within a cell and the ultimate variant of mtDNA present depends on their relative replication rates. Using yeastSaccharomyces cerevisiaecells as a model, we studied the effects of mitochondrial inhibitors on the competition between wild-type mtDNA and mutant selfish mtDNA in heteroplasmic zygotes. We found that decreasing mitochondrial transmembrane potential by adding uncouplers or valinomycin changes the competition outcomes in favor of the wild-type mtDNA. This effect was significantly lower in cells with disrupted mitochondria fission or repression of the autophagy-related genesATG8,ATG32orATG33, implying that heteroplasmic zygotes activate mitochondrial degradation in response to the depolarization. Moreover, the rate of mitochondrially targeted GFP turnover was higher in zygotes treated with uncoupler than in haploid cells or untreated zygotes. Finally, we showed that vacuoles of zygotes with uncoupler-activated autophagy contained DNA. Taken together, our data demonstrate that mitochondrial depolarization inhibits clonal expansion of selfish mtDNA and this effect depends on mitochondrial fission and autophagy. These observations suggest an activation of mitochondria quality control mechanisms in heteroplasmic yeast zygotes.
authors.affiliation: Faculty of Bioengineering and Bioinformatics, Moscow State University, Leninskiye Gory 1-73, Moscow 119991, Russia.
authors.forename: Iuliia E
authors.initials: IE
authors.lastname: Karavaeva
authors.affiliation: Belozersky Institute of Physico-Chemical Biology, Moscow State University, Leninskiye Gory 1-40, Moscow 119991, Russia.
authors.forename: Sergey A
authors.identifier: 0000-0002-4877-1061
authors.initials: SA
authors.lastname: Golyshev
authors.affiliation: Belozersky Institute of Physico-Chemical Biology, Moscow State University, Leninskiye Gory 1-40, Moscow 119991, Russia.
authors.forename: Ekaterina A
authors.initials: EA
authors.lastname: Smirnova
authors.affiliation: Belozersky Institute of Physico-Chemical Biology, Moscow State University, Leninskiye Gory 1-40, Moscow 119991, Russia.
authors.forename: Svyatoslav S
authors.identifier: 0000-0002-1395-8862
authors.initials: SS
authors.lastname: Sokolov
authors.affiliation: Belozersky Institute of Physico-Chemical Biology, Moscow State University, Leninskiye Gory 1-40, Moscow 119991, Russia.
authors.forename: Fedor F
authors.initials: FF
authors.lastname: Severin
authors.affiliation: Belozersky Institute of Physico-Chemical Biology, Moscow State University, Leninskiye Gory 1-40, Moscow 119991, Russia knorre@belozersky.msu.ru.
authors.forename: Dmitry A
authors.identifier: 0000-0001-7468-6963
authors.initials: DA
authors.lastname: Knorre
mesh_terms: D001343:Autophagy / Q000187:drug effects; D002259:Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone / Q000494:pharmacology; D002999:Clone Cells; D004272:DNA, Mitochondrial / Q000378:metabolism*; D004171:Diploidy; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008564:Membrane Potentials / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D063154:Mitochondrial Dynamics / Q000187:drug effects; D063306:Mitophagy / Q000187:drug effects; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D015053:Zygote / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure
chemical_list: D004272:DNA, Mitochondrial; D002259:Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone
keywords: ATG32; Heteroplasmy; Mitochondrial dynamics; Mitophagy; Uncoupler; mtDNA