title: Homeostatic Responses Regulate Selfish Mitochondrial Genome Dynamics in C. elegans.
abstract: Mutant mitochondrial genomes (mtDNA) can be viewed as selfish genetic elements that persist in a state of heteroplasmy despite having potentially deleterious metabolic consequences. We sought to study regulation of selfish mtDNA dynamics. We establish that the large 3.1-kb deletion-bearing mtDNA variant uaDf5 is a selfish genome in Caenorhabditis elegans. Next, we show that uaDf5 mutant mtDNA replicates in addition to, not at the expense of, wild-type mtDNA. These data suggest the existence of a homeostatic copy-number control that is exploited by uaDf5 to "hitchhike" to high frequency. We also observe activation of the mitochondrial unfolded protein response (UPR(mt)) in uaDf5 animals. Loss of UPR(mt) causes a decrease in uaDf5 frequency, whereas its constitutive activation increases uaDf5 levels. UPR(mt) activation protects uaDf5 from mitophagy. Taken together, we propose that mtDNA copy-number control and UPR(mt) represent two homeostatic response mechanisms that play important roles in regulating selfish mitochondrial genome dynamics.
authors.affiliation: Department of Biological Sciences, Vanderbilt University, Nashville, TN 37232, USA; Interdisciplinary Graduate Program, Vanderbilt University, Nashville, TN 37232, USA.
authors.forename: Bryan L
authors.initials: BL
authors.lastname: Gitschlag
authors.affiliation: Department of Biological Sciences, Vanderbilt University, Nashville, TN 37232, USA; Biological Sciences Graduate Program, Vanderbilt University, Nashville, TN 37232, USA.
authors.forename: Cait S
authors.initials: CS
authors.lastname: Kirby
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37232, USA; Vanderbilt Genetics Institute, Vanderbilt University, Nashville, TN 37232, USA.
authors.forename: David C
authors.initials: DC
authors.lastname: Samuels
authors.affiliation: Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
authors.forename: Rama D
authors.initials: RD
authors.lastname: Gangula
authors.affiliation: Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Institute for Immunology and Infectious Diseases, Murdoch University, Murdoch, WA 6150, Australia.
authors.forename: Simon A
authors.initials: SA
authors.lastname: Mallal
authors.affiliation: Department of Biological Sciences, Vanderbilt University, Nashville, TN 37232, USA; Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN 37232, USA. Electronic address: maulik.r.patel@vanderbilt.edu.
authors.forename: Maulik R
authors.initials: MR
authors.lastname: Patel
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics*; D004272:DNA, Mitochondrial / Q000235:genetics; D017353:Gene Deletion; D018628:Gene Dosage; D054629:Genome, Mitochondrial; D006706:Homeostasis / Q000235:genetics*; D063154:Mitochondrial Dynamics; D009154:Mutation / Q000235:genetics; D034622:RNA Interference; D014158:Transcription, Genetic; D056811:Unfolded Protein Response / Q000235:genetics
chemical_list: D004272:DNA, Mitochondrial
keywords: C. elegans; droplet digital PCR; evolution; heteroplasmy; mitochondrial unfolded protein response; mitophagy; mtDNA; mtDNA copy number control; selfish genetic element