Homeostatic Responses Regulate Selfish Mitochondrial Genome Dynamics in C. elegans

Cell Metab. 2016 Jul 12;24(1):91-103. doi: 10.1016/j.cmet.2016.06.008.

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.

Keywords: C. elegans; droplet digital PCR; evolution; heteroplasmy; mitochondrial unfolded protein response; mitophagy; mtDNA; mtDNA copy number control; selfish genetic element.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Caenorhabditis elegans / genetics*
  • DNA, Mitochondrial / genetics
  • Gene Deletion
  • Gene Dosage
  • Genome, Mitochondrial*
  • Homeostasis / genetics*
  • Mitochondrial Dynamics
  • Mutation / genetics
  • RNA Interference
  • Transcription, Genetic
  • Unfolded Protein Response / genetics

Substances

  • DNA, Mitochondrial