Current strategies towards therapeutic manipulation of mtDNA heteroplasmy

Front Biosci (Landmark Ed). 2017 Jan 1;22(6):991-1010. doi: 10.2741/4529.


Mitochondrial disease is a multifactorial disorder involving both nuclear and mitochondrial genomes. Over the past 20 years, great progress was achieved in the field of gene editing which raised the possibility of partial or complete elimination of mutant mtDNA that causes disease phenotypes. Each cell contains thousands of copies of mtDNA which can be either wild-type (WT) or mutant, a condition called heteroplasmy. As there are multiple copies of mtDNA inside a cell, the percentage of mutant mtDNA can vary and a directional shift in the heteroplasmy ratio towards an increase of WT mtDNA copies would have therapeutic value. Gene editing tools have been adapted to translocate to mitochondria and were able to change heteroplasmy in a predictable manner. These include mitochondrial targeted restriction endonucleases, Zinc-finger nucleases, and TAL-effector nucleases. These procedures could also be adapted to reduce the levels of mutant mtDNA in embryos, offering an option to the controversial mitochondrial replacement techniques during in vitro fertilization. The current strategies to induce heteroplasmy shift of mtDNA and its implications will be comprehensively discussed.

Publication types

  • Review

MeSH terms

  • Animals
  • DNA Restriction Enzymes / therapeutic use
  • DNA, Mitochondrial / genetics*
  • DNA, Mitochondrial / metabolism*
  • Energy Metabolism / genetics
  • Female
  • Gene Editing
  • Germ-Line Mutation
  • Humans
  • Male
  • Maternal Inheritance / genetics
  • Mitochondria / genetics
  • Mitochondria / metabolism
  • Mitochondrial Diseases / genetics*
  • Mitochondrial Diseases / metabolism
  • Mitochondrial Diseases / therapy*
  • Mitosis / genetics
  • Models, Genetic
  • Mutation*
  • Transcription Activator-Like Effector Nucleases / therapeutic use
  • Zinc Fingers


  • DNA, Mitochondrial
  • Transcription Activator-Like Effector Nucleases
  • DNA Restriction Enzymes