Advances in methods for reducing mitochondrial DNA disease by replacing or manipulating the mitochondrial genome

Essays Biochem. 2018 Jul 20;62(3):455-465. doi: 10.1042/EBC20170113. Print 2018 Jul 20.

Abstract

Mitochondrial DNA (mtDNA) is a multi-copy genome whose cell copy number varies depending on tissue type. Mutations in mtDNA can cause a wide spectrum of diseases. Mutated mtDNA is often found as a subset of the total mtDNA population in a cell or tissue, a situation known as heteroplasmy. As mitochondrial dysfunction only presents after a certain level of heteroplasmy has been acquired, ways to artificially reduce or replace the mutated species have been attempted. This review addresses recent approaches and advances in this field, focusing on the prevention of pathogenic mtDNA transfer via mitochondrial donation techniques such as maternal spindle transfer and pronuclear transfer in which mutated mtDNA in the oocyte or fertilized embryo is substituted with normal copies of the mitochondrial genome. This review also discusses the molecular targeting and cleavage of pathogenic mtDNA to shift heteroplasmy using antigenomic therapy and genome engineering techniques including Zinc-finger nucleases and transcription activator-like effector nucleases. Finally, it considers CRISPR technology and the unique difficulties that mitochondrial genome editing presents.

Keywords: mitochondrial dysfunction; mitochondrial therapeuticsss; mtDNA.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Clustered Regularly Interspaced Short Palindromic Repeats
  • DNA Restriction Enzymes / metabolism
  • DNA, Mitochondrial / genetics*
  • Gene Editing / methods*
  • Genetic Engineering
  • Genetic Therapy*
  • Genome, Mitochondrial / genetics*
  • Humans
  • Mitochondrial Diseases / diagnosis
  • Mitochondrial Diseases / genetics*
  • Mitochondrial Diseases / metabolism
  • Mitochondrial Diseases / prevention & control*
  • Nuclear Transfer Techniques
  • Oxidative Phosphorylation
  • Preimplantation Diagnosis
  • Trans-Activators / metabolism
  • Zinc Fingers

Substances

  • DNA, Mitochondrial
  • Trans-Activators
  • DNA Restriction Enzymes