Mitochondrially-targeted APOBEC1 is a potent mtDNA mutator affecting mitochondrial function and organismal fitness in Drosophila

Nat Commun. 2019 Jul 23;10(1):3280. doi: 10.1038/s41467-019-10857-y.

Abstract

Somatic mutations in the mitochondrial genome (mtDNA) have been linked to multiple disease conditions and to ageing itself. In Drosophila, knock-in of a proofreading deficient mtDNA polymerase (POLG) generates high levels of somatic point mutations and also small indels, but surprisingly limited impact on organismal longevity or fitness. Here we describe a new mtDNA mutator model based on a mitochondrially-targeted cytidine deaminase, APOBEC1. mito-APOBEC1 acts as a potent mutagen which exclusively induces C:G>T:A transitions with no indels or mtDNA depletion. In these flies, the presence of multiple non-synonymous substitutions, even at modest heteroplasmy, disrupts mitochondrial function and dramatically impacts organismal fitness. A detailed analysis of the mutation profile in the POLG and mito-APOBEC1 models reveals that mutation type (quality) rather than quantity is a critical factor in impacting organismal fitness. The specificity for transition mutations and the severe phenotypes make mito-APOBEC1 an excellent mtDNA mutator model for ageing research.

Publication types

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

MeSH terms

  • APOBEC-1 Deaminase / genetics
  • APOBEC-1 Deaminase / metabolism
  • APOBEC-1 Deaminase / physiology*
  • Animals
  • DNA, Mitochondrial / chemistry*
  • Drosophila / genetics*
  • Drosophila / physiology
  • Mitochondria / metabolism
  • Mitochondria / physiology
  • Models, Genetic
  • Mutation
  • Organisms, Genetically Modified

Substances

  • DNA, Mitochondrial
  • APOBEC-1 Deaminase