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


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Authors
Andreazza, Simonetta  ORCID logo  https://orcid.org/0000-0001-8816-4955
Sanchez-Martinez, Alvaro  ORCID logo  https://orcid.org/0000-0002-2728-6251
Fernandez-Vizarra, Erika  ORCID logo  https://orcid.org/0000-0002-2469-142X
Gomez-Duran, Aurora  ORCID logo  https://orcid.org/0000-0002-5895-6860
Abstract

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.

Description
Keywords
Article, /631/208/191/1908, /631/208/737, /38, /38/1, /38/88, /38/77, /45/23, /45/29, /64/24, /45/22, article
Journal Title
Nature Communications
Conference Name
Journal ISSN
2041-1723
Volume Title
10
Publisher
Nature Publishing Group UK