Mitochondrially-targeted APOBEC1 is a potent mtDNA mutator affecting mitochondrial function and organismal fitness in Drosophila
Authors
Andreazza, Simonetta
Samstag, Colby
Sanchez-Martinez, Alvaro
Fernandez-Vizarra, Erika
Gomez-Duran, Aurora
Lee, Juliette
Tufi, Roberta
Hipp, Michael
Schmidt, Elizabeth
Nicholls, Thomas
Gammage, Payam
Pallanck, Leo
Kennedy, Scott
Journal Title
Nature Communications
ISSN
2041-1723
Publisher
Nature Publishing Group
Volume
10
Number
3280
Type
Article
This Version
VoR
Metadata
Show full item recordCitation
Whitworth, A., Andreazza, S., Samstag, C., Sanchez-Martinez, A., Fernandez-Vizarra, E., Gomez-Duran, A., Lee, J., et al. (2019). Mitochondrially-targeted APOBEC1 is a potent mtDNA mutator affecting mitochondrial function and organismal fitness in Drosophila. Nature Communications, 10 (3280)https://doi.org/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 proof-reading 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.
Sponsorship
European Commission FP7 ERC Starting Independent Researcher Grant (SIRG) (309742)
MRC (MC_UP_1501/1)
MRC (MC_UU_00015/6)
WELLCOME TRUST (101876/Z/13/Z)
Wellcome Trust (212219/Z/18/Z)
MRC (MC_UU_00015/4)
Embargo Lift Date
2100-01-01
Identifiers
External DOI: https://doi.org/10.1038/s41467-019-10857-y
This record's URL: https://www.repository.cam.ac.uk/handle/1810/293669