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

Simonetta Andreazza, Colby L. Samstag, Alvaro Sanchez-Martinez, Erika Fernandez-Vizarra, Aurora Gomez-Duran, Juliette J. Lee, Roberta Tufi, Michael J. Hipp, Elizabeth K. Schmidt, Thomas J. Nicholls, Payam A. Gammage, Patrick F. Chinnery, Michal Minczuk, Leo J. Pallanck, Scott R. Kennedy and Alexander J. Whitworth ()
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Simonetta Andreazza: University of Cambridge, Cambridge Biomedical Campus
Colby L. Samstag: University of Washington
Alvaro Sanchez-Martinez: University of Cambridge, Cambridge Biomedical Campus
Erika Fernandez-Vizarra: University of Cambridge, Cambridge Biomedical Campus
Aurora Gomez-Duran: University of Cambridge, Cambridge Biomedical Campus
Juliette J. Lee: University of Cambridge, Cambridge Biomedical Campus
Roberta Tufi: University of Cambridge, Cambridge Biomedical Campus
Michael J. Hipp: University of Washington
Elizabeth K. Schmidt: University of Washington
Thomas J. Nicholls: University of Cambridge, Cambridge Biomedical Campus
Payam A. Gammage: University of Cambridge, Cambridge Biomedical Campus
Patrick F. Chinnery: University of Cambridge, Cambridge Biomedical Campus
Michal Minczuk: University of Cambridge, Cambridge Biomedical Campus
Leo J. Pallanck: University of Washington
Scott R. Kennedy: University of Washington
Alexander J. Whitworth: University of Cambridge, Cambridge Biomedical Campus

Nature Communications, 2019, vol. 10, issue 1, 1-14

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.

Date: 2019
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DOI: 10.1038/s41467-019-10857-y

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