|Title||Mitochondrially-targeted APOBEC1 is a potent mtDNA mutator affecting mitochondrial function and organismal fitness in Drosophila|
|Publication Type||Journal Article|
|Year of Publication||2019|
|Authors||Andreazza, S, Samstag, CL, Sanchez-Martinez, A, Fernandez-Vizarra, E, Gomez-Duran, A, Lee, JJ, Tufi, R, Hipp, MJ, Schmidt, EK, Nicholls, TJ, Gammage, PA, Chinnery, PF, Minczuk, M, Pallanck, LJ, Kennedy, SR, Whitworth, AJ|
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.
|Short Title||Nature Communications|