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

https://www.nature.com/articles/s41467-019-10857-y

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 & Alexander J. Whitworth

• The authors describe a new mtDNA mutator model, whereby a cytidine deaminase is targetted to mitochondria to induce mutations (mito-APOBEC1), in fruit flies.
• The most established system for understanding the physiological consequences of mtDNA mutation is to knock-in a proofreading deficient version of the mtDNA polymerase (POLG). Doing so introduces high levels of point mutations, and also small indels, but has surprisingly limited impact on organismal longevity or fitness in flies, given the level of mutation which this mutation induces (see here). In contrast, mito-APOBEC1 exclusively introduces C:G>T:A transitions (which is the most predominant mutation profile in human ageing), with no indels or mtDNA depletion. The authors argue that mutations of this type (rather than those induced by the POLG mutation) cause dramatic reduction in organismal fitness, even at modest heteroplasmy.