Andreazza, S., Samstag, C.L., Sanchez-Martinez, A., Fernandez-Vizarra, E., Gomez-Duran, A., Lee, J.J., Tufi, R., Hipp, M.J., Schmidt, E.K., Nicholls, T.J., Gammage, P.A., Chinnery, P.F., Minczuk, M., Pallanck, L.J., Kennedy, S.R., Whitworth, A.J. (2019). Mitochondrially-targeted APOBEC1 is a potent mtDNA mutator affecting mitochondrial function and organismal fitness in Drosophila.  Nat. Commun. 10(1): 3280.

FBrf0243041

Research paper

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.

PMC6650417 (PMC) (EuropePMC)