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

Andreazza, S. et al. (2019) Mitochondrially-targeted APOBEC1 is a potent mtDNA mutator affecting mitochondrial function and organismal fitness in Drosophila. Nature Communications, 10, 3280. (doi: 10.1038/s41467-019-10857-y) (PMID:31337756) (PMCID:PMC6650417)

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.

• Item Type: Articles
• Additional Information: This work is supported by MRC core funding (MC_UU_00015/4, MC-A070-5PSB0 and MC_UU_00015/6) and ERC Starting grant (DYNAMITO; 309742). S.A. was supported by an MRC Career Development Fellowship. A.G.D. receives support from NIHR Biomedical Research Centre pilot studies (RROI.GAAB). Work was further supported by DOD/CDMRP grant W81XWH-16-1-0579 to S.R.K., National Institute of Neurological Disorders and Stroke (R21NS090073) to L.J.P., and the Genetic Approaches to Aging Training Grant (T32AG000057) to C.L.S. P.F.C. is a Wellcome Trust Principal Research Fellow (212219/Z/18/Z), and a UK NIHR Senior Investigator, who receives support from the Medical Research Council Mitochondrial Biology Unit (MC_UP_1501/2), the Medical Research Council (UK) Centre for Translational Muscle Disease (G0601943), the Evelyn Trust, and the National Institute for Health Research (NIHR) Biomedical Research Centre based at Cambridge University Hospitals NHS Foundation Trust and the University of Cambridge. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. Stocks were obtained from the Bloomington Drosophila Stock Center which is supported by grant NIH P40OD018537.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Gammage, Dr Payam
• Authors: 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., and Whitworth, A. J.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Nature Communications
• Publisher: Nature Research
• ISSN: 2041-1723
• ISSN (Online): 2041-1723
• Copyright Holders: Copyright © 2019 The Authors
• First Published: First published in Nature Communications 10(1):3280
• Publisher Policy: Reproduced under a Creative Commons License