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Nat Commun. 2019 Jul 23;10(1):3280. doi: 10.1038/s41467-019-10857-y.

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

Author information

1
MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge Biomedical Campus, Hills Road, Cambridge, CB2 0XY, UK.
2
Department of Genome Sciences, University of Washington, Seattle, WA, 98195, USA.
3
Department of Pathology, University of Washington, Seattle, WA, 98195, USA.
4
Department of Clinical Neuroscience, School of Clinical Medicine, University of Cambridge, Cambridge, CB2 0QQ, UK.
5
MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge Biomedical Campus, Hills Road, Cambridge, CB2 0XY, UK. a.whitworth@mrc-mbu.cam.ac.uk.

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.

PMID:
31337756
PMCID:
PMC6650417
DOI:
10.1038/s41467-019-10857-y
[Indexed for MEDLINE]
Free PMC Article

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