دورية أكاديمية
Mitochondrially-targeted APOBEC1 is a potent mtDNA mutator affecting mitochondrial function and organismal fitness in Drosophila.
| العنوان: | Mitochondrially-targeted APOBEC1 is a potent mtDNA mutator affecting mitochondrial function and organismal fitness in Drosophila. |
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| المؤلفون: | Andreazza S; MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge Biomedical Campus, Hills Road, Cambridge, CB2 0XY, UK., Samstag CL; Department of Genome Sciences, University of Washington, Seattle, WA, 98195, USA., Sanchez-Martinez A; MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge Biomedical Campus, Hills Road, Cambridge, CB2 0XY, UK., Fernandez-Vizarra E; MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge Biomedical Campus, Hills Road, Cambridge, CB2 0XY, UK., Gomez-Duran A; MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge Biomedical Campus, Hills Road, Cambridge, CB2 0XY, UK., Lee JJ; MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge Biomedical Campus, Hills Road, Cambridge, CB2 0XY, UK., Tufi R; MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge Biomedical Campus, Hills Road, Cambridge, CB2 0XY, UK., Hipp MJ; Department of Pathology, University of Washington, Seattle, WA, 98195, USA., Schmidt EK; Department of Pathology, University of Washington, Seattle, WA, 98195, USA., Nicholls TJ; MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge Biomedical Campus, Hills Road, Cambridge, CB2 0XY, UK., Gammage PA; MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge Biomedical Campus, Hills Road, Cambridge, CB2 0XY, UK., Chinnery PF; MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge Biomedical Campus, Hills Road, Cambridge, CB2 0XY, UK.; Department of Clinical Neuroscience, School of Clinical Medicine, University of Cambridge, Cambridge, CB2 0QQ, UK., Minczuk M; MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge Biomedical Campus, Hills Road, Cambridge, CB2 0XY, UK., Pallanck LJ; Department of Genome Sciences, University of Washington, Seattle, WA, 98195, USA., Kennedy SR; Department of Pathology, University of Washington, Seattle, WA, 98195, USA., Whitworth AJ; MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge Biomedical Campus, Hills Road, Cambridge, CB2 0XY, UK. a.whitworth@mrc-mbu.cam.ac.uk. |
| المصدر: | Nature communications [Nat Commun] 2019 Jul 23; Vol. 10 (1), pp. 3280. Date of Electronic Publication: 2019 Jul 23. |
| نوع المنشور: | Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: Nature Pub. Group Country of Publication: England NLM ID: 101528555 Publication Model: Electronic Cited Medium: Internet ISSN: 2041-1723 (Electronic) Linking ISSN: 20411723 NLM ISO Abbreviation: Nat Commun Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: [London] : Nature Pub. Group |
| مواضيع طبية MeSH: | APOBEC-1 Deaminase/*physiology , DNA, Mitochondrial/*chemistry , Drosophila/*genetics, APOBEC-1 Deaminase/genetics ; APOBEC-1 Deaminase/metabolism ; Animals ; Drosophila/physiology ; Mitochondria/metabolism ; Mitochondria/physiology ; Models, Genetic ; Mutation ; Organisms, Genetically Modified |
| مستخلص: | 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. |
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| معلومات مُعتمدة: | MC_UU_00015/6 United Kingdom MRC_ Medical Research Council; MC_UP_1501/1 United Kingdom MRC_ Medical Research Council; R21 NS090073 United States NS NINDS NIH HHS; P40 OD018537 United States OD NIH HHS; T32 AG000057 United States AG NIA NIH HHS; United Kingdom WT_ Wellcome Trust; MC_UU_00015/4 United Kingdom MRC_ Medical Research Council; G0601943 United Kingdom MRC_ Medical Research Council |
| المشرفين على المادة: | 0 (DNA, Mitochondrial) EC 3.5.4.36 (APOBEC-1 Deaminase) |
| تواريخ الأحداث: | Date Created: 20190725 Date Completed: 20200204 Latest Revision: 20240306 |
| رمز التحديث: | 20240306 |
| مُعرف محوري في PubMed: | PMC6650417 |
| DOI: | 10.1038/s41467-019-10857-y |
| PMID: | 31337756 |
| قاعدة البيانات: | MEDLINE |
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