Modeling pathogenic mutations of human twinkle in Drosophila suggests an apoptosis role in response to mitochondrial defects
Open accessAbstract
The human gene C10orf2 encodes the mitochondrial replicative DNA helicase Twinkle, mutations of which are responsible for a significant fraction of cases of autosomal dominant progressive external ophthalmoplegia (adPEO), a human mitochondrial disease caused by defects in intergenomic communication. We report the analysis of orthologous mutations in the Drosophila melanogaster mitochondrial DNA (mtDNA) helicase gene, d-mtDNA helicase. Increased expression of wild type d-mtDNA helicase using the UAS-GAL4 system leads to an increase in mtDNA copy number throughout adult life without any noteworthy phenotype, whereas overexpression of d-mtDNA helicase containing the K388A mutation in the helicase active site results in a severe depletion of mtDNA and a lethal phenotype. Overexpression of two d-mtDNA helicase variants equivalent to two human adPEO mutations shows differential effects. The A442P mutation exhibits a dominant negative effect similar to that of the active site mutant. In contrast, overexpression of d-mtDNA helicase containing the W441C mutation results in a slight decrease in mtDNA copy number during the third instar larval stage, and a moderate decrease in life span in the adult population. Overexpression of d-mtDNA helicase containing either the K388A or A442P mutations causes a mitochondrial oxidative phosphorylation (OXPHOS) defect that significantly reduces cell proliferation. The mitochondrial impairment caused by these mutations promotes apoptosis, arguing that mitochondria regulate programmed cell death in Drosophila. Our study of d-mtDNA helicase overexpression provides a tractable Drosophila model for understanding the cellular and molecular effects of human adPEO mutations.
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31 dominant and 3 recessive Twinkle mutations have been recognized, the majority of which cause age-related disease.
“In all, 31 dominant and 3 recessive mutations have been recognized, the majority of which cause age-related disease (Sanchez-Martinez et al., 2012; Spelbrink et al., 2001).”
From Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases (2017) · cites this paper as Sanchez-Martinez et al., 2012
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- [30]Ziviani E, Whitworth AJ (2010) How could Parkin-mediated ubiquitination of mitofusin promote mitophagy? Autophagy 6. PMC4196639 20484985
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- Authors
- Sanchez-Martinez, A., Calleja, M., Peralta, S., Matsushima, Y., Hernandez-Sierra, R., Whitworth, A. J., Kaguni, L. S., & Garesse, R.
- Affiliations
- Consejo Superior de Investigaciones Científicas (ES)
- Michigan State University (US)
- University of Sheffield (GB)
- Corresponding author
- Garesse, Rafael
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2012-08-28
- Volume
- 7
- Issue
- 8
- Pages
- e43954
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC3429445
- OpenAlex
- W2092574106
- Cited by
- 25
- References
- 48
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 3 · 2023: 3 · 2022: 2 · 2021: 1 · 2019: 1 · 2018: 3 · 2017: 1 · 2016: 1 · 2015: 3 · 2014: 3 · 2013: 1
- FWCI
- 0.90
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- White Rose Research Online (University of Leeds, The University of Sheffield, University of York) (acceptedVersion)
- Tesis Doctorals en Xarxa (Consorci de Serveis Universitaris de Catalunya) (submittedVersion)
- DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Hispana (submittedVersion, other-oa)
- Biblos-e Archivo (Universidad Autónoma de Madrid) (submittedVersion, public-domain)
- Funders
- Wellcome Trust (089698)
- Comunidad de Madrid (GEN-0269, GEN-0269/2006)
- Centro de Biología Molecular Severo Ochoa
- National Institutes of Health
- Medical Research Council (MC_G1000735)
- Instituto de Salud Carlos III (PI 07/0167)
- National Institute of General Medical Sciences (R01GM045295, GM45295)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Keywords
- Twinkle helicase, chronic progressive external ophthalmoplegia, mitochondrial DNA helicase, Drosophila melanogaster, pathogenic variants, mitochondrial DNA copy number, apoptosis, oxidative phosphorylation defects, dominant negative effect, mitochondrial disease, lifespan, cell proliferation
- MeSH terms
- Amino Acid Sequence, Animals, Disease Models, Animal, DNA Helicases, Drosophila melanogaster, Humans, Longevity, Male, Mitochondria, Mutation, Ophthalmoplegia, Oxidative Phosphorylation, Apoptosis, Mitochondrial Proteins, Mitochondrial Diseases, Cell Proliferation, Mice
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