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Front. Genet. | doi: 10.3389/fgene.2019.00245

A Drosophila mitochondrial Complex I deficiency phenotype array

 Sarah Foriel1, 2, 3,  Herma Renkema1, 2, 3,  Yvonne Lasarzewski2, 3, Job Berkhout1,  Richard J. Rodenburg2, 3, Jan A. Smeitink1, 2, 3,  Julien Beyrath1* and  Annette Schenck3, 4, 5*
  • 1Khondrion BV, Netherlands
  • 2Department of Pediatrics, Radboud Center for Mitochondrial Medicine (RCMM), Netherlands
  • 3Radboud University Nijmegen Medical Centre, Netherlands
  • 4Department of Human Genetics, Radboud University, Netherlands
  • 5Donders Institute for Brain, Cognition and Behaviour, Radboud University, Netherlands

Mitochondrial diseases are a group of rare life-threatening diseases often caused by defects in the oxidative phosphorylation system. No effective treatment is available for these disorders. Therapeutic development is hampered by the high heterogeneity in genetic, biochemical and clinical spectra of mitochondrial diseases and by limited preclinical resources to screen and identify effective treatment candidates. Alternative models of the pathology are essential to better understand mitochondrial diseases and to accelerate the development of new therapeutics. The fruit fly Drosophila melanogaster is a cost- and time-efficient model that can recapitulate a wide range of phenotypes observed in patients suffering from mitochondrial disorders. We targeted three important subunits of Complex I of the mitochondrial oxidative phosphorylation system with the flexible UAS-Gal4 system and RNA interference: NDUFS4 (ND-18), NDUFS7 (ND-20) and NDUFV1 (ND-51). Using two ubiquitous driver lines at two temperatures, we established a collection of phenotypes relevant to complex I deficiencies. Our data offer models and phenotypes with different levels of severity that can be used for future therapeutic screenings. These include qualitative phenotypes that are amenable to high-throughput drug screening and quantitative phenotypes that require more resources but are likely to have increased potential and sensitivity to show modulation by drug treatment.

Keywords: mitochondrial disease, Complex I deficiency, Drosophila melanogaster, disease model, screening

Received: 03 Aug 2018; Accepted: 05 Mar 2019.

Edited by:

Gyorgy Szabadkai, University College London, United Kingdom

Reviewed by:

Samantha Loh, University of Cambridge, United Kingdom
Marcos T. Oliveira, São Paulo State University, Brazil  

Copyright: © 2019 Foriel, Renkema, Lasarzewski, Berkhout, Rodenburg, Smeitink, Beyrath and Schenck. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence:
Dr. Julien Beyrath, Khondrion BV, Nijmegen, Netherlands,
Dr. Annette Schenck, Department of Human Genetics, Radboud University, Nijmegen, 6525, Gelderland, Netherlands,