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Abstract
ABSTRACTMitochondrial diseases are associated with a wide variety of clinical symptoms and variable degrees of severity. Patients with such diseases generally have a poor prognosis and often an early fatal disease outcome. With an incidence of 1 in 5000 live births and no curative treatments available, relevant animal models to evaluate new therapeutic regimes for mitochondrial diseases are urgently needed. By knocking down ND-18, the unique Drosophila ortholog of NDUFS4, an accessory subunit of the NADH:ubiquinone oxidoreductase (Complex I), we developed and characterized several dNDUFS4 models that recapitulate key features of mitochondrial disease. Like in humans, the dNDUFS4 KD flies display severe feeding difficulties, an aspect of mitochondrial disorders that has so far been largely ignored in animal models. The impact of this finding, and an approach to overcome it, will be discussed in the context of interpreting disease model characterization and intervention studies.This article has an associated First Person interview with the first author of the paper.
Highlights
Among the five complexes forming the mitochondrial oxidative phosphorylation system (OxPhos), NADH:ubiquinone oxidoreductase, or Complex I (CI), is the largest and represents a privileged target for mutation
The efficiency of the dNDUFS4 knockdown in the RNA interference (RNAi) flies was assessed by quantitative reverse transcription PCR
CIII activity was increased in the ubiquitous KD flies, potentially representing a compensatory mechanism. These results show that ubiquitous dNDUFS4 KD led to isolated CI deficiency (Fassone et al, 2011; Swalwell et al, 2011)
Summary
Among the five complexes forming the mitochondrial oxidative phosphorylation system (OxPhos), NADH:ubiquinone oxidoreductase, or Complex I (CI), is the largest and represents a privileged target for mutation. Mutations in 33 structural subunit genes are associated with human disease (Mayr et al, 2015). NADH dehydrogenase (ubiquinone) Fe-S protein 4, 18 kDa (NDUFS4) is an accessory subunit of CI which stabilizes the assembly of the N-module to the Q-module
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