Associated with a great variety in clinical symptoms and a variable degree of severity, mitochondrial diseases in general have a poor prognosis and an often 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 orthologue of NDUFS4, an accessory subunit of the NADH:ubiquinone oxidoreductase (Complex I), we developed and characterized several dNDUFS4 models that recapitulate key features of the disease. Like in humans, the dNDUFS4 KD flies also display severe feeding difficulties, an aspect of mitochondrial disorders that so far has 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.