Impaired mitochondrial energy metabolism contributes to a wide range of pathologic conditions, including neurodegenerative diseases. Mitochondrial apoptosis-inducing factor (AIF) is required for the correct maintenance of mitochondrial electron transport chain. An emerging body of clinical evidence indicates that several mutations in the AIFM1 gene are causally linked to severe forms of mitochondrial disorders. Here we investigate the consequence of WAH-1/AIF deficiency in the survival of the nematode Caenorhabditis elegans. Moreover, we assess the survival of C. elegans strains expressing a disease-associated WAH-1/AIF variant. We demonstrate that wah-1 downregulation compromises the function of the oxidative phosphorylation system and reduces C. elegans lifespan. Notably, the loss of respiratory subunits induces a nuclear-encoded mitochondrial stress response independently of an evident increase of oxidative stress. Overall, our data pinpoint an evolutionarily conserved role of WAH-1/AIF in the maintenance of proper mitochondrial activity.