Complex I deficiency represents the most frequent pathogenetic cause of human mitochondria-associated diseases (HMAD). Therapeutic options for these devastating, life-threating disorders, which in most cases present with neurodevelopmental defects, do not exist, in part due to the scarcity of appropriate model systems to study them. Caenorhabditis elegans is a powerful, genetically tractable model organism widely used to investigate neuronal development and degenerative pathologies. Here, we generated new C. elegans models for HMAD and we focused on two complex I disease models associated with Leigh Syndrome,
nuo-5/NDUFS1- and
lpd-5/NDUFS4-depleted animals, which nicely recapitulated biochemical, cellular and neurodevelopmental defects of the human diseases. The two models were exploited for a suppressor screening that identified lutein, among a library of natural compounds, for its ability to rescue the developmental arrest and neuronal deficits observed upon
nuo-5 and
lpd-5 depletion. We specifically found that lutein exerts its beneficial activity by rescuing a neuroligin-mediated synaptic defect we disclosed for the first time upon
nuo-5 depletion, thus pointing to possible novel therapeutic targets for the human disease.