Defining disease mechanisms and testing novel therapeutic approaches in NUBPL deficiency

Complex I defects of the mitochondrial respiratory chain represent the most frequent cause of pediatric encephalomyopathies and result from mutations in nuclear or mitochondrial genes involved in complex assembly and stability. Among these, NUBPL (nucleotide-binding protein like) has been identified as a critical factor in the correct assembly of Complex I subunits. Mutations in NUBPL lead to severe bioenergetic deficits associated with complex clinical phenotypes, including mitochondrial encephalopathy and multisystem involvement. Despite several clinical cases being reported, the molecular mechanisms through which NUBPL contributes to the formation and maintenance of Complex I remain incompletely defined, and no validated therapeutic options are currently available. Our laboratory aims to systematically define the pathogenic mechanisms associated with NUBPL defects and to develop innovative experimental platforms for the evaluation of potential therapeutic strategies. We employ advanced cellular models and three-dimensional neuronal differentiation systems to characterize the consequences of mutations on the development and function of the central nervous system. These models are also used as preclinical tools to test the efficacy of pharmacological and molecular approaches capable of improving mitochondrial function and supporting neuronal maturation. The long-term goal is to identify concrete therapeutic targets and to develop innovative strategies that can be translated into treatment perspectives for patients with NUBPL deficiency and, more broadly, for disorders arising from Complex I dysfunction.