Project Summary/Abstract Our long-term goal is to define the molecular and cellular mechanisms involved in the pathogenesis and complex clinical presentations of mitochondrial dysfunction. Our overall objective in the studies proposed here, which are a next step in pursuing this goal, is to define the relationship between development and onset of disease resulting from mitochondrial electron transport chain complex I (ETC CI) dysfunction. We hypothesize, based on substantial preliminary data, that some of the major neurologic sequelae of mitochondrial disease are mechanistically driven by the interaction between mitochondrial function and specific events in postnatal development. In particular, our preliminary data reveal a striking specificity to age of disease onset and, more telling, that treatment during a specific post-natal period is both necessary and sufficient for lasting benefits from rapamycin treatment, a well-validated intervention in pre-clinical studies of mitochondrial disease. Our experiments will take advantage of the Ndufs4(KO) mouse, apremier model of mitochondrial disease closely resembling human LS. In addition, we have generated a novel nematode model of LS which has a robust developmental phenotype and is defective in the C. elegans homologue of Ndufs4, lpd-5. We will use these models to define the role of postnatal neurodevelopment in the onset of neurological features of mitochondrial disease i) probe the interaction between development and onset of major neurological sequelae of disease ; ii) define the critical window in development for interventions targeting disease; iii) identifying genetic factors involved in developmental arrest associated with mitochondrial dysfunction in C. elegans. Ultimately, this work will advance our understanding of the role of mitochondria in developmental biology and help define the cellular and molecular pathogenesis of mitochondrial diseases. Relevance Genetic mitochondrial diseases involve an array of symptoms, can impact one organ or present as a multisystem disorder, are remarkably heterogeneous, and currently there are no proven treatments for mitochondrial disease of any etiology. A clear understanding of the pathogenesis of individual mitochondrial diseases is severely needed; the molecular, cellular, physiological, and developmental mechanisms underlying the complex clinical syndromes arising from primary genetic mitochondrial dysfunction have not been undefined.