Dissecting the role of mitochondrial (dys)function in neurogenesis and in rare neurodevelopmental diseases

Leigh Syndrome (LS) and Maternally Inherited Leigh Syndrome (MILS) are pediatric mitochondrial disorders characterized by severe lesions of the central nervous system and rapid disease progression. While traditionally classified as early-onset neurodegenerative conditions, recent evidence suggests that primary mitochondrial dysfunction may impair neurogenesis, thereby preventing proper neuronal maturation from the earliest stages of development. In cellular and organoid models, mitochondrial alterations hinder the activation of transcriptional programs essential for neuronal morphogenesis, leading to the persistence of immature and disorganized phenotypes. These findings suggest that pediatric mitochondrial syndromes can be regarded not only as neurodegenerative disorders but also as disorders of neurogenesis. The aim of this project is to elucidate the mechanisms by which mitochondrial dysfunction affects neural development. The working hypothesis is that different aspects of metabolic and bioenergetic impairment represent critical bottlenecks for neuronal generation and maturation. To address this, we will employ integrated approaches in cellular and organoid systems, as well as diverse genetic animal models of mitochondrial dysfunction, including the pig, which provides a particularly relevant paradigm for studying neurodevelopmental defects. The ultimate goal is to elucidate how mitochondrial function shapes neurogenesis and to establish its role in the pathogenesis of rare neurodevelopmental disorders.