Nr2f1 shapes mitochondria in the mouse brain unraveling new insights into the neurodevelopmental disorder BBSOAS

The nuclear receptor Nr2f1 acts as a strong transcriptional regulator in embryonic and postnatal neural cells. In humans, mutations in the NR2F1 gene cause the Bosch-Boonstra-Schaaf Optic Atrophy-intellectual Syndrome (BBSOAS), a rare neurodevelopmental disorder characterized by multiple clinical features including vision impairments, intellectual disability and autistic traits that might be compatible with mitochondrial dysfunction in the nervous system. Interestingly, clinical investigations reported defective electron transport chain/OxPhos machinery in the muscles of two BBSOAS patients. However, whether mitochondrial dysfunction is a general mechanism in BBSOAS and how NR2F1 haploinsufficiency might lead to mitochondria-related functional defects in neurons is completely unknown. By genome-wide analyses we identified a wide set of nuclear-encoded mitochondrial genes as potential genomic targets under direct Nr2f1 transcriptional control in neurons. Notably, Nr2f1 mitochondrial putative targets form a highly interconnected network of functional and physical protein associations, suggesting that Nr2f1 may contribute to a coordinated regulation of multiple aspects of mitochondrial biogenesis and function. By combining mouse genetics, neuroanatomical and imaging approaches we demonstrated that conditional Nr2f1 loss-of-function within the adult mouse hippocampal neurogenic niche reduces mitochondrial mass and induces mitochondrial fragmentation and downregulation of key mitochondrial proteins in adult-born hippocampal newborn neurons, whose functional integration and survival are impaired. Importantly, we also found dysregulation of several nuclear-encoded mitochondrial genes and downregulation of key mitochondrial proteins in the brain of Nr2f1-heterozygous mice, a validated BBSOAS model. Notably, altered Nr2f1 expression in neural tissues has been reported in Down syndrome as well as in mouse models of Alzheimer’s and Parkinson’s diseases. Therefore, our findings open new perspectives for the future investigation on the implication of Nr2f1 in the mitochondrial dysfunction associated with the pathogenesis and progression of BBSOAS as well as multiple neurological disorders, opening new possibilities for therapeutic intervention.