NR2F1 DEFICIENCY CAUSES NEURONAL MITOCHONDRIAL DYSFUNCTION ACROSS MOUSE AND HUMAN MODELS OF THE NEURODEVELOPMENTAL DISORDER BBSOAS

Mitochondria are essential organelles whose dynamic regulation in neural cells is critical for neurogenesis. However, the mechanisms controlling mitochondrial dynamics in neurons remain poorly understood. We previously demonstrated that the transcriptional regulator NR2F1 is expressed in mouse hippocampal neural stem/progenitor cells and neurons. Importantly, by identifying direct target genes, we found that NR2F1 regulates multiple nuclear‑encoded genes involved in mitochondrial dynamics and function. Consistently, Nr2f1‑deficient hippocampal neurons exhibit reduced mitochondrial mass and increased mitochondrial fragmentation.

These findings are particularly relevant in the context of Bosch‑Boonstra‑Schaaf optic atrophy syndrome (BBSOAS), a rare autosomal dominant neurodevelopmental disorder caused by NR2F1 mutations. BBSOAS is characterized by optic nerve atrophy, intellectual disability, and autistic traits - features compatible with mitochondrial dysfunction. Notably, two independent clinical studies have reported mitochondrial abnormalities in BBSOAS patients. To elucidate how NR2F1 deficiency affects mitochondria and contributes to BBSOAS pathophysiology, we are investigating both mouse and human disease models.

In constitutive Nr2f1‑heterozygous (Nr2f1+/-) mice, mitochondrial gene expression is deregulated, and essential mitochondrial proteins are reduced. Similarly, human induced pluripotent stem cells (hiPSCs)-derived NR2F1‑deficient neurons display fragmented, spherical mitochondria, reduced dendritic mitochondrial content, and decreased levels of electron transport chain (ETC)/OxPhos proteins.

Together, these findings reveal a conserved role of NR2F1 in regulating mitochondrial organization and function across mouse and human systems. This highlights mitochondrial dysfunction as a key cellular mechanism contributing to BBSOAS pathophysiology and suggests mitochondria‑related pathways as potential targets for future therapeutic strategies.