Mitochondrial dynamics control the organelle's morphology, with fusion leading to the formation of elongated tubules and fission leading to isolated puncta, as well as mitochondrial functions. Recent reports have shown that disruptions of mitochondrial dynamics contribute to
neurodegenerative diseases. Mutations of the inner membrane
GTPase OPA1 are responsible for type 1
dominant optic atrophy, by mechanisms not fully understood. We show here that in rodent cortical primary neurons, downregulation of the OPA1
protein leads to fragmented mitochondria that become less abundant along the dendrites. Furthermore, this inhibition results in reduced expression of mitochondrial respiratory complexes as well as
mitochondrial DNA, decreased mitochondrial membrane potential, and diminished
reactive oxygen species levels. The onset of synaptogenesis was markedly impaired through reductions in pre- and postsynaptic structural
protein expression and synapse numbers without first affecting the dendritic arborization. With longer time in culture, OPA1 extinction led to a major restriction of dendritic growth, together with reduction of synaptic
proteins. Furthermore, in maturing neurons we observed a transitory increase in mitochondrial filament length, associated with marked changes in the expression levels of OPA1, which occurred at the onset of synaptogenesis simultaneously with transitory increase in
reactive oxygen species levels and NRF2/NFE2L2 nuclear translocation. This observation suggests that mitochondrial hyperfilamentation acts upstream of a
reactive oxygen species-dependent NRF2 transcriptional activity, possibly impacting neuronal maturation, such a process being impaired by insufficient amount of OPA1. Our findings suggest a new role for OPA1 in synaptic maturation and dendritic growth through maintenance of proper mitochondrial oxidative metabolism and distribution, highlighting the role of mitochondrial dynamics in neuronal functioning and providing insights into
dominant optic atrophy pathogenesis, as OPA1 loss affecting neuronal maturation could lead to early synaptic dysfunction.